What is Lymphoblastic Lymphoma?
Acute leukemia, a type of cancer, represents up to 30% of all cancers in children. Specifically, Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL) is a disease that starts in the stem cells that produce our blood, specifically from B or T cells. These stem cells are the initial cells that turn into different types of blood cells. The World Health Organization (WHO) classifies these diseases under the term “precursor lymphoid neoplasm”.
To further understand, the WHO 2017 system splits this disease into four distinct categories: B-ALL/LBL not otherwise specified (which means there’s no clear cause or type); B-ALL/LBL with recurring genetic abnormalities; T-ALL/LBL; and NK-ALL/LBL. Lymphoblasts, which are immature cells that become lymphocytes (a type of white blood cell), characterize this disease.
These lymphoblasts are known for being small to medium-sized cells with very little cytoplasm (the jelly-like material that holds the cell’s parts), moderately condensed to dispersed chromatin (the material in the cell’s nucleus, containing DNA), and inconspicuous nucleoli (a small round body within a cell that plays a role in protein synthesis).
Typically, lymphoblasts affect the bone marrow or blood in cases of ALL and impact the lymph nodes in cases of LBL. The disease is confirmed as ALL when over 20% of the cells counted are these immature cells. Sometimes, patients initially show signs of the disease in their lymph nodes or at spots outside the lymph nodes (LBL). In some cases, there’s an overlap between ALL and LBL, and doctors will diagnose it as a combined condition. NK-ALL/LBL classification is currently a provisional one in the WHO 2017 system as it is rare and often overlaps with T-ALL/LBL.
ALL is notable for being one of the first cancers where chemotherapy showed a positive result. Also, it’s one of the first cancers where understanding the biology of the disease led to changes in patient treatment.
What Causes Lymphoblastic Lymphoma?
There is strong proof that ALL/LBL, or acute lymphoblastic leukemia/lymphoblastic lymphoma, has a genetic aspect to it. This is based on the observation that the disease is tied to several specific genetic changes called translocations, and it’s more common in identical twins. Studies have found that variations in certain genes including GATA3, CEBPE, ARID5B, IKZF1, and CDKN2A are also linked to ALL/LBL.
Also, people with certain disorders that affect the immune system, such as Down syndrome, neurofibromatosis type 1, Bloom syndrome, and ataxia-telangiectasia, have a higher chance of developing ALL/LBL. This supports the idea that the disease is connected to our genes and the immune system.
Risk Factors and Frequency for Lymphoblastic Lymphoma
Each year, about 6000 new cases of Acute Lymphoblastic Leukemia (ALL) are detected in the United States. This disease majorly affects children who are less than 6 years old, and it is slightly more common in males. The origins of ALL can be traced back to two types of cells: B-cells and T-cells. About 85% of ALL cases originate from B-cells, while the remaining 15% start from T-cells. Another related disease, Lymphoblastic Lymphoma (LBL), represents about 2% of all Non-Hodgkin’s Lymphoma (NHL). 10% of all LBL cases stem from B-LBL, and the remaining 90% are T-LBL. T-cell ALL is more common in males, African Americans, and adolescents. Additionally, T-ALL represents about 25% of all adult ALL cases.
- Every year, approximately 6000 new cases of ALL are reported in the United States.
- ALL primarily affects children less than 6 years old and is slightly more common in boys.
- 85% of ALL cases come from B-cells, while 15% come from T-cells.
- LBL makes up around 2% of all NHL cases.
- Of all LBL cases, 10% are B-LBL, and 90% are T-LBL.
- T-cell ALL is more commonly observed in males, African Americans, and teenagers.
- About 25% of all adult ALL cases are T-ALL.
Signs and Symptoms of Lymphoblastic Lymphoma
Diagnosis of ALL/LBL, which are types of cancers, relies on clinical signs, cell morphology, certain protein patterns (immunophenotyping), and molecular characteristics. Molecular studies play an important role in diagnosis and treatment. It can be challenging to identify ALL since its symptoms are similar to common childhood diseases. The most common symptoms stem from the bone marrow being overwhelmed with cancerous cells, also known as lymphoblasts.
