follicular lymphoma



Overview of the disease

A malignant B-lymphocyte proliferative disease with painless lymph node enlargement, accompanied by systemic symptoms such as fever, night sweats, and weight loss. The cause of the disease is unclear, and may be related to genetics, the environment, and lifestyle factors.

Definition

Follicular lymphoma (FL) is one of the common types of non-Hodgkin’s lymphoma and a common subtype of inert B-cell lymphoma.

It is derived from follicular center (germinal center) B lymphocytes and consists of cells in the form of centroblasts and centroblasts, which usually show at least a partial follicular growth pattern.

Classification

According to the new WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, follicular lymphomas are classified into the following types:

In situ follicular tumors, previously known as in situ follicular lymphomas.

Duodenal-type follicular lymphoma, which generally has a good prognosis.

Large B-cell lymphoma with IRF4 gene rearrangement, which often occurs in the pharyngeal lymphatic ring and cervical lymph nodes, and is more common in children and young adults.FISH reveals the presence of an IRF4 rearrangement, and the prognosis for this type is relatively good.

Childhood-type follicular lymphoma, is a type of lymphoma that occurs mainly in children and young adults. the prognosis for this type is very good, and most patients can be cured by surgical resection alone, without the need for radiation therapy or chemotherapy.

Follicular center lymphoma that originates in the skin is rare.

Incidence

This disease accounts for 22% to 35% of patients with non-Hodgkin’s lymphoma (NHL) in Western countries, and a slightly lower proportion than in Western countries, accounting for 8.1% to 23.5% of patients with NHL in China.

Follicular lymphoma occurs mostly in the elderly, with a median age of onset of about 60 years.

The incidence rate in Europe and the United States is higher than that in China, and the incidence in China has been on the rise in recent years.

Causes

Causes

The etiology of follicular lymphoma is still unclear, and although many potential risk factors have been proposed, most have not been validated in independent studies.

However, the following factors may increase the risk of developing this disease as one of the types of non-Hodgkin’s lymphoma.

Family history of hematologic tumors.

History of occupational exposure to asbestos, agricultural pesticides, and hair dyes, which increase the risk of developing this disease.

Use of patients with immunosuppression and autoimmune disorders, increased incidence.

Smokers with increased incidence.

Certain viral infections such as EBV and human herpesvirus type 8 (HHV-8) may be associated with the development of this disease.

Symptoms

The most common symptom of follicular lymphoma is multiple enlarged lymph nodes throughout the body, usually without pain. However, this is a disease that can only be determined after a pathologic diagnosis, and it is not possible to determine whether or not you have the disease based on symptoms alone.

Enlarged lymph nodes

Enlarged lymph nodes can be located in the neck, armpits, groin and other palpable superficial areas, as well as in the mediastinum, abdominal cavity, pelvis and other deep parts of the body that cannot be reached from the surface.

Superficial enlarged lymph nodes

They are usually multiple, round, tough, smooth, movable, slowly and continuously enlarging nodules without obvious tenderness.

Enlarged lymph nodes deep in the body

Enlarged lymph nodes in the deep part of the body are usually asymptomatic when their size is small.

Symptoms may occur when the size increases significantly, squeezing the space of normal organs or affecting function.

For example, if the lymph nodes in the abdominal cavity are significantly enlarged, symptoms such as poor feeding, abdominal pain, abdominal distension, etc., and if the lymph nodes in the pelvis are enlarged and compress the veins, resulting in obstruction of blood return, swelling and discomfort in the lower limbs can occur.

Other symptoms

When accompanied by obvious bone marrow involvement, anemia symptoms such as pallor, fatigue and loss of appetite may occur.

If accompanied by obvious enlargement of the spleen, fullness, pain and discomfort in the left upper abdomen may occur.

Besides involving lymph nodes, follicular lymphoma can also involve various organs and tissues outside lymph nodes, and the more common one is gastrointestinal tract, which can present with symptoms such as feeling of fullness and bloating after eating, acid reflux, diarrhea or change of bowel movement.

