About Lymphoma
Lymphoma is a term used to describe a group of cancers that originate in the lymphatic system, which helps the body fight infection and disease. Specifically, lymphomas are derived from lymphocytes (a type of white blood cell).
Like other cancers, lymphomas arise when cells divide uncontrollably. Lymphomas generally start in lymph nodes, spleen, bone marrow or blood. As they grow unchecked, they begin to crowd, invade, and destroy lymphoid tissues. They can also metastasize (spread) to other organs such as the liver, lung, skin and brain.
There are two major categories of lymphomas: Hodgkin’s lymphoma (also called Hodgkin’s disease), and all other types, collectively called non-Hodgkin’s lymphomas (NHL).
Hodgkin’s Lymphoma

Hodgkin’s lymphoma accounts for less than 12 percent of all lymphomas diagnosed annually. It is characterized by painless enlargement of one or more lymph nodes, usually in the neck and/or shoulders. They may feel swollen and rubbery. Lymph nodes in the chest may also be affected.
Hodgkin’s lymphoma is distinguished from all other cancers of the lymphatic system by the presence of a large malignant abnormal cell in the lymph node called the Reed-Sternberg cell (diagnosed by microscopic examination of a lymph node biopsy. Up to 50% of Reed-Sternberg cells show the presence of Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis.
Hodgkin’s lymphoma occurs relatively frequently among adolescents and young adults, and typically has very high survival rates. Outright cures are often achieved when diagnosed in early stages.
Non-Hodgkin’s Lymphoma

Non-Hodgkin’s lymphomas are a very diverse group of cancers, each with different characteristics of the cancerous cells and prognosis. Each type is diagnosed and treated differently. Generally, these lymphomas are divided into those that arise from the B cells in a lymph node (antibody producing cells) and those that originate in T cells (an important cell in the immune system for fighting viruses). T cell lymphomas often affect the skin. The treatments for B and T cell lymphoma are very different, so it is important to be sure of the correct diagnosis. Lymphomas can also derive from NK (natural killer) cells, another type of lymphocyte.

Lymphomas can present in many different locations. The most common primary sites are nodal, or in the lymph nodes. Many lymph nodes are found throughout the body; the most familiar are cervical (neck), axillary (underarm), and inguinal (groin) lymph nodes.

Because lymphomas can occur anywhere lymphocytes are normally found, it can present in extranodal primary locations, i.e. not in the lymph nodes. Primary lymphomas may thus be diagnosed in the liver, lung and pleura, bone and bone marrow, spleen, skin, and mucosal linings (stomach, nose, etc.). Lymphomas of mucosal tissue are known as MALT lymphomas – these are mostly gastric lymphomas related to Helicobacter pylori infection.

The following information is a fairly exhaustive listing of non-Hodgkin’s lymphoma varieties. While there are certain commonalities with regard to causation, diagnostic tests, and treatment modalities across the spectrum of non-Hodgkin’s lymphomas, specific information for particular types is provided where applicable.

B-Cell Lymphomas
(adapted from Lymphoma Information Network – lymphomainfo.net)
Non-Hodgkin's lymphomas caused by malignant (cancerous) B-cell lymphocytes represent a large subset (about 85% in the US) of the known types of lymphoma (the other two subsets being T-cell lymphomas and lymphomas where the cell type is the natural killer (NK) cell or unknown).
B-cells undergo many changes in their life cycle dependent on complex signaling processes between cells and interaction with foreign substances in the body.

Various types of lymphoma or leukemia can occur in the B-cell life cycle, as summarized in the chart below (click to enlarge):

As with much of the biology underlying lymphoma, the chart represents what researchers believe but not conclusive knowledge. No comparable chart exists for T-cell malignancies.

