Hodgkin's lymphoma

    Last updated date: 13-Mar-2023

    Originally Written in English

    Hodgkin’s lymphoma

    Hodgkin’s lymphoma

    Hodgkin lymphoma accounts for around one-third of all lymphomas. The absolute incidence has remained constant throughout the years. Hodgkin lymphoma begins in lymph nodes, most commonly in the cervical area, and spreads to neighboring lymph nodes. The majority of those afflicted are young adults. Hodgkin lymphoma has a pediatric variant that is more common in developing countries. Hodgkin lymphoma has a male predominance, although this male predominance is not evident in the nodular sclerosis subtype.

    Tumor cells are frequently found in relatively small numbers in neoplastic tissues. A low number of scattered tumor cells reside in an enormous heterogeneous admixture of nonneoplastic inflammatory and supportive cells. Background cells, lymphocytes, histiocytes, plasma cells, eosinophils, and neutrophils are all present due to the production and release of cytokines by tumor cells.


    What is Hodgkin’s Lymphoma?

    Hodgkin’s lymphoma, formerly called Hodgkin's disease, is a rare monoclonal lymphoid malignancy with high cure rates.

    The two types of Hodgkin lymphoma are:

    • classical Hodgkin lymphoma
    • nodular lymphocyte-predominant Hodgkin lymphoma

    The clinical presentation and pathophysiology of these two disease entities differ. Classical Hodgkin lymphoma accounts for about 95 percent of all HL cases and is divided into four different subsets: 

    1. nodular sclerosis (NSHL).
    2. lymphocyte-rich (LRHL). 
    3. mixed cellularity (MCHL).
    4. lymphocyte-depleted (LDHL).

    Hodgkin lymphomas are distinguished by four features. 

    They most commonly develop in the cervical lymph nodes, there may be scattered large mononuclear Hodgkin and multinucleated cells (Reed-Sternberg) intermixed in a background of non-neoplastic inflammatory cells; and, finally, T lymphocytes are frequently seen surrounding the distinctive neoplastic cells. Hodgkin lymphoma has a great overall prognosis, with a cure rate of around 80%.



    Hodgkin lymphoma is an uncommon cancer with an approximate incidence rate of 3 cases for every 100,000 individuals. Approximately, the disease accounts for one-tenth of all lymphomas. It has a bimodal distribution, with the majority of affected patients being between the ages of 20 and 40, and another peak occurring between the ages of 55 and beyond. Males are more affected than females, especially in the pediatric group, where boys account for 85 percent of cases. Young persons are more likely to develop nodular sclerosis Hodgkin lymphoma, whereas elderly adults are more likely to develop mixed cellularity Hodgkin lymphoma.

    Nodular sclerosis classical Hodgkin lymphoma accounts for 70% of cases, mixed cellularity classical HL accounts for 25%, lymphocyte-rich classical Hodgkin lymphoma accounts for 5%, and lymphocyte-depleted classical HL accounts for less than 1 percent. nodular lymphocyte-predominant Hodgkin lymphoma accounts for about 5% of all Hodgkin lymphomas.


    What is The Cause of Hodgkin’s Lymphoma?

    Hodgkin lymphoma has an unknown cause. Infectious agents, especially Epstein-Barr virus (EBV), may have a role in the disease's pathogenesis. Data suggests that up to 30% of cases of classical Hodgkin lymphoma may be positive for EBV antigens. Furthermore, a case-control study suggests that EBV infection increases the chance of developing classical Hodgkin lymphoma by about 1 in 1000 cases.

    EBV positive is more common in some subtypes than others. EBV antigens are infrequently detected in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), whereas EBV positive is more common in the mixed-cellularity subtype of classical Hodgkin lymphoma.

    In addition, HIV-positive patients had a higher rate of Hodgkin lymphoma than HIV-negative patients. Hodgkin lymphoma, on the other hand, is not regarded as an AIDS-defining tumor. HIV patients commonly present with a late disease stage, atypical lymph node’s locations, and a poorer prognosis.

    The development of Hodgkin lymphoma is affected by genetic predisposition. About 1% of individuals with Hodgkin lymphoma have a family history of the disease, and siblings of someone who has had the disease have a 3- to 7-fold greater chance of getting it. In the distinct subtype of non-sclerosing Hodgkin lymphoma, the majority of evidence suggesting a genetic origin has been found. NSHL has been demonstrated to be one of the most genetically inherited kinds of neoplasm, with identical twins having a 100-fold greater risk.