Some patients may have systemic symptoms such as fever, night sweats and significant weight loss.

Consultation

Department of Medicine

Hematology

When there are multiple enlarged lymph nodes throughout the body, and/or accompanied by unexplained fever, night sweats and significant weight loss, it is recommended to consult the Department of Hematology.

Medical Oncology

When a patient is diagnosed with follicular lymphoma, he/she may choose to seek medical treatment from the Department of Medical Oncology. Some hospitals have specialties for lymphoma, which are also available.

Preparation for medical treatment

Preparation for consultation: registration, preparation of information, common problems

Tips for Medical Consultation

It is recommended that you wear loose clothing, no dresses or jumpsuits, and no metal jewelry before your visit.

List of Preparation for Medical Visit

Symptom list

Pay particular attention to the time of onset of symptoms, special manifestations, etc.

Are there fever, night sweats, weight loss, joint pain, fatigue, itchy skin, etc.?

Are there enlarged nodule-like lumps in the neck, armpits, groin, etc.? Is it painful?

How long have these symptoms been present?

List of medical history

Is there a history of viral infections such as EBV, human herpes virus type 8 (HHV-8), etc.?

Has anyone in the family ever had a hematologic tumor?

Are there any smoking habits?

Are you exposed to pesticides, hair dyes, asbestos, etc. in your regular work?

Checklist

Test results in the last six months, which can be brought to the doctor’s office

Laboratory tests: blood routine, blood biochemistry, blood immunity, bone marrow examination, etc.

Imaging tests: CT, PET-CT, MRI and ultrasound, etc.

Diagnostic pathology report and diagnostic slides, and if necessary, white slides (slides that have not been processed for diagnostic staining), in case they are needed for perfecting the pathology diagnosis.

Diagnosis

Diagnostic basis

The diagnosis of the disease is based on histopathologic examination including morphology and immunohistochemistry, with reference to flow cytometry and cytogenetic findings if necessary.

A complete lymph node excisional biopsy should be performed prior to treatment, and if an excisional biopsy is not possible, a crude needle aspiration biopsy should be performed to clarify the pathologic diagnosis.

Medical History.

Patients may have a history of viral infections, a family history of hematologic malignancies, and a history of smoking.

Clinical manifestations

Patients may have the following clinical manifestations:

Painless, progressive lymph node enlargement.

Unexplained fever, night sweats and weight loss.

Laboratory tests

Routine blood tests

Used to detect the presence of abnormal white blood cells, red blood cells and platelets in the peripheral blood.

In the absence or early stage of bone marrow invasion, blood tests may be normal; when bone marrow invasion is obvious, lymphocyte and white blood cell counts may increase; when bone marrow hematopoiesis is affected, red blood cell and platelet counts may decrease.

Bone marrow examination

40% to 70% of follicular lymphoma is associated with bone marrow invasion.

Cytology of the bone marrow, bone marrow biopsy and bone marrow flow cytometry tests can complement each other to more accurately determine the presence of bone marrow involvement and the severity of involvement.

Blood biochemistry

It can find out whether the patient’s blood electrolytes are normal or not, and the condition of liver and kidney functions.

High and low values of lactate dehydrogenase (LDH) and β2-microglobulin in the blood are usually associated with tumor load and can be used as prognostic indicators.

Imaging

The main purpose of imaging examination is to assess the extent of tumor involvement and the size of tumor load.

CT

The most widely used imaging method for follicular lymphoma is CT, which usually requires scans of the neck, chest, abdomen, and pelvis because lymphoma can involve tissues and organs throughout the body.

Enhanced CT can provide more imaging information.

Ultrasound

Ultrasound is more advantageous for organs such as the thyroid and testes.

Magnetic Resonance

Magnetic resonance examination has a higher resolution for lesions occurring in soft tissues and intracranial areas.

PET-CT examination

PET-CT examination has a wider scanning range and greater sensitivity in detecting lesions compared with CT.

