OVERVIEW
Lymphoblastic lymphoma (LBL) is a group of malignant tumors originating from immature precursor T/B lymphocytes T-LBL manifests primarily as an anterior mediastinal mass, and B-LBL manifests primarily as enlarged lymph nodes The etiology of LBL has not yet been clarified The main use of chemotherapeutic regimens for acute lymphoblastic leukemia, as well as hematopoietic stem cell transplants
Definition.
Lymphoblastic lymphoma (LBL) is a group of malignant tumors originating from immature precursor T or B lymphocytes and are highly aggressive lymphomas.
LBL is a non-Hodgkin’s lymphoma, with T-LBL presenting primarily as an anterior mediastinal mass and B-LBL presenting primarily as enlarged lymph nodes.
LBL shares similar biological features with acute lymphoblastic leukemia (ALL) and is considered to be a different stage of development of the same disease. According to the 2017 edition of the World Health Organization classification criteria for tumors of hematopoietic and lymphoid tissues, ALL is diagnosed when the ratio of primitive and naïve lymphocytes in the bone marrow is >25% [1-4].
Typing.
Based on immunophenotype, it can be classified into T-lymphoblastic lymphoma (T-LBL) and B-lymphoblastic lymphoma (B-LBL).
T-LBL
originates from immature precursor T cells and accounts for approximately 80% to 90% of lymphoblastic lymphomas.
T-LBL mainly presents with compressive symptoms of an anterior mediastinal mass, such as cough and shortness of breath, and pleural effusion may occur. There is often bone marrow and central nervous system involvement.
B-LBL
Derived from immature precursor B cells, it accounts for about 10% to 20% of lymphoblastic lymphomas.
B-LBL mainly presents with enlarged lymph nodes and most often invades the skin and bone marrow.
Pathogenesis
Lymphoblastic lymphoma (LBL) is a non-Hodgkin’s lymphoma that accounts for approximately 3% to 4% of non-Hodgkin’s lymphomas in adults and 40% of non-Hodgkin’s lymphomas in children.
It is more common in males, with a male-to-female ratio greater than 2.5:1.
Causes
Causes
The cause of lymphoblastic lymphoma is not well defined and may be related to the following factors.
Exposure to ionizing radiation during childhood and young adulthood.
Genetic factors, such as increased risk in children with Down syndrome [5].
High risk factors
Long-term exposure to ionizing radiation or benzene agents.
A familial genetic history of lymphoma or other hematologic tumors, etc.
Symptoms
Major Symptoms
Localized symptoms
T-lymphoblastoid lymphoma (T-LBL) is mainly manifested as a mass in the anterior mediastinum, which compresses the trachea leading to cough, chest tightness, shortness of breath, etc. It may be accompanied by pleural effusion and pericardial effusion. Compression of the esophagus may cause dysphagia. Compression of superior vena cava may cause edema of head, neck and forearms.
B-lymphoblastoid lymphoma (B-LBL) is mainly characterized by enlarged lymph nodes, which are more common in the skin, soft tissues, and bones. In the skin, it may be characterized by multiple red nodules in the skin, which are hard. In the bone, it is mostly an isolated mass in the bone, and in a few patients, it is a solid osteolytic lesion, commonly in the femur and tibia, which manifests as bone pain [1,6-8].
Systemic symptoms
Both T-LBL and B-LBL can involve the bone marrow, manifested by anemia symptoms such as pallor and fatigue, and bleeding symptoms such as rhinorrhea.
Both T-LBL and B-LBL can involve the central nervous system, manifesting as dizziness, headache, vomiting, convulsions, and coma.
Lymphoma B symptoms, i.e. unexplained fever, night sweats and wasting.
Consultation
Department of Medicine
Hematology
If there are symptoms such as painless lymph node enlargement, chest tightness, dyspnea, dysphagia, multiple red nodules on the skin, bone and joint pain, fever and pallor, it is recommended to consult the Department of Hematology promptly.
Preparation for medical treatment
Preparation for Consultation: Registration, Preparation of Documents, Frequently Asked Questions
Tips for seeking medical treatment
Record the symptoms, duration and other relevant information for your doctor’s reference.
If red nodules appear on the skin, it is recommended to take photos of them.