- Anemia, which can result in paleness or fatigue
- Leucopenia or thrombocytopenia, which can lead to bruising or bleeding
- Recurrent infections due to neutropenia/leucopenia
- Bone pains
- Enlarged lymph nodes (lymphadenopathy)
- Enlarged liver (hepatomegaly) and/or spleen (splenomegaly)
For patients who suffer a relapse, they usually face persistent low blood cell counts.
On the other hand, B-LBL patients typically do not exhibit any symptoms (asymptomatic). B-LBL mostly affects the skin, bone-soft tissue, and lymph nodes, while rarely impacting the area between the lungs (mediastinum).
B- and T-cell LBL show different symptoms. T-LBL often impacts the thymus (mediastinum), and other possible sites include the skin, tonsils, and spleen. Rapid growth of masses in the mediastinum is a common symptom of T-LBL. To differentiate T-lymphoblasts from B-lymphoblasts, the use of diagnostic tests such as immunohistochemistry (IHC) and flow cytometry is crucial.
Testing for Lymphoblastic Lymphoma
When a doctor suspects a patient has Acute Lymphoblastic Leukemia/Lymphoma (ALL/LBL), a few tests need to be conducted to confirm the diagnosis. This includes a complete blood count (CBC), a test to evaluate the average size and hemoglobin content of your red blood cells, among others, along with smear evaluation, comprehensive metabolic panel (CMP), and viral screening for diseases such as cytomegalovirus, Epstein-Barr virus, HIV, hepatitis B virus, and varicella-zoster virus. These tests will help to properly determine the condition.
In the blood sample, the doctors might find lymphoblasts, which are immature white blood cells. The confirmation of ALL/LBL diagnosis requires finding more than 20% lymphoblasts in the bone marrow. Should there be any uncertainty, further tests, such as flow-cytometry, might be needed to confirm the preliminary findings. When B-cell lymphoblasts are present, they might show in the form of a diffuse or paracortical pattern in the lymph node.
There are two types of lymphoblasts: B and T lymphoblasts. These can’t be differentiated based on their appearance and require special testing. For this, immunostaining and immunophenotyping are used. Immunophenotyping is a crucial test for diagnosing and monitoring ALL/LBL patients. It uses markers to identify different stages of B-cell ALL/LBL. For instance, the earliest stage is the precursor B-ALL, which expresses certain markers like CD19, cytoplasmic C079a, cytoplasmic CD22, and nuclear TdT.
Molecular studies are crucial for diagnosis, as well as prognosis, classification, and treatment planning. Choosing the correct genetic testing approach for each patient depends on national guidelines and sometimes on the patient’s individual risk.
Doctors can differentiate between T-ALL/LBL and B-ALL/LBL through immunohistochemistry and flow cytometry. Lymphoblasts in T-ALL/LBL express different markers such as CD3, CD99, TdT, and CD7. There are also different stages of intrathymic differentiation in T-ALL/LBL, which are determined by each cell’s immunophenotype (characteristic antigens found on its surface).
Genetic studies for T-ALL/LBL typically present irregularities in most cases, most commonly in three specific areas of the genetic material. This information is vital in confirming the diagnosis of T-ALL/LBL and in planning the treatment approach.
Treatment Options for Lymphoblastic Lymphoma
Combination chemotherapy has been a successful treatment for Acute Lymphoblastic Leukemia (ALL) since the 1950s. The chemo treatment usually consists of three distinct phases: induction, consolidation, and maintenance, and it typically involves a treatment aimed at the central nervous system, known as intrathecal treatment.
Though chemotherapy plans can differ, most patients undergo an eight-week multi-drug induction phase, followed by a consolidation phase that lasts for four to eight months. The most commonly used medications during the induction phase include a steroid called glucocorticoid, a drug called vincristine, an asparaginase preparation, a type of medicine known as anthracycline, and intrathecal chemotherapy. During the consolidation phase, patients often receive cytarabine, methotrexate, another round of anthracycline, alkylating agents (which are medicines that act against cancer), and epipodophyllotoxins (a type of chemotherapy).