    Hodgkin's lymphoma Pathophysiology

    The Reed-Sternberg cell is the neoplastic cell in classic Hodgkin lymphoma. Only 1-2 percent of the overall tumor cell volume are Reed-Sternberg cells. The rest is made up of lymphocytes, plasma cells, neutrophils, eosinophils, and histiocytes, which are all reactive, mixed inflammatory cells.

    The majority of Reed-Sternberg cells are B-cells that is originated in lymph node germinal centers but are not anymore capable of generating antibodies. Cases of Hodgkin lymphoma with a Reed-Sternberg cell of T-cell origin are uncommon, accounting for less than 1-2 percent of all cases of classical Hodgkin lymphoma.

    CD30 (Ki-1) and CD15 (Leu-M1) antigens are consistently expressed in Reed-Sternberg cells. CD30 is a lymphocyte activation marker that is expressed by both reactive and malignant lymphoid cells. It was first detected on Reed-Sternberg cells as a cell surface antigen. CD15 is a granulocyte, monocyte, and activated T-cell marker that is not generally expressed by B-cells.


    Nodular sclerosis Hodgkin’s Lymphoma

    The morphology of Nodular sclerosing Hodgkin lymphoma, which accounts for 60-80 percent of all cases of Hodgkin lymphoma, is nodular. The node is divided into nodules by broad bands of fibrosis. The capsule has become thicker. The lacunar-type Reed-Sternberg cell, which has a monolobed or multilobed nucleus, a small nucleolus, and copious pale cytoplasm, is the typical cell.

    Adolescents and young adults are frequently affected by NSHL. The mediastinum and other supradiaphragmatic areas are frequently involved.

     [H3] Mixed-cellularity Hodgkin’s lymphoma

    The infiltration in Mixed-cellularity Hodgkin lymphoma, which accounts for 15-30% of cases, is usually diffuse. Reed-Sternberg cells are of the classical Kind of cells. The abdominal lymph nodes and spleen are frequently affected by MCHL. The majority of patients with this histology have advanced-stage cancer with systemic symptoms. In patients with human immunodeficiency virus (HIV) infection, MCHL is the most prevalent histologic type.


    Lymphocyte-depleted Hodgkin’s lymphoma

    Lymphocyte-depleted Hodgkin lymphoma accounts for fewer than 1% of all cases. In LDHL, the infiltrate is widespread and frequently appears hypocellular. There are a lot of Reed-Sternberg cells and strange sarcomatous variations.

    LDHL is linked to being older and being HIV-positive. Patients frequently have an advanced-stage disease at presentation. Many of these tumors express Epstein-Barr virus (EBV) antigens. Many cases of previously diagnosed LDHL were actually non-Hodgkin lymphomas, particularly anaplastic large-cell lymphomas.


    Lymphocyte-rich classical Hodgkin’s lymphoma

    Lymphocyte-rich classical Hodgkin lymphoma accounts for five percent of all cases. Reed-Sternberg cells of the classical or lacunar type are seen in LRHL, along with a lymphocyte infiltration. It needs to be diagnosed via immunohistochemistry. A nodular pattern may be present in some situations. In terms of clinical presentation and survival, the patterns are identical to those seen in MCHL.


    Nodular lymphocyte-predominant Hodgkin’s lymphoma

    Nodular lymphocyte-predominant Hodgkin lymphoma accounts for less than five percent of cases. It is a separate clinical entity that is not classified as a form of classical Hodgkin lymphoma. In NLPHL, typical Reed-Sternberg cells are either few or nonexistent. Alternatively, lymphocytic and histiocytic cells, also known as popcorn cells (because their nuclei mimic an exploded kernel of corn) are observed among inflammatory cells, the majority of which are benign lymphocytes. lymphocytic and histiocytic cells, different from Reed-Sternberg cells, are positive for B-cell.

    Because it can resemble LRHL or even other non-Hodgkin lymphomas, immunohistochemistry investigations are required to confirm a diagnosis of NLPHL.