Precursor B-cell neoplasm:
  • Lymphoblastic lymphoma
    • Lymphoblastic lymphoma occurs mainly in children and adolescents, and accounts for about half of childhood lymphomas. About two-thirds of the patients are males. A second peak in incidence occurs in patients over 40 years of age.
    • Under the newest World Health Organization (WHO) lymphoma classification, lymphoblastic lymphoma is determined to be either a precursor T-cell neoplasm or a precursor B-cell neoplasm depending on the type of lymphatic cells that are cancerous.
    • The distinction from acute lymphoblastic leukemia is in part arbitrary, based on the degree of marrow involvement. The chief biologic difference is that lymphoblastic leukemias are predominantly B-cell diseases, whereas lymphoblastic lymphomas are often extramedullary (meaning outside the bone marrow), and predominantly T-cell in origin.
    • A majority of patients have tumors above the diaphragm - abdominal involvement is uncommon.
    • In childhood lymphoblastic lymphoma, with intensive chemotherapy, long-term disease-free survival may be attained, and the complete remission rate is as high as 96%.
    • Combined chemotherapy is standard treatment with the specific type dependent on the stage of the disease.
Mature (peripheral)
  • B-cell neoplasmsB-cell
    • small lymphocytic lymphoma (SLL) / chronic lymphocytic leukemia (CLL)Small lymphocytic lymphoma (SLL) is almost identical to chronic lymphocytic leukemia (CLL) both morphologically and clinically. A somewhat arbitrary distinction is drawn between them based on the relative degree of lymph node and lymphoid tissue involvement (pointing to lymphoma) versus the numbers of cells primarily in the bone marrow and peripheral blood (pointing to leukemia).
    • As a lymphoma, SLL accounts for about 4-5% of non-Hodgkin's lymphomas. As a leukemia, CLL accounts for about 30% of adult leukemias in Western countries. In SLL, the patients are elderly (median age 60 years) and usually present with diffuse lymphadenopathy (swelling of the lymph nodes) and some degree of marrow and peripheral blood involvement (Stage IV disease). Men appear to get the disease as often as women.
    • This lymphoma is very indolent (slow-growing) but relentless, with median survivals of almost a decade. Although the slowly proliferating cells are sensitive to chemotherapeutic agents, chemotherapy is almost never curative and relapse inevitably follows.
    • Most studies find no benefit in treating patients until they develop symptoms, or if they have certain cytogenetic profiles (determined by FISH testing), such as the presence or absence of specific chromosomal deletions, that portend a poorer prognosis. Therapy tends to be low-intensity: single alkylator therapy such as chlorambucil or combination therapy with cyclophosphamide/vincristine/prednisone. Fludarabine is often used, but it has not been shown to prolong survival so far. Using immunotherapies such as Rituxan® or Campath® may be helpful.
    • High dose chemotherapy with bone marrow or stem cell transplant has been used to treat a small number of people with SLL/CLL. The advent of the mini-transplant, or “mini-HCT,” has allowed for treatment of many older patients who ordinarily were not transplant candidates. Initial results have shown sustained remissions, and the possibility exists that stem cell transplantation may in fact be curative in some cases of SLL/CLL.
    • About 30% of cases of SLL progress to a higher grade disease process such as prolymphocytic lymphoma or diffuse large cell lymphoma (Richter's syndrome). Over time, 10% to 20% of cases of small lymphocytic lymphoma progress to chronic lymphocytic leukemia.
  • B-cell prolymphocytic lymphoma
    • This rare disorder may result from Richter’s transformation of SLL/CLL (described above) or arise de novo. It usually affects older adults and has an aggressive course.
  • Lymphoplasmacytic lymphoma (Waldenstrom’s macroglobulinemia)
    • Lymphoplasmacytic lymphoma (LPL), sometimes called Waldenstrom's macroglobulinemia, is an indolent lymphoma. It starts in plasma cells which develop from B lymphocytes. It is a rare disease, representing only 1.5% of all non-Hodgkin’s lymphomas in one study. Men are slightly more likely to get this lymphoma and the average patient is 63 years old at diagnosis. The disease is more common among whites than blacks.
    • Symptoms
      This lymphoma is usually associated with Waldenstrom's macroglobulinemia - a condition of increased monoclonal immunoglobulin paraprotein (IgM) greater than 3 grams per deciliter. Some patients may develop hyperviscosity syndrome, an increased thickness of the blood, as a result. Typically when LPL is found, the patient is in later stages with lymph node, bone marrow, and spleen involvement. If it spreads outside the lymph system the lung and gastrointestinal tract are most likely to be involved.
    • Causes
      The etiology (root cause) of LPL is unknown but it has been suggested that occupational exposure to paints, rubber dyes and leather may be a cause. However, this has not been confirmed. The disease has been reported in families suggesting a genetic link - gene translocation t(9;14)(p13;q32) and rearrangement of the PAX-5 gene are reported in some cases. An association with hepatitis C has also been reported.
    • Diagnosis & Staging
      The following tests may be performed by your medical team during the diagnosis and staging of the disease:
      • Full blood count
      • Renal and liver function tests
      • Serum uric acid
      • Serum viscosity
      • Cold agglutinins/cryoglobulins
      • Beta-2-microglobulin
      • Bone marrow aspiration and trephine biopsy  
      • CT scans
  • Treatment of lymphoplasmacytic lymphoma is divided into two parts:
    • Treatment for hyperviscosity: this can be accomplished by plasmapheresis if treatment of the lymphoma is not reducing IgM levels.
    • Treating the lymphoma
      • Chemotherapy
        Chemotherapy with chlorambucil has about a 70% response rate and a mean survival time of 5.4 years. CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone) has also been used, with a response rate of 60% and median survival of 5 years. Fludarabine and 2-CDA have also been used.
      • Stem Cell Transplant
        High dose chemotherapy with stem cell transplant has been used in smaller numbers of patients.
      • Immunotherapy
