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Lymphomas

Pathology

Lymphomas are a heterogeneous group of tumors originating from lymphocytes, the fundamental cells of the immune system. These cells circulate throughout the body to identify and eliminate foreign agents such as bacteria and viruses. When lymphocytes become malignant, they retain their ability to move through the blood and lymphatic system, which explains why lymphomas can involve not only lymph nodes, but also other lymphatic organs such as the bone marrow and spleen, as well as extra-lymphatic organs including the skin, lungs, central nervous system, stomach, and liver.

The incidence of lymphomas has been increasing in both sexes since 1975. However, mortality has decreased due to advances in research and the development of new treatments, which have significantly improved patient outcomes.

Types

Lymphomas are broadly classified into two main categories:

  • Hodgkin lymphoma: Named after the physician who first described it, Hodgkin lymphoma primarily affects young individuals, typically between 15 and 35 years of age, with a second, less frequent peak after 60 years. It is a rare disease, with an incidence of approximately 3–5 cases per 100,000 people per year.
  • Non-Hodgkin lymphoma: Non-Hodgkin lymphomas represent a highly heterogeneous group of malignancies of the lymphatic system. They can occur across a wide age range, most commonly between 30 and 80 years, with a peak between 50 and 70 years. They are significantly more common than Hodgkin lymphoma, accounting for about 3 percent of all cancers and ranking among the most frequent malignancies in Italy. More than 60 subtypes are currently recognized.

Their classification depends on the type of lymphocyte involved. In about 80–85 percent of cases, they originate from B lymphocytes, while 15–20 percent arise from T lymphocytes. Because lymphocytes are distributed throughout lymphoid tissues in multiple organs, non-Hodgkin lymphomas are often widespread at diagnosis.

A key feature is growth behavior. Some subtypes are slow-growing (indolent), such as follicular lymphoma, which accounts for about 20–25 percent of cases. Others are rapidly progressive and require urgent treatment, such as diffuse large B-cell lymphoma, the most common subtype, representing approximately 30–40 percent of all non-Hodgkin lymphomas.

The Numbers in Italy

According to data from the AIRTUM (Italian Association of Cancer Registries), in 2024 there were approximately 13,271 new cases of non-Hodgkin lymphoma (7,321 men and 5,950 women) and 2,218 new cases of Hodgkin lymphoma (1,203 men and 1,015 women).

Risk Factors

The exact causes of lymphomas are not fully understood, but several factors may increase risk. The presence of these factors does not necessarily imply disease development.

  • Age: risk increases with advancing age
  • Sex: slightly higher incidence in men
  • Family history: a history of lymphoma in close relatives may increase risk
  • Infections: HIV, hepatitis C virus (HCV), Epstein–Barr virus (EBV), HHV8, Helicobacter pylori, and Chlamydia psittaci
  • Chemical exposure: prolonged exposure to benzene or pesticides
  • Immunosuppression: post-transplant patients or those on immunosuppressive therapy
  • Autoimmune diseases: such as Sjögren’s syndrome and systemic lupus erythematosus

Symptoms

Lymphomas can present with variable and sometimes non-specific symptoms. The most common sign is enlarged lymph nodes, particularly in the neck, armpits, or groin. In some cases, this may be the only manifestation.

General symptoms may include fever of unknown origin, night sweats, unintentional weight loss, and sometimes persistent itching.

Clinical presentation varies depending on disease location:

  • Abdominal involvement may cause pain, bloating, or early satiety, often linked to splenic enlargement
  • Thoracic involvement may cause cough or breathing difficulties
  • Bone marrow involvement may lead to fatigue due to anemia, increased bleeding tendency, and higher infection risk

Prompt medical evaluation is essential, especially when symptoms persist or occur in combination, as early diagnosis significantly improves outcomes.

Diagnosis and Examination

The diagnostic pathway often begins with the general practitioner, who performs a physical examination of lymph nodes and assesses possible enlargement of the liver and spleen. Initial tests may include blood and urine analyses, abdominal ultrasound, or chest X-ray, to exclude infectious or alternative causes.

If lymphoma is suspected, referral to an oncohematologist is required. The key diagnostic test is lymph node biopsy, involving removal of a suspicious lymph node for histological examination by a pathologist.