Preparation Checklist
Symptom list
Pay particular attention to the time of onset of symptoms, special manifestations, etc.
Is there any symptom such as chest tightness, breath-holding, difficulty in swallowing, edema, etc.?
Are there any symptoms such as multiple skin nodules?
Are there any symptoms such as bone and joint pain, fever, fatigue, pallor, etc.?
How long have these symptoms been present?
Medical History Checklist
Is there a history of exposure to ionizing radiation, benzene agents, such as X-rays, gamma rays, etc.?
Is there a family history of lymphoma or other hematologic tumors?
Checklist
Test results from the last six months, which can be brought with you to the doctor’s office
Laboratory tests: blood counts, coagulation function, bone marrow examination.
Imaging examination: ultrasonography of cervical lymph nodes, abdomen, lesion site, CT examination of chest, abdomen and pelvis, X-ray examination of chest and bone, positron emission computed tomography CT (PET/CT).
Pathologic examination: pathomorphology, immunophenotyping, cytogenetics and molecular biology.
Diagnosis
Diagnosis is based on
Medical history
History of exposure to ionizing radiation, benzene agents, family history of lymphoma and other hematologic tumors.
Clinical manifestations
Symptoms
There are symptoms such as chest tightness, breath-holding, dysphagia, bone and joint pain, headache, fever, malaise, and pallor.
Physical signs
Lymph node enlargement: painless, progressive enlargement of lymph nodes, enlarged lymph nodes can be movable or adherent to each other, tender texture.
Multiple red nodules on the skin.
Enlarged liver and spleen.
Testicular enlargement.
Laboratory Tests
Blood counts
OBJECTIVE: To find out the patient’s white blood cell, red blood cell, and platelet counts.
Significance: Most white blood cells are elevated. Anemia may be present and hemoglobin concentration is less than 120 g/L. Naïve cells are present in the peripheral blood when bone marrow is involved.
Precautions: Fasting is required, and try to wear looser clothing for the blood draw.
Bone marrow examination
Purpose: To assist in the diagnosis of lymphoblastic lymphoma.
Significance: Bone marrow has active proliferation of nucleated cells, with proliferation of primitive and naïve lymphocytes predominating. Granulocytic and erythroid proliferation is suppressed. Primitive/naïve lymphocytes in the bone marrow are usually less than 20%.
Precautions: After bone marrow aspiration, take care to prevent wound infection.
Imaging
Ultrasonography of cervical lymph nodes, abdomen, and lesion sites
Purpose: To clarify the site of involvement and assist in staging.
Significance: Ultrasound may show enlarged lymph nodes, and liver and spleen enlargement may also be present.
Precautions: Eat a light diet before the examination, avoid eating high-fat and greasy food. Take rest before the examination and avoid staying up late. Wear clothes and shoes that are easy to take off and change on the day of examination. Pay attention to maintaining the body position during the examination.
CT examination of chest, abdomen and pelvis
Purpose: To clarify the site of lymphoma involvement and assist in staging.
Significance: It can show enlarged lymph nodes in the abdominal cavity and pelvis, enlarged lymph nodes in the mediastinum and hilar lungs, and single or multiple nodules in the liver.
Precautions: Remove metal objects, such as necklaces and earrings, from the body before the examination. Maintain the body position during the examination and do not swing freely.
Chest and bone X-ray examination
Purpose: To understand the site of lymphoma involvement and assist in staging.
Significance: If it shows that the patient’s mediastinum is widened, the lung hilum is enlarged, and the lower end of the lung has a high density shadow, it suggests that the lymphoma involves the mediastinum and the lung. If osteolytic destruction is present, it suggests involvement of bone.
Precautions: Remove metal objects from the body before the examination. Avoid shaking as much as possible during the examination.
Positron Emission Tomography (PET/CT)
Purpose: To find out the site of lymphoma involvement.
Significance: Enlarged lymph node shadows may be seen in the neck, clavicular region, mediastinum, subcutaneous anterior upper limbs on both sides, axilla on both sides, pulmonary hilar on both sides, retroperitoneum, intramesenteric, parietal to iliac blood vessels, and inguinal area.
Precautions: Keep the body position during the examination and do not swing freely.
Pathologic examination
Pathologic morphology
Purpose: To assist in the diagnosis of lymphoblastic lymphoma.