    Hodgkin’s Lymphoma Symptoms

    Signs and Symptoms

    • Painless lymphadenopathy above the diaphragm (1-2 lymph node areas)
    • B symptoms (unexplained clinically significant weight loss within the last 6 months, unexplained fever, or profuse night sweats). 
    • B symptoms present in up to 40% of patients and are typically more common in stage 3 to 4 of the disease, mixed cellularity, and lymphocyte depleted Hodgkin’s lymphoma subtypes.
    • Chest pain, cough, shortness of breath, or a combination of those may be present due to a large mediastinal mass or lung involvement; rarely, hemoptysis develops.
    • Chronic pruritus may also be encountered.
    • Pain at nodal disease location, precipitated by consuming alcohol, occurs in fewer than ten percent of patients.
    • Backache or bone ache maybe rarely occur.
    • A family history is particularly beneficial. nodular sclerosis Hodgkin lymphoma has a significant genetic component and is frequently identified in the family.


    The hemophagocytic syndrome seems to be a manifestation of Hodgkin lymphoma (hemophagocytic lymphohistiocytosis). The hemophagocytic syndrome, which has the following characteristics, is more common in patients who have Epstein-Barr virus (EBV) antigen expression:

    • Pancytopenia
    • Fever
    • Hepatosplenomegaly with liver function test abnormalities
    • Elevated serum ferritin and triglycerides
    • Phagocytosis of hematopoietic cells by macrophages


    Physical Exam 

    • Palpable, painless lymphadenopathy can be present in the cervical region, axilla (armpit), and, less commonly, in the inguinal area (groin)
    • Involvement of the back of the throat, including the tonsils, or lower rear of the head, or inside the upper arm near the elbow region is typically observed
    • Splenomegaly and/or hepatomegaly may be evident 
    • Superior vena cava syndrome may occurs in patients with massive mediastinal lymphadenopathy
    • Central nervous system (CNS) signs and symptoms, maybe due to paraneoplastic syndromes, including cerebellar degeneration, neuropathy, Guillain-Barre syndrome, or multifocal leukoencephalopathy


    Differential Diagnoses

    • Cytomegalovirus (CMV)
    • Epstein-Barr Virus (EBV) Infectious Mononucleosis (Mono)
    • Non-Hodgkin Lymphoma (NHL)
    • Sarcoidosis
    • Serum Sickness
    • Small Cell Lung Cancer (SCLC)
    • Syphilis
    • Toxoplasmosis
    • Tuberculosis (TB)


    Hodgkin’s Lymphoma How to Diagnose

    A biopsy of a lymph node or suspicious organ is required for a definitive diagnosis of Hodgkin lymphoma. Because of the low ratio of malignant cells and the loss of architectural information, fine-needle aspiration or core-needle biopsy frequently produce non-specific findings. If there is a strong suspicion of Hodgkin lymphoma, an excisional biopsy should be performed. To make a conclusive diagnosis, RS cell or LP cell must be found in the biopsy samples. Additional testing is required to determine the stage, which will guide treatment and provide prognostic information.


    Laboratory Tests 

    • Complete blood count. CBC should be done to look for anemia, lymphopenia (low white blood cells), excess neutrophils (neutrophilia), and eosinophilia (eosinophilia). As mentioned in Prognosis, several of these variables have prognostic implications. The most frequent anemia of chronic disease is Hodgkin lymphoma–associated anemia.
    • Erythrocyte sedimentation rate. ESR is a general inflammatory biomarker, may be increased in Hodgkin lymphoma. A greater ESR has been associated with a worse prognosis. The ESR, on the other hand, is a nonspecific test that should not be used to screen for Hodgkin lymphoma.
    • Lactate dehydrogenase. LDH levels may be elevated. LDH levels may be linked to the bulk of the disease.
    • Serum creatinine. Creatinine may be high, as in rare cases of nephrotic syndrome linked with Hodgkin lymphoma.
    • Alkaline phosphatase. ALP levels may be elevated Because of the presence of liver or bone involvement.
    • Hypercalcemia, hypernatremia, and hypoglycemia (due to the presence of insulin autoantibodies) are other uncommon laboratory results.
    • Testing for HIV should be done because antiretroviral medications can improve the prognosis in HIV patients.
    • Serum levels of cytokines correlate with tumor burden, systemic symptoms, and prognosis. They are tested only for specific patients and in clinical trials.