Once lymphoma is confirmed, further investigations are performed to determine the stage and extent of disease, which is essential for defining the most appropriate treatment strategy.

Lymph Node Biopsy

This procedure consists of the partial or complete removal of one or more suspicious lymph nodes.

If the suspected lymph node is superficial and palpable, the procedure is performed in an outpatient setting under local anesthesia, through a small skin incision.

If the lymph node is located deep in the chest or abdomen, tissue sampling can be performed in two main ways:

  • Image-guided needle biopsy: performed using minimally invasive techniques with dedicated needles under CT or ultrasound guidance. This approach, carried out under local anesthesia, allows collection of small tissue fragments from the lymph node or involved organ where imaging suggests possible lymphoma. An adequate tissue sample is essential for accurate pathological evaluation.
  • Surgical biopsy: performed under general anesthesia, involving removal of a lymph node or tissue sample suspected for lymphoma. The procedure is guided by CT or ultrasound imaging to ensure precision and diagnostic accuracy.

Histological and Molecular Examination

Lymph nodes or tissue samples obtained by biopsy are sent to the pathology laboratory, where they undergo histological examination, complemented by immunohistochemical, cytogenetic, and molecular analyses.

The diagnosis of lymphoma is complex and requires a multidisciplinary team of pathologists, cytogeneticists, and other specialized professionals to ensure an accurate diagnosis and precise identification of the lymphoma type and subtype. This step is essential because treatment selection depends primarily on a correct and detailed diagnosis, as different lymphoma subtypes require different therapeutic approaches. For this reason, such evaluations should be performed in highly specialized centers. The Candiolo Cancer Institute is one such center, equipped with advanced diagnostic technologies and a dedicated team for lymphoma diagnosis, ensuring accurate classification and individualized treatment planning.

In addition to conventional microscopic evaluation, biopsy samples undergo molecular analyses to identify abnormalities in tumor DNA, allowing for highly precise characterization of the lymphoma subtype.

Once the diagnosis is confirmed, patients undergo additional examinations to assess their overall health status and to determine the extent and stage of the disease.

Blood Test

Blood tests are used to assess the blood count, including possible anemia, white blood cell levels, and platelet counts, as well as kidney and liver function. They also measure specific molecules such as lactate dehydrogenase (LDH) and beta-2 microglobulin, which can provide information about the biological characteristics of the disease, including its potential aggressiveness.

Bone Marrow Needle Aspiration and Bone Marrow Biopsy

These tests are performed to determine whether lymphoma cells are present in the bone marrow.

The procedure is carried out under local anesthesia. The physician inserts a needle into the upper part of the buttock, reaching the pelvic bone, and collects two samples: one of bone marrow aspirate and one of bone tissue.

In some lymphoma subtypes, such as Hodgkin lymphoma and diffuse large B-cell lymphoma, this examination is no longer routinely required, while it remains important in other types.

The collected samples are sent to anatomical pathology for histological examination and further analyses.

Total Body CT

CT (computed axial tomography) is a radiological examination in which data obtained from X-rays passing through the body are processed by a computer to generate three-dimensional images of different tissues.

A total body CT scan (neck, chest, abdomen, and pelvis) allows visualization of deep lymph nodes potentially involved by the disease, assessment of their size, and detection of possible involvement of organs such as the lungs or liver.

The examination requires the injection of an intravenous contrast agent. It is performed on an empty stomach in the radiology department.

PET (Positron Emission Tomography)

PET (positron emission tomography) is a diagnostic technique in nuclear medicine that identifies tumor presence and activity by detecting abnormal cellular metabolism. After the injection of a radioactive glucose tracer, PET imaging can highlight cancer cells because they consume more glucose than normal cells.

By measuring cellular glucose uptake, PET allows the identification of the initial sites of disease and is considered more sensitive than CT in detecting very small lesions or disease in locations that are difficult to evaluate with CT, such as bone.

In addition, PET is a key tool for assessing response to therapy. The disappearance of areas showing increased metabolic activity is often indicative of a complete treatment response in many types of lymphoma.

Assessment of Cardiac Function

Lymphoma treatment may involve drugs that can have adverse effects on the heart. For this reason, a careful evaluation of cardiac function is required.