Significance: Destruction of lymph node structure. Tumor cells show diffuse dense relatively homogeneous infiltrative growth. The cells are medium-sized, with rounded or oval nuclei, high nuclear-to-plasmic ratios, inconspicuous nucleoli, and frequent nuclear schizophrenia. In some cases, the “starburst phenomenon” is seen.
Immunophenotype
Purpose: To assist in the diagnosis of lymphoblastic lymphoma.
Significance: Lymphoblastoid markers (including TdT, CD99, CD34, CD1a) are seen; T-lymphoblastic lymphomas may express specific antigens such as CD3, CD2, CD5, CD7; B-lymphoblastic lymphomas may express CD10, CD19, CD20, CD22, CD79a.
Cytogenetics and molecular biology
PURPOSE: To aid in the diagnosis of lymphoblastic lymphoma.
SIGNIFICANCE: More than 95% of T-lymphoblast lymphomas have clonal rearrangements of T-cell receptor genes. 50% to 70% of T-lymphoblast lymphomas have chromosomal karyotype abnormalities. Approximately 60% of B lymphoblastoid lymphomas have characteristic genetic changes.
Cerebrospinal fluid examination
Purpose: To aid in the diagnosis of CNS invasion.
Significance: If the results show elevated cerebrospinal fluid pressure, increased white blood cell count, increased protein, and decreased sugar quantification, and tumor cells can be found in the smear, it can aid in the diagnosis of CNS involvement.
Staging
The Ann Arbor staging system was used for staging.
Stage I: invading a single lymph node area or a single extra-lymph node organ or site.
Stage II: on one side of the diaphragm, invasion of two or more lymph node areas, or additional limited invasion of a single extra-lymph node organ or site.
Stage III: Simultaneous invasion of lymph node areas above and below the diaphragm, or plus limited invasion of a single extra-lymph node organ or site or the spleen, or both.
Stage IV: diffuse or disseminated invasion of a single or more extra-lymph node organs with or without lymph node involvement.
Special notes
The absence of systemic symptoms is categorized as Group A. Systemic symptoms with unexplained fever (greater than 38°C for 3 consecutive days or more), night sweats (for 7 consecutive days or more), and weight loss (more than 10% within 6 months) are categorized as Group B.
Involvement of a single extra-lymph node site and invasion of organs/tissues directly connected to lymph nodes/lymphoid tissues will be recorded with the letter “E” after each stage and will not be recorded as stage IV. If the lymphoma involves only the left cervical lymph node, stage I. If the lymphoma also invades the skin connected to the left cervical lymph node, it is recorded as stage IE instead of stage IV [1].
Differential diagnosis
Sleeve cell lymphoma
Similarities: both may present with clinical manifestations such as enlarged lymph nodes, fever, hemorrhage, pallor, and malaise.
Differences:
Immunophenotype, condylomatous cell lymphoma shows high expression of CyclinD1 in the nucleus.
Lymphoblastic lymphoma expresses TdT and lacks membrane surface immunoglobulin.
Burkitt lymphoma
Similarities: Both may present with enlarged lymph nodes, fever, and hemorrhage. Morphologically, both are characterized by medium-sized monomorphic tumor cells that exhibit the “starburst phenomenon”.
Differences:
Burkitt’s lymphoma has a “starry sky” phenomenon throughout the tumor tissue, and expresses sIgM, CD10, and positive EBER1/2 in situ hybridization.
Lymphoblastic lymphoma expresses TdT and T or B lymphocyte markers.
Thymoma
Similarities: both may present with an anterior mediastinal mass and symptoms such as chest tightness and breath-holding.
Differences:
Thymoma tissue is lobulated, with a distinct fibrous envelope as well as coarse fibrous septa visible.
Lymphoblastic lymphoma has an infiltrative growth of tumor cells in the fibrous tissue and specifically expresses TdT as well as T or B lymphocyte markers.
Tuberculous lymphadenitis
Similarities: both are common in children and adolescents and may present with enlarged lymph nodes, low-grade fever, and night sweats.
Differences:
In tuberculous lymphadenitis, the enlarged lymph nodes are mostly confined to the neck, adherent to the surrounding tissues, and antacid bacilli are seen in the punctured pus.
