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 with HIV are at slightly higher risk than the general population.[6] For patients who were previously diagnosed with an AIDS-defining illness, the risk of developing indolent lymphoma is 14-fold higher.[7]

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

With a few exceptions, indolent lymphomas are of B cell origin.[10] They are classified based on pathological and cytological features.[10] Subtypes include follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, chronic lymphocytic leukemia, and hairy cell leukemia.[11]

Follicular lymphoma (FL) is a lymphoproliferative disorder generally associated with an indolent course.[12] It originates from follicular center B cells.[12] About 85% of cases show t(14;18)(q32;q21) chromosomal translocation, which causes the overexpression of the anti-apoptotic protein Bcl-2.[13]

FL is characterized by diffuse lymphadenopathy, bone marrow involvement, and splenomegaly.[12] Involvement of non-lymphatic areas is less common.[12] Cytopenias are relatively common, but constitutional symptoms such as fever, night sweats, and weight loss are rare in the absence of transformation to diffuse large B cell lymphoma.[12] The five-year survival rate in the United States is 88.4%.[14]

FL is the most prevalent form of indolent lymphoma, accounting for 70% of indolent cases and 20–30% of all non-Hodgkin lymphoma cases, with a yearly incidence of 1.6 to 3.1 per 100,000.[13][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.[14]

Cutaneous T-cell lymphoma (very high magnification)

Unlike most NHL subtypes, cutaneous T-cell lymphoma (CTCL) is derived from T cells. Mycosis fungoides, which attacks the skin, is the most common form of CTCL.[16] When cancer cells infiltrate and accumulate in the blood, it is known as Sézary syndrome.[16]

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 dermatitis, eczema, parapsoriasis, psoriasis, and adverse drug reactions.[16] It takes six years on average from disease onset to confirmation of diagnosis.[16]

Marginal zone lymphoma (MZL) is a heterogeneous group of indolent B cell lymphomas that arise from the marginal zone of lymphoid tissues.[17] It accounts for 5–10% of all NHL cases, with an annual incidence of 0.4 to 1.0 per 100,000 in Western countries.[18] The median age at diagnosis is 67 years, and the disease is slightly more common in women than in men.[19]

The World Health Organization categorizes MZL into three subtypes: nodal, extranodal, and splenic.[18] Nodal MZL occurs within the lymph nodes. Extranodal MZL occurs in areas outside the lymph nodes, with the stomach being the most common site.[19] Splenic MZL develops in the spleen and may spread to the blood.[17][20]

Chronic lymphocytic leukemia (CLL) and small cell lymphocytic lymphoma (SLL) are different manifestations of the same disease and are managed in the same way.[21] When the abnormal lymphocytes are located mostly in the lymph nodes, it is referred to as SLL; when the abnormal lymphocytes are mostly in the blood and bone marrow, it is called CLL.[22]

CLL is the most common leukemia in Western countries, but it is very rare in East Asia.[23] The median age at diagnosis is 72 years.[21]

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 the blood.[2] The Lugano modification of the Ann Arbor system is used to stage lymphoma.[24]

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

Stage II: The lymphoma is in two or more groups of lymph nodes; or in one nearby area outside the lymphatic system, with or without involvement of other lymph nodes (IIE). In either case, 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 threshold depends on the type of lymphoma.[2]

Stage III: The lymphoma is on both sides of the diaphragm,[2] either in lymph nodes both above and below the diaphragm, or in lymph nodes above the diaphragm and in the spleen.[2]

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

A patient's stage may be determined through blood tests, bone marrow biopsy, chest X-rays, computed tomography (CT) scans, positron emission tomography (PET) scans, and magnetic resonance imaging (MRI).

External radiation therapy (or external beam radiation therapy) may be given to affected lymph nodes and nearby lymph nodes. Other treatments include chemotherapy and monoclonal antibody therapy with rituximab.

Treatments include rituximab, either alone or combined with chemotherapy; obinutuzumab; combination immunotherapy with lenalidomide and rituximab; and radiolabeled monoclonal antibody therapy. Phosphatidylinositol 3-kinase (PI3K) inhibitors such as copanlisib, idelalisib, or duvelisib may be used to treat relapsed indolent lymphoma.[27] Clinical trials are also an option.

Some patients do not need treatment for several years, while others whose cancer has spread widely need it immediately.[17] In some cases, the disease can transform into an aggressive type of lymphoma such as diffuse large B-cell lymphoma (DLBCL).[17]

Patients who have Stage I or II follicular lymphoma may be treated with radiation therapy alone or with chemotherapy.[17] For patients who are in Stage II but have bulky disease, are in Stage III or IV, or have relapsed or refractory disease, treatment depends on the patient's age, overall health, disease progression, symptoms, and personal preferences.[17] Treatment options include watchful waiting, radiation aimed directly at the affected lymph nodes, chemotherapy, and immunotherapy. For patients whose disease becomes more aggressive, autologous stem cell transplantation may be used.

There is no consensus on the optimal first-line treatment for follicular lymphoma. Some studies have found no difference in life expectancy or quality of life between asymptomatic patients who receive treatment and those who are closely monitored without treatment. Other doctors believe that potentially curative radiation therapy is underused, and that this 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 antibiotics alone.[17] 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.[17]