B-Cell Unclassifiable Lymphoma High Grade

B-cell unclassifiable lymphoma high grade is an aggressive form of blood cancer that poses unique challenges for both diagnosis and treatment, requiring specialized approaches that differ from other types of lymphoma.

Table of contents

• What Is B-Cell Unclassifiable Lymphoma High Grade
• Classification and Related Conditions
• Genetic Changes and Causes
• Symptoms
• Diagnosis
• Treatment Options
• Prognosis and Outlook

What Is B-Cell Unclassifiable Lymphoma High Grade

B-cell unclassifiable lymphoma high grade is a provisional diagnostic category in the World Health Organization classification of lymphomas. This category was designed as a measure to accommodate borderline cases that cannot be reliably classified into a single distinct disease entity after all available morphological, immunophenotypical and molecular studies have been performed^[1].

Lymphoma is a type of blood cancer that develops when white blood cells called lymphocytes (a type of white blood cell) grow abnormally and multiply to form tumors. Your lymphatic system is a large network of organs, vessels and tissues, so this type of lymphoma can develop in many places in your body and cause different symptoms^[2].

This condition is part of a larger group called non-Hodgkin lymphoma (NHL), specifically affecting B cells. B-cell lymphomas account for about 85 percent of all non-Hodgkin lymphomas^[3].

B-cell lymphoma unclassifiable, gray zone lymphoma, unclassifiable lymphoma

Classification and Related Conditions

The revised Classification of Lymphoproliferative diseases published in 2016 by the World Health Organization identified four categories of large B-cell lymphomas: DLBCL not otherwise specified (NOS), other lymphomas of large B cells, high grade B-cell lymphoma, and B-cell lymphoma unclassifiable^[8].

Typically, these unclassifiable cases share features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Burkitt lymphoma (BL) or include characteristics of both lymphomas. The rarity of such cases poses a tremendous challenge to both pathologists and oncologists because its differential diagnosis has direct implications for management strategies^[2].

High-grade B-cell lymphomas include the entities carrying MYC, BCL2 and/or BCL6 translocations or cases with blastoid morphology without these gene changes^[8].

Genetic Changes and Causes

High-grade B-cell lymphoma is characterized by rearrangements (parts of genes switch places within chromosomes) in two particular genes. One rearrangement involves the MYC gene, and the other involves the BCL2 gene or, less commonly, the BCL6 gene^[1].

With respect to gene mutations, this condition shares many features with two other types of B-cell lymphomas—diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. In fact, about five percent of DLBCLs and about 32 to 78 percent of Burkitt lymphomas have rearrangements of the MYC and BCL2/BCL6 genes^[1].

An unusual morphological subgroup has been identified with blastoid features that is frequently associated with BCL2 and/or MYC gene rearrangements and carries a poor prognosis^[5].

Symptoms

Patients usually present with a rapidly enlarging tumor mass at single or multiple nodal or extranodal sites. Many patients are asymptomatic, but B symptoms may be present^[6].

Symptoms that may be related to B-cell lymphoma include:

• Abdominal (belly) pain: Some types start in your belly, causing pain that doesn’t go away or gets worse^[3].
• Drenching night sweats: Sweating that soaks through clothing and bedding^[3].
• Swollen lymph nodes: Enlarged lymph nodes that may be painless^[3].
• Fatigue: Persistent tiredness and lack of energy^[3].

Specific localizing symptoms may be present and are highly dependent on the site of extranodal involvement. Patients may present with nodal or extranodal disease. The most common extranodal site is the gastrointestinal site (stomach and ileocecal region). Other common sites of extranodal presentation include the bone, testes, spleen, Waldeyer ring, salivary glands, thyroid, liver, kidneys, and adrenal glands^[6].

Diagnosis

This histology can be determined by positive histology (including peripheral blood) with or without genetics and/or immunophenotyping^[6].

Molecular tests allow doctors to check for gene rearrangements in chromosomes under a microscope and are used to confirm a diagnosis. These molecular and genetic studies are essential because the condition cannot be reliably classified without them^[1].

The diagnosis requires performing all available morphological, immunophenotypical and molecular studies. Only after these comprehensive tests have been completed can doctors determine whether a case fits into this unclassifiable category^[2].

Treatment Options

Since high-grade B-cell lymphoma is a fairly new classification of lymphoma, ongoing research is helping doctors learn more about the best ways to treat this disease^[7].

HGBCLs are generally treated with one of the following combination chemotherapy regimens:

• DA-EPOCH-R: dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab^[7]
• R-Hyper-CVAD: rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with high-dose methotrexate and cytarabine^[7]
• R-CODOX-M/R-IVAC: rituximab plus cyclophosphamide, vincristine, doxorubicin, and methotrexate, alternating with rituximab plus ifosfamide, etoposide, and cytarabine^[7]

Patients treated with high-intensity chemotherapy regimens such as DA-EPOCH-R, R-CODOX-M/IVAC, or R-Hyper-CVAD have shown superior progression-free survival and overall survival compared with patients treated with the R-CHOP regimen^[9].

Some patients with HGBCL may undergo high-dose chemotherapy followed by either an autologous stem cell transplant (using the patient’s own cells) or an allogeneic stem cell transplant (using donor cells)^[7].

Compared with other types of B-cell lymphomas, HGBCL cells are more likely to spread to a patient’s central nervous system (CNS). To reduce this risk, patients with HGBCL may receive CNS prophylaxis in addition to one of the combination chemotherapy regimens described above. CNS prophylaxis is administered through a lumbar puncture, which allows the doctor to inject one or more chemotherapy drugs directly into the spinal fluid^[7].

Prognosis and Outlook

Among patients studied with high-grade B-cell lymphomas not otherwise specified, the median progression-free survival was 6.0 months and the median overall survival was 18.0 months^[9].

Patients with low International Prognostic Index (IPI) scores (≤2) had better survival rates than those with high scores (>2)^[9].

There are treatments that put the condition into remission (a state where symptoms disappear and tests don’t find signs of cancer), but it often comes back^[3].

The overall survival rate for the double-expressor lymphoma subgroup was inferior to that for the non-double-expressor lymphoma subgroup. Similarly, patients with single-hit lymphoma with MYC rearrangement had worse outcomes than those without this genetic change^[9].

The unusual morphological subgroup with blastoid features is associated frequently with BCL2 and/or MYC gene rearrangements and carries a poor prognosis^[5].