Pathologic examination

Pathology is the final basis for the diagnosis of follicular lymphoma.

Pathological diagnosis of follicular lymphoma needs to be combined with the overall structure of the biopsy tissue under the microscope, cellular morphology, immunohistochemical staining, identification of chromosomal translocations, and other integrated application of various technical means.

Grading

Follicular lymphoma is graded according to the number of centroblasts in the tumor tissue.

Grade 1: 0-5 centroblasts per high magnification field of view.

Grade 2: 6 to 15 centroblasts per high magnification field of view.

Grade 3: >15 centroblasts per high magnification field of view. Among them, the presence of a few centroblasts is 3A, and the presence of patches of centroblasts and disappearance of centroblasts is 3B.

Staging

The 2014 version of Lugano staging criteria is mostly used [2].

Limited stage

Stage I

Invasion of only a single lymph node region (I), or invasion of a single extranodal organ without lymph node involvement (IE).

Stage II

Invasion of ≥2 lymph node regions, but all ipsilateral to the diaphragm (II), which may be accompanied by limited extranodal organ involvement in the ipsilateral lymph node drainage region (IIE).

Stage II large masses, i.e., those with large masses in stage II, are usually the staging test for CT, MRI, or PET/CT.

Progressive stage

Stage III.

Invasion of the lymph node region above and below the diaphragm, or invasion of the supradiaphragmatic lymph nodes + splenic involvement (IIIS).

Stage IV

Invasion of extranodal organs beyond the lymph node drainage area (IV).

Differential diagnosis

Infected lymph node enlargement

Similarities: Infections by bacteria, viruses, fungi, and other rare pathogens may result in enlarged lymph nodes.

Differences: Pathologic biopsy is required to differentiate.

Metastatic carcinoma of lymph nodes

Similarity: It can also manifest as enlarged lymph nodes.

Difference: Patients with metastatic lymphoma usually have a history of primary malignant tumor.

Other subtypes of lymphoma

Similarity: Other subtypes of lymphoma also usually present with multiple enlarged lymph nodes.

Differences: Pathologic diagnosis is required for differentiation.

Treatment

Aims of treatment: Early-stage patients with limited lesions can be partially cured. Advanced patients with more extensive lesions can achieve long-term survival with tumor through treatment.

Treatment principle: The treatment of follicular lymphoma needs to be stratified in combination with pathological grading and staging.

Basic principles of first-line treatment for grades l to 3a

Patients with stage I/II

Stage I/Stage II with limited invasion

Involved site radiotherapy (ISRT) is generally recommended.

The following treatment options may also be considered:

Observation.

ISRT + rituximab or otuzumab ± chemotherapy.

Rituximab or otolizumab ± chemotherapy + ISRT (stage I patients with large abdominal masses or mesenteric lesions).

Unconfined stage II

The first recommendation is rituximab or otolizumab ± chemotherapy + ISRT.

The secondary recommendation is observation.

Patients with stage III/IV

No indication for treatment

When there is no indication for treatment, the general recommendation is to wait and observe, and the secondary recommendation is to participate in a clinical trial.

With indication for treatment

Common indications for treatment include:

Having a suitable clinical trial;

Any uncomfortable symptoms that interfere with normal work and life;

Impaired end-organ function;

Hematopenia secondary to lymphoma invasion of the bone marrow;

Massive lesions (refer to GELF criteria);

Persistent or rapidly progressive disease.

When the above therapeutic indications are present, the general recommendation is chemotherapy ± rituximab or otuzumab, and the secondary recommendation is enrollment in a clinical trial and also local radiotherapy for local relief.

First-line immunochemotherapy regimens in grades l to 3a

First-line treatment

General recommendations

RCHOP regimen: rituximab + cyclophosphamide + doxorubicin/epirubicin + vincristine + prednisone.

RCVP regimen: rituximab + cyclophosphamide + vincristine + prednisone.

Pendamustine + rituximab.

CHOP regimen + otolizumab.

Lenalidomide + rituximab.