    Imaging Studies

    CT Scan 

    Imaging investigations are essential for correct Hodgkin lymphoma staging. Plain x-rays, computed tomography (CT) scans, and positron emission tomography (PET) scans are among the tests used. Furthermore, imaging examinations can assist in determining the bulk of the disease, which has prognostic significance. The bulky disease is defined as any nodal mass bigger than 10 cm and a mediastinal mass larger than one-third of the thoracic diameter.

    • CT Scan 

    Enlarged lymph nodes, hepatomegaly and/or splenomegaly (with or without localized parenchymal abnormalities), lung nodules or infiltrates, and pleural effusions are all possible abnormal findings on CT scans of the chest, abdomen, and pelvis.

    • PET Scan 

    Because of its ability to differentiate between viable tumor and necrosis or fibrosis in residual masses that are often present after treatment in patients who haven’t any other clinical or biochemical evidence of disease, PET scanning is now considered essential for the initial staging of Hodgkin lymphoma. CT scanning is frequently used in conjunction with this imaging study. Although it is unusual in nodular lymphocyte-predominant Hodgkin lymphoma, a mediastinal mass, which represents mediastinal lymphadenopathy, is a common observation in classical Hodgkin lymphoma.



    Hodgkin lymphoma must always be diagnosed histologically. Because the lymph node structure is critical for histologic classification, an excisional biopsy of the lymph node is indicated. A fine-needle aspiration (FNA), which doesn’t help in Hodgkin lymphoma, is commonly recommended as the first diagnostic step when a patient arrives with neck lymphadenopathy and health concerns for head and neck cancer, followed by an excisional biopsy if squamous cell histology is excluded.

    In some circumstances, bone marrow biopsies are required. Patients with advanced-stage disease, systemic symptoms, or high-risk histology are more likely to have bone marrow involvement. Given the low incidence of bone marrow involvement, however, some specialists and experts groups believe that a bone marrow biopsy can be avoided, especially in early-stage disease. A bone marrow risk calculator (depending on the presence of B symptoms, staging, hemoglobin level, WBC count, age, and presence of inguinal or iliac disease) can be used to evaluate whether a bone marrow biopsy is necessary.

    Thoracentesis collection of pleural effusion and inspection of the cells recovered may be helpful in the diagnosis of Hodgkin lymphoma. The pleural fluid maybe an exudate, a transudate, or a chylous fluid.


    Staging for Hodgkin’s Lymphoma

    Hodgkin lymphoma treatment is determined by the disease's clinical stage. The most prevalent staging system is the modified Ann Arbor staging system. The staging approach for Hodgkin lymphoma is based on lymphadenopathy location, lymph node number, and size, and if extranodal lymph node involvement is systemic. The disease is divided into four stages by the most widely used staging system as follow:

    • Stage I: One lymph node region or lymphoid structure is involved.
    • Stage II: Two or more lymph nodes areas on the same side of the diaphragm are involved.
    • Stage III: Lymph nodes or lymphoid tissue along both sides of the diaphragm are involved.
    1. III1: With or without splenic, hilar, celiac, or portal nodes
    2. III2: With paraaortic, iliac, or mesenteric nodes


    • Stage IV: Involvement of extranodal sites. 

    A or B letters indicate the presence or absence of B symptoms. (See above under Signs and Symptoms)



    Is Hodgkin’s Lymphoma Curable?

    Treatment for Hodgkin lymphoma varies based on the type of cancer, the stage of the disease, and the risk of developing resistance. Although Hodgkin lymphoma is thought to be curable cancer, treatments for it can have substantial long-term adverse effects. Radiation therapy, induction chemotherapy, salvage chemotherapy, and hematopoietic stem cell transplantation are all common treatment options.

    The current treatment for Hodgkin lymphoma aims at maximizing the treatment's risk-benefit ratio. As a result, medication is individualized to each patient's age, risk of short- and long-term toxicity, and the likelihood of relapse.

    The treatment of Hodgkin lymphoma is mostly determined by the subtype. Classic Hodgkin lymphoma is classified into three categories by most oncologists:

    • Early-stage favorable
    • Early-stage unfavorable
    • Advanced-stage disease


    Unfavorable factors involve the following:

    • bulky mediastinal or >10 cm disease
    • elevated erythrocyte sedimentation rate >50, or ESR >30 with B symptoms
    • more than three sites of involvement
    • extranodal disease


    Treatment of Early-Stage Favorable Disease

    Early-stage, favorable disease is defined as patients with clinical stages IA or IIA classical Hodgkin lymphoma who do not have any unfavorable factors.