This assessment is performed through a cardiological examination and an echocardiogram, which help determine the presence or absence of cardiac abnormalities to be considered when planning lymphoma therapy.

Staging

Once the investigations are completed, the stage of the lymphoma and the presence of specific prognostic factors are determined based on the findings. This information is essential for planning the most appropriate treatment strategy.

Hodgkin’s Lymphomas

For Hodgkin lymphoma, the Ann Arbor system is used, consisting of four stages:

  • Stage I: lymphoma confined to a single group of lymph nodes
  • Stage II: lymphoma involving two or more lymph node groups, all located either above or below the diaphragm (the muscle separating the chest from the abdomen)
  • Stage III: lymphoma present in lymph node regions both above and below the diaphragm
  • Stage IV: lymphoma spread to extralymphatic organs, such as the bone marrow or liver

At each stage, the letter A is added if there are no systemic symptoms (fever, night sweats, weight loss), while the letter B is added if one or more of these symptoms are present.

Non-Hodgkin’s Lymphomas

For non-Hodgkin lymphomas, in addition to the Ann Arbor staging system, several internationally recognized prognostic factors specific to the lymphoma subtype are used to estimate the likelihood of response to treatment and overall survival.

These factors are combined into validated risk scores, which consider multiple clinical and biological parameters:

  • Extent of disease: stage and number of involved lymph nodes or extranodal organs
  • Laboratory findings: such as anemia or elevated lactate dehydrogenase (LDH) levels in the blood
  • Patient-related factors: particularly age and overall general condition (performance status)

These parameters make it possible to distinguish more aggressive forms from those with a more favorable clinical course, allowing for a more tailored and appropriate treatment strategy.

Treatment Planning and Reassessment

After diagnosis is confirmed, the Multidisciplinary Team evaluates multiple factors, including stage, symptoms, risk factors, age, general condition, and any associated diseases, in order to define a personalized treatment plan. The hematologic oncologist explains the therapeutic strategy to the patient, clarifying treatment modalities, duration, possible side effects, and, when available, alternative options with comparable efficacy.

The main treatments include chemotherapy, immunotherapy, radiotherapy, and stem cell transplantation in selected cases. The choice of therapy depends on the type and aggressiveness of the lymphoma, as well as the patient’s age, overall health status, and prognostic factors, including stage, disease distribution, and laboratory results.

In indolent non-Hodgkin lymphomas, when there are no significant symptoms or bulky disease, an active surveillance approach may be adopted, involving regular outpatient monitoring without immediate treatment initiation.

For selected patients with particularly aggressive or treatment-resistant disease, participation in experimental clinical trials at the Candiolo Cancer Institute may be considered, following shared discussion with the patient.

During and after therapy, a careful reassessment of disease status is performed using the same diagnostic tools employed at baseline, such as CT, PET, and in some cases bone marrow biopsy, to evaluate complete or partial remission or treatment failure. Based on these results, discussed within the Interdisciplinary Team, a decision is made whether to conclude therapy or to modify and continue the treatment plan.

Chemotherapy

The term chemotherapy refers to drugs that eliminate cancer cells by exploiting their faster rate of reproduction compared to healthy cells. Because chemotherapy interferes with cellular replication mechanisms, it can also damage normal cells in the body, leading to side effects. These effects often resolve after treatment and are generally well controlled with appropriate supportive therapies.

In most cases, chemotherapy is administered intravenously, and less frequently orally. The duration of each administration, performed in either an outpatient or inpatient setting depending on the treatment regimen, may vary from minutes to several hours, particularly when multiple drugs are combined. In some cases, the placement of a central venous access device is required before starting therapy, allowing medication to be delivered safely into a large vein.

Chemotherapy is administered in cycles. Each cycle may last one or more days and is followed by a rest period of several weeks. The total number of cycles depends on the type of lymphoma and the patient’s response to treatment, which can vary significantly between individuals.

Immunotherapy

Immunotherapy involves the use of drugs that act through mechanisms similar to the immune system or restore the patient’s ability to recognize and eliminate cancer cells.