        Rituxan® has been tried in studies, especially with Waldenstrom's macroglobulinemia - it appears to decrease IgM but the results were rarely permanent, lasting a mean time of 8 months. Studies are being done combining Rituxan® and fludarabine. Since Rituxan® has an effect, other immunotherapies like Bexxar® may also be studied. Zevalin® has entered into some preliminary studies. Other investigators have combined CHOP with Rituxan® for various lymphomas with positive results.
  • Marginal zone lymphomas
  • Splenic marginal zone B-cell lymphoma (+/- villous lymphocytes)
    Splenic marginal zone lymphoma (SMZL) is an indolent B-cell lymphoma confined to the spleen. The spleen is an organ in the chest important for fighting infection. It is a rare lymphoma, accounting for less than 1% of all non-Hodgkin's lymphomas. This lymphoma occurs in adults and is slightly more frequent in women than in men.
  • Presentation
    The appearance of symptoms related to the disease often occurs several years after the first biological manifestation. The cancer is marked by massive splenomegaly (enlargement of the spleen) and peripheral blood and bone marrow involvement, usually without adenopathy (swollen lymph nodes).
  • Causes
    It has been suggested that the deletion of the 7q31-32 chromosome may be specific to this lymphoma, indicating that the normal gene in this region is used to suppress tumors. Other cytogenetic alterations include abnormalities in chromosomes 1, 7, and 8.
  • Treatment
    Therapeutic options include treatment abstention(watchful waiting), splenectomy (removal of the spleen), splenic irradiation, and chemotherapy. Splenectomy may result in a prolonged remission.Since this is a B-cell lymphoma, it is possible that treatment with recent monoclonal antibody drugs (Rituxan®, Bexxar®, etc.) may be effective.
  • SLVL
    Splenic lymphoma with villous lymphocytes (SLVL) is a recently recognized entity among chronic B- cell lymphoproliferative disorders. It has a distinct clinical, morphological and immunophenotypic pattern, and was previously described under a variety of designations. SLVL can be misdiagnosed as chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), or hairy cell leukemia (HCL).
  • Nodal marginal zone lymphoma
    • Nodal marginal zone lymphoma (NMZL) is an indolent B-cell lymphoma confined primarily to lymph nodes. It is rare, only comprising 1 to 3% of all non-Hodgkin's lymphomas.
    • Presentation - Many patients are diagnosed with stage I or stage II disease, although it may be diagnosed at all stages. Nodal marginal zone lymphomas are slightly more aggressive diseases compared to MALT lymphomas, tending to present at a higher stage.
    • Causes - The disease has been seen in patients with and without Hepatitis C infection. It appears that a gene rearrangement may be the cause of this form of NHL although studies in this area are continuing.
    • Treatment -Localized involvement can be treated with radiation or surgery. The chemotherapy drugs chlorambucil or fludarabine have also been used to treat NMZL.
Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type
Mucosa-associated lymphatic tissue lymphomas (MALT or MALToma) are forms of marginal zone lymphomas that involve places outside the lymph nodes (gastrointestinal tract, thyroid, breast, or skin). They are indolent (slow growing) B-cell lymphomas, accounting for about 10% of all types of NHL.
  • Presentation
    Most patients have their cancer diagnosed with stage I or stage II disease outside the lymph nodes. In general, patients have stomach pain, ulcers, or other localized symptoms, but rarely do they suffer from systemic complaints such as fatigue or fever. Many patients have a history of autoimmune disease such as Helicobacter gastritis, Hashimoto's thyroiditis, or Sjogren's syndrome. It is most often diagnosed in people in their 60s, but cases are sometimes found in people in their 20s or 30s.
  • Causes
    The bacterium Helicobacter pylori has been shown to cause MALT in the digestive system in about 90% of cases. Chromosomal translocations have also been noted in this form of NHL.
  • Treatment
    Gastric - treatment of Helicobacter pylori infection is effective in cases of local gastric involvement. After standard antibiotic regimens, 50% of patients show resolution of gastric MALT (when checked by endoscopy) after 3 months. Other patients may resolve after 12 to 18 months of observation. Stage III or IV disease may be treated with surgery or CHOP chemotherapy with or without radiation.
Non-gastric-localized involvement can be treated with radiation or surgery. When in the lymph nodes, bone marrow, or blood, MALT behaves like other indolent low-grade lymphomas.
As with all B-cell lymphomas, use of immunotherapy drugs is possible and there are a number of clinical trials running using newer monoclonal antibody drugs like Rituxan®, Bexxar®, and Zevalin® to induce responses.
Primary cutaneous extranodal marginal zone lymphoma
This relatively rare B-cell lymphoma of the skin typically presents as asymptomatic single or multiple red or reddish-brown papules, nodules or plaques. Immenophenotyping typically shows positive results for CD-20 and Bcl-2. A curious association exists between this type of cutaneous lymphoma and infection with Borrelia burgdorferi, the organism responsible for Lyme disease, although patients with this lymphoma may or may not show evidence of prior infection. Treatment is usually by surgical excision, followed by local radiotherapy in cases of multiple lesions. Antibiotic treatment is indicated in patients who show evidence of Borrelia infection. Because this lymphoma is indolent in nature, there is usually no further involvement with other parts of the body, and prognosis is typically excellent.
Plasma cell myeloma/plasmacytoma (Please see Myeloma.)
Follicular lymphoma
Follicular lymphomas are one of the more common non-Hodgkin's lymphomas in North America. They afflict almost exclusively adults, particularly the middle-aged and elderly. Because the small-cleaved cells of follicular lymphomas circulate readily in the blood, patients usually present with disseminated lymphadenopathy (lymph node swelling in several areas of the body).
Most cases of follicular lymphoma, especially those rich in small-cleaved cells, have a t(14;18) gene translocation. This results in a rearranged and over-expressed gene called Bcl-2.

