Indolent lymphoma

The risk of developing indolent lymphoma increases with age. Although the disease can occur at any age, it mainly affects older adults. It is uncommon in people under age 40 and very rare in children.

People infected with human immunodeficiency virus (HIV) are at a slightly higher risk of developing indolent lymphoma than the general population.[6] For patients who were previously diagnosed with an AID-defining illness, the risk of developing indolent lymphoma is 14-fold higher.[7]

First degree family history of NHL, hematological malignancy and hepatitis C virus (HCV) infection are linked to an increased risk of indolent lymphoma (iNHL).[8]There are also specific risk factors related to iNHL sub-types. Higher body mass index (BMI) as a young adult, occupation as a spray painter, sedentary lifestyle, high level of dietary animal protein intake are associated with risk of follicular lymphoma.[8][9]Residence on farm are associated with an increased risk of mantle cell lymphoma.[8] Sjögren's syndrome, systemic lupus erythematosus, tobacco smoking for more than 40 years are linked to an increased risk of Waldenstrom macroglobulinemia.

Indolent lymphomas encompasses a heterogeneous group of non-Hodgkin Lymphomas (NHL) that are slowly progressive.[10][11] Except for a few exceptions, indolent lymphomas are almost entirely of B cell origin.[10] They are classified based on pathological and cytological features.[10] Types of indolent lymphomas include follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, small cell lymphocytic lymhoma/chronic lymphocytic leukemia, and hairy cell leukemia.[12]

Follicular lymphoma (FL) is a type of B cell lymphoproliferative disorder and is generally associated with an indolent course.[13] It originates from the follicular center B cells.[13] About 85% of the cases show t(14;18)(q32;q21) chromosomal translocation, which causes the overexpression of the anti-apoptotic protein BCL-2.[14] FL is the most prevalent form of indolent lymphoma, accounts for 70% of indolent cases and 20~30% of all NHL cases, with an incidence of 1.6 to 3.1 per 100 000 persons/year.[14][15] It is most frequently diagnosed among people in their 50s and 60s, and is more common among white populations than black or Asian populations.[16] It is characterized by diffuse lymphadenopathy, bone marrow involvement, and splenomegaly.[13] Involvement of areas outside the lymphatic sites is less common.[13] Cytopenias are relatively common but constitutional symptoms of fever, night sweats, and weight loss are uncommon in the absence of transformation to diffuse large B cell lymphoma.[13] The 5-year survival rate in the United States is 88.4%.[16]

Cutaneous T-cell lymphoma - very high mag

CTCL is a subtype of NHL that mainly attacks the skin, but it can also involve lymph nodes, blood and other organs. This sub-type, unlike most NHL subtypes, is derived from the T cells. Mycosis Fungoides is the most common form of CTCL, and the disease typically attacks the skin.[17] When cancer cells infiltrates into the blood and accumulates in the blood, it becomes what is called the Sézary syndrome.[17] Diagnosis of CTCL is often delayed due to the presence of multiple clinical presentations and the lack of definitive diagnostic criteria. Patients can be misdiagnosed with a variety of benign skin conditions including but not limited to dermatitis, eczema, parapsoriasis, psoriasis and adverse drug reactions.[17] It takes 6 years on average from disease onset to confirmation of diagnosis in most cases.[17]

Marginal zone lymphoma (MZL) is a heterogeneous group of indolent B cell NHL that arises from the marginal zone of lymphoid tissues.[18] It accounts for 5~10% of all NHL cases, with an annual incidence of 0.4 to 1.0 per 100,000 cases in Western countries.[19] The median age of diagnosis is 67 years, and it is slightly more common in women than in men.[20]The World Health Orgnisation categorises MZL into three distinct subtypes: nodal, extranodal and splenic.[19] Extranodal MZL occurs in areas outside the lymph nodes, with stomach being the most common site.[20]Nodal MZL occurs within the lymph nodes, and splenic MZL develops in the spleen and may spread to the blood.[18][21]

Small cell lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL) are the same disease differing in its manifestations and are managed in the same way.[22] When the abnormal lymphocytes are located mostly in the lymph nodes, it is referred to as SLL, when the abnormal lymphocytes are mostly located in the blood and bone marrow, it is called CLL.[23] CLL is the commonest leukemia in the western countries, but it is very rare East Asia, including Japan.[24]The median age at diagnosis is 72 years.[22]