CVP regimen + otolizumab.

Bendamustine + otolizumab.

Secondary recommendations

The following regimens are available:

Rituximab monotherapy for patients with low tumor load.

Lenalidomide + otuzumab.

First-line therapy for elderly or frail patients

In such patients, rituximab monotherapy is generally recommended, or a lenalidomide + rituximab regimen may be used.

First-line maintenance or consolidation therapy

First-line maintenance or consolidation regimens, primarily rituximab monotherapy, are recommended, especially for patients presenting with a high tumor burden at the time of initial diagnosis.

Treatment of relapse-refractory and transformation

Primarily second-line treatment of relapsed, refractory follicular lymphoma (grades l to 3a) and treatment of transformation to diffuse large B-cell lymphoma.

The standard treatment for patients with relapsed, refractory follicular lymphoma is not yet fully standardized, and the choice of salvage regimen depends on the efficacy of previous regimens, duration of remission, patient age, physical status, type of pathology at the time of relapse, and therapeutic goals.

Second-line therapy

General Recommended Regimens

The following commonly used regimens are generally available and may also be referred to as second-line treatment options for diffuse large B-cell lymphoma.

RCHOP regimen.

RCVP regimen.

Bendamustine + rituximab (not recommended for patients with prior use of bendamustine).

Lenalidomide + rituximab.

Participation in clinical trials.

Secondary recommended regimen

CHOP regimen + otolizumab.

CVP regimen + otolizumab.

Bendamustine + otuzumab (not recommended for patients with prior use of bendamustine).

Lenalidomide + otuzumab.

Single agent regimen: otuzumab, rituximab, lenalidomide.

Copanlisib: this drug is a PI3K inhibitor, as of August 26, 2022, has not yet been marketed in China, and can be used in relapsed or refractory patients who have received second-line treatment, please follow the doctor’s instructions strictly.

Second-line treatment for elderly or frail patients

Generally, single-agent rituximab is recommended, but also alkylating agent single-agent ± rituximab regimen.

Second-line consolidation and maintenance therapy

Single agent rituximab is generally recommended, and autologous hematopoietic stem cell transplantation may be used as appropriate for some young high-risk patients who are still sensitive to chemotherapy after multiple relapses.

There are many effective therapeutic drugs, but some of them may not be available in China, therefore, the choice of drug treatment and how to combine different drugs need to be based on diagnostic and therapeutic specifications and combined with the individual’s specific situation.

Prognosis

The prognosis of follicular lymphoma can be roughly assessed using the Follicular Lymphoma International Prognostic Index (FLIPI)-2 scoring system.

FLIPI-2 scoring system

The FLIPI-2 is a prognostic index for the rituximab era, with key items including age, hemoglobin level, beta2-microglobulin, bone marrow invasion, and maximum diameter of the largest lymph node.

Scoring

Hemoglobin level

≥120g/L

<120g/L

β2-microglobulin normal above normal

Bone marrow invasion

Bone marrow invasion

yes

Maximum diameter of largest lymph node <6cm>6cm

Maximum diameter of the largest lymph node

<6cm

>6cm

Grouping

Each indication was scored 1 point, and based on the score, patients with follicular lymphoma were categorized into 3 risk groups: low risk, intermediate risk, and high risk, with 0-1 categorized as the low risk group, 2 categorized as the intermediate risk group, and 3-5 categorized as the high risk group.

Survival rate

Survival of patients with follicular lymphoma can be predicted by the 5-year survival rate and is strongly correlated with FLIPI-2.

Subgroup 5-year survival rate

Low-risk 98%

Low-risk

98%

Intermediate risk 88%

Intermediate Risk

88 percent

High risk 77 percent

High Risk

77% High Risk

5-year survival rate refers to the percentage of patients who survive for more than 5 years after various comprehensive treatments for their tumors. 5-year survival rate is only used for clinical research and does not represent the specific survival period of an individual; the expected survival period of a patient is affected by a variety of factors, so it is recommended to consult with the physician.