The Bcl-2 gene tells the body to produce a protein that blocks programmed cell death ( apoptosis ). Therefore, over-expression of this gene causes unchecked cancer growth.
Follicular Cell Lymphomas: A Breakdown
Follicular lymphomas are divided into three types according to the ratio of small-cleaved and large cells:
  • Small-cleaved cell type has less than 20-25% large cells. This lymphoma is rich in small-cleaved cells, which circulate readily in the blood, and are often found there as well as in the marrow and liver. Patients nevertheless have a median survival of 7.5-9 years. As in other indolent lymphomas, however, standard chemotherapy cannot always secure a protracted remission or cure.
  • Mixed small-cleaved and large cell type has between 25 to 50 percent large cells. Though these lymphomas are also indolent, the increased percentage of large cells is associated with a reduced average survival.
  • Large cell type has more than 50% large cells.Large cell lymphomas with a follicular growth pattern are uncommon, and the nodularity can be hard to perceive. These lymphomas are the only intermediate grade follicular lymphomas - they are classified as indolent, but their aggressive nature is noted by NCI.
  • Treatment options depend on the stage and grade of the disease. Adult patients with early-stage disease may be treated with local radiation, with or without chemotherapy. Patients with more advanced but low-grade disease may remain untreated as long as no symptoms or lymphoma-related organ compromise are present (watch and wait). When treatment becomes necessary, the options include:
  • single-agent alkylator chemotherapy, e.g. chlorambucillow-intensity combined chemotherapy without an anthracycline (anthracyclines are chemotherapy drugs such as doxorubicin and daunorubicin)
  • whole-body irradiation
Large-cell follicular lymphoma is classified as an intermediate-grade lymphoma, and patients may benefit from the inclusion of an anthracycline in their chemotherapy. Immunotherapy , and monoclonal antibody therapy specifically, has shown promise in the treatment of follicular lymphomas. This includes drugs such as Rituxan® (rituximab) and possibly others like Bexxar® and Zevalin®.
T-cell immunotherapy
Cytotoxic T-lymphocytes (CTL), also known as killer T-cells, are an important component of the immune system, and specifically directing these immune cells to fight lymphoma cells by gene therapy is an emerging technology. Genetically modified CTL can recognize lymphoma cells like a monoclonal antibody, but then attack the lymphoma cells like a killer T-cell.
Mantle cell lymphoma
Mantle cell lymphoma (MCL) is a B-cell lymphoma previously called diffuse small-cleaved cell lymphoma, intermediate differentiation lymphoma, or centrocytic lymphoma. Despite all these names, it is not common.
  • Presentation - MCL primarily afflicts men over 50, who almost always present with advanced Stage III or IV disease. Bone marrow involvement is seen in 60% to 90% of patients. Four histologic subtypes have been noted: nodular, diffuse, mantle zone and blastic
  • Blastic MCL appears to have the worst prognosis, with nodular and diffuse subtypes having longer average survival times.
  • Treatment - Mantle cell lymphoma is an aggressive non-Hodgkin's lymphoma that has historically been resistant to current standard chemotherapeutic approaches. Despite response rates to many regimens of 50% to 70%, the disease typically progresses after chemotherapy, with a median survival time of approximately 2.5 to 4 years.