Four main types of immunotherapy are used in lymphomas:

  • Monoclonal antibodies
  • Immunoconjugated antibodies
  • Bispecific antibodies
  • CAR T-cell therapy

Monoclonal Antibodies

Monoclonal antibodies act similarly to natural antibodies produced by the immune system. They bind to specific proteins (receptors) on the surface of cancer cells and activate immune mechanisms that lead to their destruction, in a manner comparable to the immune response against viruses or bacteria.

Examples include Rituximab and Obinutuzumab, which target the CD20 protein expressed in B-cell lymphomas.

These drugs are commonly combined with chemotherapy to enhance treatment efficacy and are administered intravenously.

Immunoconjugated Antibodies

Immunoconjugated antibodies are monoclonal antibodies linked in the laboratory to cytotoxic agents. After administration, the antibody binds to tumor cells and delivers the toxic substance directly into them, leading to cell death.

Examples include:

  • Brentuximab vedotin, targeting CD30 in Hodgkin lymphoma and some T-cell lymphomas
  • Polatuzumab vedotin, targeting CD79b in diffuse large B-cell lymphoma
  • Loncastuximab tesirine, targeting CD19

Bispecific Antibodies

Bispecific antibodies are engineered to bind simultaneously to two targets: one on the tumor cell and one on the patient’s immune cells, particularly T lymphocytes. This brings the two cells into close proximity, enabling immune-mediated destruction of the malignant cell.

Currently used bispecific antibodies typically target CD20 on tumor cells and CD3 on T cells. Examples include epcoritamab, glofitamab, and mosunetuzumab.

Administration is usually intravenous or subcutaneous. Early side effects may include fever, chills, fatigue, and muscle pain, and in some cases cytokine release syndrome, which presents with flu-like symptoms but is generally manageable with appropriate treatment.

CAR T-Cell Therapy

CAR T-cell therapy is a form of personalized cellular treatment. The patient’s own T lymphocytes are collected, genetically modified in the laboratory to express a chimeric antigen receptor (CAR), and reinfused to specifically recognize and destroy cancer cells.

The CAR receptor is designed to target CD19, a protein expressed on many lymphoma cells.

This therapy is generally indicated for younger patients but may also be used in selected older patients (up to approximately 75–80 years of age, depending on clinical condition) who are in good overall health, due to the potential for significant side effects.

Treatment is administered as a single intravenous infusion, following a short course of preparatory chemotherapy, and requires inpatient monitoring. During hospitalization, vital signs and neurological status are closely observed to manage possible early inflammatory reactions such as fever, chills, fatigue, or confusion.

Follow-up after discharge is essential to evaluate response and ensure safe recovery. Patients and families are instructed to promptly report any concerning symptoms.

CAR T-cell therapy is used in cases of relapsed or refractory disease, particularly in:

  • Diffuse large B-cell lymphoma
  • Mantle cell lymphoma
  • Follicular lymphoma

Molecularly Targeted or Immunomodulatory Drugs

These drugs are capable of blocking specific molecular alterations that drive the growth of certain types of lymphoma, including mantle cell, lymphocytic, and marginal zone lymphomas.

They are generally administered orally and are typically taken on a continuous schedule.

Examples include Ibrutinib, Acalabrutinib, Zanubrutinib, and Lenalidomide.

Radiation Therapy

Radiation therapy is a treatment modality that uses high-energy radiation to destroy cancer cells. In lymphoma treatment, it may be used as a standalone therapy or in combination with chemotherapy and immunotherapy. It is mainly indicated in early-stage disease and is typically delivered to the lymph node regions involved by lymphoma.

Radiation therapy is administered using a device called a linear accelerator (LINAC), in daily sessions from Monday to Friday over several weeks. Each session usually lasts about 10 to 15 minutes.

Treatment consists of the application of radiation fields shaped to match the tumor volume, allowing protection of surrounding healthy organs. This approach enables delivery of a higher dose to the tumor while minimizing exposure to normal tissues.

Intensity-modulated radiation therapy (IMRT) allows modulation of the intensity of each radiation beam, ensuring a high degree of dose conformity to diseased tissues while further reducing exposure to healthy structures.

In addition, image-guided radiotherapy (IGRT) enables real-time verification of the target’s position and its relationship to surrounding organs, ensuring accurate patient positioning for each treatment session.