    Early-stage favorable Hodgkin lymphoma is usually treated with a combination of chemotherapy and radiotherapy, but chemotherapy alone may have a function. Combination chemotherapy followed by radiation has been demonstrated to be superior to radiation alone in terms of survival.

    ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) for 2-4 cycles followed by involved-site radiation therapy is the most frequently used regimen.


    Treatment of Early-Stage Unfavorable Disease

    Early-stage unfavorable Hodgkin lymphoma is defined as patients with early-stage disease and unfavorable prognostic features. These people are managed differently than those who are in the early stages with favorable features. Chemotherapy is usually administered in 4 to 6 cycles, followed by involved-site radiation therapy.

    ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine) is the optimum regimen, however, Stanford V and dose-escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) are also effective.


    Treatment of Advanced Disease

    Patients with stage III or IV Hodgkin lymphoma are considered to have advanced disease. Chemotherapy is the cornerstone of therapy, with radiation is reserved for initial bulky sites or residual activity on positron emission tomography (PET) images, although even in these cases, the usefulness of radiation is debatable.

    ABVD is the most widely utilized regimen (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine).


    Treatment of Nodular Lymphocyte-Predominant Hodgkin Lymphoma

    Local excision, involved-field radiation therapy (IFRT), or expectant care can be used to treat early-stage Nodular Lymphocyte-Predominant Hodgkin Lymphoma. The advanced-stage disease could be T-cell-rich B-cell lymphoma or diffuse large cell B-cell lymphoma, both of which should be treated with a standard non-Hodgkin's regimens like RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone).


    Treatment of Refractory or Relapsed Disease

    When treated with standard chemotherapy and radiation, patients with Hodgkin lymphoma who have never achieved complete remission or whose disease has relapsed after achieving complete remission have an extremely poor prognosis. For these individuals, high-dose chemotherapy combined with autologous stem cell transplantation is suggested.



    • Mantle radiation causes cardiac disease. Pericarditis, valvular heart disease, and coronary artery disease can all result from this type of radiation.
    • Furthermore, some medicines, such as anthracyclines, might cause cardiomyopathy.
    • Drugs including bleomycin and radiation therapy can cause pulmonary diseases.
    • Secondary tumors are a common cause of morbidity and mortality. Lung carcinoma is the most prevalent secondary malignancy in persons with Hodgkin lymphoma after treatment.
    • Following alkylation therapy, myelodysplastic syndrome and acute myeloid leukemia are also important concerns.
    • Breast, soft tissue sarcoma, pancreatic, and thyroid malignancies are among the tumors that can occur.
    • Infertility can affect any patient, but it affects more than half of them.
    • Infectious complications 
    • Depression, neuropathy, and impaired sexual function.


    Prognosis Hodgkin’s Lymphoma

    The prognosis of a patient is mainly determined by the stage of the disease and other prognostic variables, which are described differently by many major cooperative groups.

    The most commonly utilized prognostic system is the International Prognostic System, which uses the following factors to determine prognosis:

    • Serum albumin less than 4 g/dL.
    • Hemoglobin less than 10.5 g/dL.
    • Male gender
    • Age of 45 years or older.
    • Stage IV disease.
    • White blood cell (WBC) count <15,000/mm3 .
    • Absolute lymphocyte count less than 600/mm3, less than 8% of the total WBC count, or both.



    Hodgkin lymphoma (HL) is a hematological tumor marked by malignant Reed-Sternberg cells in an inflammatory context. Patients with supra-diaphragmatic lymphadenopathy with systemic B symptoms are commonly detected in their 20s and 30s. HL is highly curable, even in advanced stages, with a combination of chemotherapy, radiotherapy, or a combination of multimodal treatment. The choice of therapy often depends on how advanced the disease is, more favorable outcomes with early-stage disease. Even though that the same ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine) chemotherapeutic regimen has been the standard of care for the past 30 years, risk-adapted techniques have helped to de-escalate treatment in low-risk patients and avoiding them from treatment’s unwanted adverse effects, while escalating treatment in higher-risk patients to increase the likelihood of disease remission.