Lymphoblastic lymphoma presents with progressive, painless lymph node enlargement, and tumor cells are visible on biopsy.
Treatment
Treatment aim: alleviate the symptoms and cure the disease.
Therapeutic principle: chemotherapy is the mainstay, and most of the chemotherapy regimens similar to that of acute lymphoblastic leukemia (ALL) are used, as well as targeted drug therapy, hematopoietic stem cell transplantation, and symptomatic supportive therapy [1,9-10].
Chemotherapy
includes three stages: induction therapy, consolidation and intensification, and maintenance therapy. Different multidrug combination regimens should be selected according to the age of the patient, such as the Berlin-Farnkfurt-Münster regimen, i.e., cyclophosphamide, vincristine, zorubicin, dexamethasone, cytarabine, methotrexate, pembrolase, and prednisone.
Targeted therapy
Adult patients with Philadelphia chromosome-positive (Ph+) disease are treated with imatinib. There are also related clinical studies targeting NOTCH1 and others currently underway.
Hematopoietic stem cell transplantation
Patients who achieve complete remission with induction therapy are tested for micro-residual disease (MRD), and if MRD is positive, allogeneic hematopoietic stem cell transplantation is recommended. If MRD is negative, autologous HSCT may be considered. Allogeneic HSCT should be considered for high-risk patients and patients with recurrent refractory disease.
Treatment of central nervous system
All patients should undergo CNS prophylaxis as early as possible, and the main regimen is intensive chemotherapy and intrathecal injection.
Treatment of testicular infiltration
If there is a persistent testicular mass after induction and consolidation therapy, and pathological biopsy confirms that there is still testicular infiltration, bilateral testicular radiotherapy should be performed after consolidation therapy.
Symptomatic supportive treatment
Actively treat and prevent infection.
Constituent blood transfusion support and extragastrointestinal nutritional support if necessary.
Patients with high tumor load, hyperuricemia before chemotherapy, and renal impairment need to be alert to tumor lysis syndrome. Vital signs should be closely monitored, allopurinol should be applied to reduce uric acid production, and active hydration and diuresis should be used.
Prognosis
Cure
The prognosis of lymphoblastic lymphoma treated with chemotherapy regimen for acute lymphoblastic leukemia is good, and some studies have reported that the 5-year event-free survival rate of patients can reach 75% to 90%.
The prognosis of lymphoblastic lymphoma in children is significantly better than in adults.
Prognostic factors
Adverse prognostic factors include high leukocytosis, invasion of the central nervous system, prolonged time to achieve complete remission with chemotherapy, residual lesions at the end of induction chemotherapy, and genetic abnormalities such as subdiploidy (<44 chromosomes), t(9;22) (q34;q11.2):BCR-ABL1.
Daily
Daily management
Dietary management
A light diet is recommended, avoiding stimulating foods.
It is recommended to supplement high quality protein food, such as lean meat and eggs.
During chemotherapy, patients are advised to eat small meals and consume nutritious, light and easy-to-digest fluid and semi-liquid food.
Lifestyle habits
Adopt good habits of work and rest, pay attention to personal hygiene, avoid contact with infectious sources and prevent infection.
Keep your room clean and ventilated, maintain air humidity, and keep warm to prevent colds and bleeding.
Be careful in daily activities and move slowly to avoid bumping and scratching the skin, which may cause local bleeding.
Psychological support
When patients have obvious symptoms or need long time continuous treatment, they are prone to be anxious, worried and fearful. The patient’s psychological activities should be understood in time, and psychological guidance should be provided to the patient.
Follow-up
Importance of follow-up: Regular follow-up helps to monitor the changes of the disease, detect recurrence and adjust the treatment plan in time.
Follow-up time: It is recommended to follow the doctor’s instructions for follow-up.
Tests to be done during follow-up: blood routine, biochemical routine, bone marrow examination, ultrasonography, CT examination, etc.
Prevention
Exposure to ionizing radiation and benzene agents, etc. should be avoided.
People with a family genetic history of lymphoma are recommended to have regular medical checkups.
Actively publicize knowledge about lymphoblastic lymphoma, such as early symptoms, to increase the rate of early diagnosis and receive treatment as early as possible.