Stem Cell Transplantation

Stem cell transplantation is a treatment reserved for selected cases in which lymphoma does not respond to standard therapies or recurs after initial treatment. Its use has become less frequent with the introduction of highly effective immunotherapies such as CAR T-cell therapy and bispecific antibodies.

The aim of transplantation is to allow the administration of high-dose chemotherapy, which is more intensive than what the bone marrow can normally tolerate, in order to achieve greater anti-tumor efficacy. Since these high doses can severely damage the bone marrow, transplantation is necessary to restore blood cell production.

Types of Transplantation

  • Autologous transplantation (most common in lymphomas):
    The patient’s own stem cells are collected and later reinfused.
  • Allogeneic transplantation:
    Stem cells are obtained from a compatible donor.

Autologous Transplantation Procedure

  1. Stem cell stimulation:
    The patient receives growth factors via subcutaneous injections to increase stem cell production.
  2. Collection (apheresis):
    Stem cells are collected from the blood using a procedure similar to blood donation and then cryopreserved.
  3. High-dose chemotherapy:
    Intensive treatment is administered to eliminate cancer cells.
  4. Reinfusion:
    Previously collected stem cells are reinfused to restore bone marrow function.

Post-Transplant Phase

After transplantation, white blood cell levels remain very low for approximately 12–15 days, until bone marrow recovery begins. During this period, the patient is hospitalized in a protected environment to reduce the risk of infection and ensure close clinical monitoring.

Ongoing Support

At the Candiolo Cancer Institute, continuous support is ensured before, during, and after treatment, accompanying each patient throughout the entire therapeutic and recovery pathway.

Management of Side Effects

All cancer treatments are associated with side effects that can affect the patient’s quality of life to varying degrees. Treatments for acute leukemia may also cause significant physical and psychological effects, which can impact daily functioning and overall well-being.

At the Canciolo Cancer Institute, attention to the patient’s quality of life remains a priority throughout the entire treatment pathway. The physicians and nurses of the Multidisciplinary Team provide ongoing support to help manage side effects, including nutritional counseling, psychological support, and pain management therapy.

Direct Access to Specialists

To ensure timely support and provide prompt answers to questions or concerns, the Candiolo Cancer Institute offers a dedicated assistance service for all patients.

From Monday through Friday, between 8:00 a.m. and 5:00 p.m., patients can contact the Oncology Day Hospital Secretariat at +39 011 993 3775 to request an urgent consultation.

Patients are promptly connected with their specialist physician, ensuring rapid access to expert advice, clear information, and immediate support when needed.

Supportive and Palliative Care

Cancer patients often have complex needs that extend beyond the treatment of the disease itself and require comprehensive, multidisciplinary care.

At the Candiolo Cancer Institute, patients who need additional support have access to specialists from a range of disciplines, ensuring personalized management of cancer-related symptoms and associated conditions. Services may include nutritional counseling, physical rehabilitation, pain management, and support for other medical needs that may arise during the course of treatment and recovery.

The goal is to improve quality of life, promote overall well-being, and provide comprehensive care tailored to each patient’s individual needs.

Psychological Support

The impact of cancer also extends to the psychological sphere. A cancer diagnosis is often a traumatic event that affects all aspects of a person’s life and may generate anxiety, fear, anger, and depression.

At the Canciolo Cancer Institute, alongside advanced medical therapies, the care pathway always includes specialized psycho-oncological support, helping patients cope not only with treatment but also with the delicate phases of physical and psychological recovery.

Patients may also participate in psychological support groups, where they can share experiences with others who are facing or have faced a similar condition.

Social Work Services

The Social Work Service at the Candiolo Cancer Institute provides information, guidance, and support to patients and their families regarding access to community services and the welfare and social security benefits available under current legislation.

During dedicated consultations, social workers assist with matters such as disability recognition, access to aids and prosthetic devices, employment-related benefits and leave, and other social support services.

The service is available on Wednesdays and Fridays from 9:00 a.m. to 1:00 p.m. and can be contacted at +39 011 993 3059.

Follow-up

With the conclusion of therapy, a follow-up period begins during which a series of clinical evaluations and diagnostic tests are performed to monitor treatment effectiveness, late side effects, and the patient’s functional recovery. Follow-up is also essential for the early detection of possible relapse, allowing timely intervention. It further provides an important opportunity for ongoing discussion between the patient and the medical specialist.