Staging describes the extent of indolent lymphoma, whether it has spread, and if so how far it has spread.[2] The disease can spread through tissue, the lymphatic system and blood.[2] The Lugano modification of the Ann Arbor systems is used to stage lymphoma.[25]There are 4 stages using the Roman numerals:

Stage I Either the lymphoma is in 1 lymph nodes or 1 group of lymph nodes; or, in rare cases, in 1 organ of the lymphatic system such as the Waldeyer’s ring, thymus, or spleen; or the lymphoma is in 1 site outside the lymphatic system (IE).[2]

Stage II Either the lymphoma is in 2 or more groups of lymph nodes; or the lymphoma is in 1 nearby area outside the lymphatic system, with or without its involvement in other lymph nodes (IIE). In both cases the lymphoma sites are on the same side of the diaphragm.[2] In stage II, bulky disease means tumor mass larger than a certain size, the measurement depends on the type of lymphoma.[2]

Stage III The lymphoma is in both side of the diaphragm.[2]Either it is in lymph nodes both above and below the diaphragm, or it is in lymph nodes above the diaphragm and in the spleen.[2]

Stage IV The lymphoma is in 1 or more organs beyond the lymphatic system, such as liver, lung, bone marrow or cerebrospinal fluid.[2]

After the diagnosis of lymphoma, tests are done to determine the stage of the disease in order to predict prognosis and develop treatment plans. The following tests may be conducted in the staging process:

Imaging tests

• Chest x-rays
• CT (computed tomography) scan
• FDG-PET (fluorodeoxyglucose (FDG) positron emission tomography) scan
• Magnetic resonance imaging (MRI)
• Positron emission tomography-computed tomography (PET-CT) scans

Blood tests

Bone Marrow Biopsy

Radiation therapy. External radiation therapy (or external beam radiation therapy) may be given to affected lymph nodes, it may also be given to nearby lymph nodes.

Rituximab monoclonal antibody therapy.

Chemotherapy.

Watchful waiting.

Watchful waiting may be offered for patients who do not have signs or symptoms.

Rituximab monoclonal antibody therapy may be given alone, or combined with chemotherapy.

Maintenance therapy with rituximab.

Obinutuzumab monoclonal antibody therapy.

Phosphatidylinositol 3-kinase (PI3K) inhibitors such as copanlisib, idelalisib, or duvelisib may be used to treat relapsed indolent lymphoma.[27]

Combination immunotherapy with lenalidomide and rituximab.

Radiolabeled monoclonal antibody therapy.

Clinical trials.

Follicular lymphoma generally presents with an indolent course, some patients do not need treatments for several years, while others whose cancer has widely spread to lymph nodes or organs need treatment immediately.[18] In some cases, the disease can transform into an aggressive type of lymphoma, mostly diffuse large B-cell lymphoma (DLBCL).[18]

Patients who have stage I or II FL may be closely monitored without receiving treatment, they may be treated with radiation therapy alone or with chemotherapy.[18] Patients who are in stage II but have bulky disease, in stage III/IV or have relapsed or refractory disease may be treated with therapies depending on the patient's age, overall health, disease progression, symptoms, and the patient's choice.[18] Patients may also be eligible to participate in clinical trials. Treatment options include: watchful waiting, radiation aims directly at the lymph nodes that are swollen or cause symptoms, chemotherapy, and immunotherapy. For patients whose disease transforms to aggressive (high grade) NHL, autologous stem cell transplantation may be used for selected patient to improve the outcome. There is no consensus on the first line optimal treatment for follicular lymphoma, some studies find that there is no difference regarding life expectancy and quality between asymptomatic patients who receive treatments or are closely monitored. Other doctors indicate there is a under-use of radiation therapy which when appropriately used could cure a portion of the patients, and this under-use of radiation therapy may lead to excessive treatments and costs in the long term.[28]

Gastric MZL is often related to Helicobacter pylori Infection, many patients can be cured with antibiotic treatment without the need of chemotherapy and radiation therapy.[18]If remission is not achieved, radiation therapy may be used. For nodal MZL that involves the spleen and blood, treatment is similar to that of follicular lymphoma.[18]