Following the consolidation phase, there’s a maintenance phase that commonly lasts between 30 to 42 months, involving therapeutic drugs such as mercaptopurine, methotrexate, vincristine, and prednisone. While this chemo treatment strategy has high success rates for most patients with ALL, there can be severe, potentially life-threatening side effects, including a rapid release of cellular products into the bloodstream (tumor lysis syndrome), blood clots (thrombosis), major bleeding, and body-wide infections (sepsis). Patients undergoing treatment for ALL may also need additional treatments such as antibiotics, bone marrow stimulants, and anti-sickness drugs to manage these side effects.
Patients with ALL are often classified into different risk groups: low, average, high, very high, and special groups. The management of each group varies based on national guidelines. For example, certain patients with a specific chromosome alteration known as t(9;22)/BCR-ABL1 translocation may require additional drugs called tyrosine kinase inhibitors. Those who experience a relapse of ALL usually require an escalated reinduction therapy and enhancement depending on which risk group they belong to. If patients do not respond to initial therapy (induction failure), they may need a procedure called allogeneic hematopoietic-cell transplantation, which involves replacing their diseased bone marrow with healthy stem cells from a donor.
What else can Lymphoblastic Lymphoma be?
When dealing with certain medical conditions, doctors look into several possible diagnoses. These include:
- Myeloid leukemia
- Diffuse large B-cell lymphoma
- Burkitt lymphoma
- Neuroblastoma, which is indicated by rosettes and neuroendocrine marker positivity
- Ewing Sarcoma, which presents with CD99 positivity
- Osteosarcoma, small cell variant: marked by osteoid
- Mesenchymal chondrosarcoma, identified by chondroid differentiation, S100+
- Juvenile idiopathic arthritis
- Osteomyelitis
- Epstein-Barr virus infection
- Immune thrombocytopenia (ITP)
- Pertussis, parapertussis infection
- Aplastic anemia
- Acute infectious lymphocytosis
- Hypereosinophilic syndrome
Comprehensive testing and investigation are necessary to identify the specific disease.
What to expect with Lymphoblastic Lymphoma
B-ALL, or B-cell Acute Lymphoblastic Leukemia, tends to have a good overall recovery rate in children, but can be tougher for adults. In fact, children get well over 95% of the time, while adults recover around 75% of the time. There are a few factors that could make the recovery process a bit harder, like being an infant, being older than 10, having a high white blood cell count (also known as leukocytosis), not responding quickly to initial treatment, still having some disease left after treatment (also called minimal residual disease), or if the disease has reached the central nervous system.
Risk in patients with ALL/LBL is often determined using a few different assessment strategies. One of these strategies classifies patients as either “standard risk” or “high risk” based on their age and white blood cell count. If patients are under 10 years old or have fewer than 50,000 white blood cells per cubic millimeter, they’re considered standard risk. If they’re older than 10 years or have more than 50,000 white blood cells per cubic millimeter, they’re high risk.
Genetic tests can also be useful for predicting how the condition might progress in patients with B-ALL. A couple of genetic abnormalities can suggest a good recovery outcome: high hyperdiploidy and the t(12;21) ETV6-RUNX1.
However, certain other genetic abnormalities might signal difficulties in the recovery process:
* Hypodiploidy (fewer than 44 chromosomes)
* MLL rearrangement
* BCR-ABL1 Ph-like ALL
* CRLF2 rearrangement
* Intrachromosomal amplification of chromosome 21
In comparison to B-ALL, patients with T-ALL, or T-cell Acute Lymphoblastic Leukemia, generally face a harder recovery process. Early T-cell precursor ALL, a rare kind of T-ALL, tends to have an especially challenging recovery. The recovery outcome for T-LBL, also known as T-cell Lymphoblastic Lymphoma, typically relies on factors like age, disease stage, and LDH (a type of enzyme) levels.
Preventing Lymphoblastic Lymphoma
Acute Lymphoblastic Leukemia (ALL) is the most frequently occurring type of cancer in children. If a child is experiencing repeated instances of infection, bleeding, or constant tiredness and paleness that is not improving with treatment, it might be an indication of ALL. It’s crucial to notice these signs as early detection can enhance the chances of successful treatment.