Follow-up schedules are individualized according to the type of lymphoma, treatment received, response to therapy, and patient-specific characteristics.

In general, follow-up visits become progressively less frequent over time:

  • every 3 months during the first 2 years
  • every 6 months during the following 3 years
  • annually after the fifth year

In addition to clinical examination and blood tests, routine follow-up may include imaging such as abdominal ultrasound, while CT and/or PET scans are performed when there is clinical or laboratory suspicion of relapse.

Multi Disciplinary Team

Every cancer requires a multidisciplinary approach at all stages of disease management. At the Candiolo Cancer Institute, this is provided by a team of specialists from various clinical and surgical departments, known as the GIC, Interdisciplinary Care Group (or MDT). The GIC ensures that each patient is supported throughout the diagnostic and therapeutic process, including arranging and coordinating examinations and maintaining communication with the patient and their family.

For each patient, the GIC (MDT) defines and shares a personalized care pathway based not only on the type and stage of the tumor but also on the patient’s individual characteristics. The goal is to achieve the best possible outcomes both oncologically and functionally, while maintaining a high quality of life.

Clinical Divisions

At the Candiolo Cancer Institute, the diagnostic and therapeutic pathway for lymphomas is managed through a coordinated multidisciplinary approach involving several specialized clinical divisions, including:

Clinical Studies

Researchers at the Candiolo Cancer Institute are actively involved in several national and international lymphoma research projects, with the goal of developing increasingly effective and personalized therapies.

The Institute is part of the Italian Lymphoma Foundation national network, participating in collaborative studies coordinated at national level. It also plays an active role in clinical trials of new drugs and monoclonal antibodies, used alone or in combination with chemotherapy and immunomodulatory agents, with the aim of improving treatment efficacy and patient prognosis.

In parallel, ongoing research programs focus on the identification of novel biomarkers in B-cell lymphomas, particularly in cases characterized by specific genetic alterations at diagnosis, such as c-MYC abnormalities, which are associated with increased treatment resistance. These studies integrate cytogenetic and molecular biology techniques to better understand why some patients do not respond adequately to standard therapies, including high-dose chemotherapy and autologous stem cell transplantation, with the ultimate goal of developing more targeted and effective therapeutic strategies.

Why Choose Us

At Candiolo Cancer Institute, acute leukemia patients are treated in a highly specialized manner, thanks to the synergistic work of the dedicated Interdisciplinary Care Group (GIC) .

Clinical Experience and Tailored Approach

Thanks to the large number of cases treated each year, the Candiolo Cancer Institute is a national reference center for the care of this disease. This extensive experience allows us to manage even the most complex cases, always using a personalized approach, tailored to the clinical and individual profile of each patient.

Imaging Technologies and Advanced Diagnostics

Establishing a treatment plan always begins with an accurate and timely diagnosis. Patients have access to state-of-the-art imaging technologies, such as ultrasound, contrast-enhanced CT, MRI, and cholangio-RM, which are critical for accurately assessing the extent of the tumor.

Advanced laboratory tests, including molecular analyses, are also available to help define biological features of the disease and guide treatment choices.

Minimally Invasive Surgical Techniques and Multidisciplinarity

When appropriate, surgeries are performed using minimally invasive, laparoscopic or robotic techniques. These approaches involve the use of camera-equipped instruments introduced into the abdomen through small incisions, thus reducing surgical trauma. Benefits to the patient include shorter hospital stay times, faster recovery, and lower risk of complications compared with traditional open surgery.

Clinical Research and Access to Trials

As an IRCCS (Scientific Institute for Research, Hospitalization, and Healthcare), the Candiolo Cancer Institute combines clinical care with a strong focus on scientific research. Patients can be considered for participation in active clinical trials, offering access to innovative therapies not yet available in standard practice. This integration of care and research is a distinctive strength that translates into tangible benefits for patients.

Care and Support Every Step of the Way

The Interdisciplinary Care Group (GIC or MDT) supports the patient at every stage: from diagnosis, through treatment, to follow-up. Special attention is paid to nutritional support, psychological health and reintegration into daily life. The organization of checkups, examinations, and treatment is designed to ensure continuity, serenity, and a humane, caring approach to each patient’s needs.