High-dose therapy with autologous stem cell transplantation may provide longer time to progression. For young patients with matched donors, allogeneic transplant is promising in the limited numbers of patients treated.
Immunotherapy treatments under development may be the best answer to mantle cell treatment. Rituxan® in combination with CHOP (CHOP-R) has a 96% response rate. Use of this treatment provides a prolonged response compared to chemotherapy alone.

One experimental protocol involves treatment with CHOP-R followed by stem cell transplant using etoposide (VP-16) and total body irradiation. Although this is an intense protocol, lasting remission rates have been very high.
As mantle cells may remain after treatment, researchers are looking at use of Rituxan® as a maintenance therapy.

Other studies employ Velcade (bortezomib); another promising therapy is Genasense - a Bcl-2 protein blocker.

Finally, researchers are investigating vaccine therapy for mantle cell lymphoma.
Diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma (DLCL) is a high-grade lymphoma that represents up to one third of non-Hodgkin's lymphoma cases. DLCL is the one type of NHL where the incidence does not vary geographically. There are several subtypes and variants of DLCL:
  • Morphologic Variants
  • Centroblastic
  • Immunoblastic
  • Anaplastic large B-Cell
  • Plasmablastic
  • Anaplastic lymphoma kinase-positive
  • Mediastinal (thymic) large B-cell lymphoma
  • Intravascular large B-cell lymphoma
  • T-cell/histiocyte-rich large B-cell lymphoma
  • Lymphomatoid granulomatosis-type large B-cell lymphoma
  • Primary effusion lymphoma
Adults - The median age at diagnosis is 57, and many patients are diagnosed in their 70s. As aggressive malignancies with a tendency to metastasize, the majority eventually demonstrate some extranodal component, including the gastrointestinal tract, testes, thyroid, skin, breast, central nervous system or bone. Although generally extranodal involvement is more common than in follicular lymphomas, the marrow is involved only about 10% of the time.

DLCL can arise from other types of lymphoma including small B-cell lymphoma, follicular lymphoma, or marginal zone lymphoma - this is called transformed diffuse large cell lymphoma.
Children - Large cell lymphomas also one of the more common NHLs in children, accounting for about 20-25% of childhood lymphomas.
There is strong evidence of a genetic factor in DLCL. 15% to 30% of the cases have a t(14;18), BCL-2 gene rearrangement. The c-MYC gene is rearranged in 5-15% of cases. The BCL6 gene is rearranged in 20-40% of cases and has some mutations in 70% of cases.
Recent advances in tissue testing allow medical personnel to know the exact features of the lymphoma, allowing them to select the therapy that may work best given the lymphoma characteristics.
Combination chemotherapy containing adriamycin (such as CHOP) is often used in DLCL with or without follow-up radiation. Stem cell transplants have been used when the above treatments have not been effective or for relapsed lymphoma.

Monoclonal antibody therapy using drugs such as Rituxan® with or without CHOP may become the standard in treatment.
Burkitt's lymphoma
Burkitt's lymphoma is an aggressive B-cell lymphoma that comes in three varieties:
Endemic Burkitt's lymphoma:
a childhood lymphoma (5 -10 year olds) prevalent in equatorial Africa, which is intimately associated with both Epstein-Barr virus (EBV) infection and a characteristic translocation of the c-myc gene (a gene involved in cellular proliferation). It is thought that endemic malaria causes increased susceptibility to EBV infection. The classic presentation of endemic Burkitt’s lymphoma involves tumors of the jaw or other facial bones; abdominal involvement may also occur.
Sporadic Burkitt's lymphoma:
a lymphoma that may occur worldwide, affecting slightly older childhood patients, sporadic Burkitt’s is also associated with c-myc changes, but not as uniformly with EBV infection (although one in five patients may be EBV-positive). Abdominal involvement is most common, while jaw involvement is rare.
Immunodeficiency-associated Burkitt’s lymphoma
occurs in immunocompromised patients, such as HIV-infected or post-transplant patients taking immunosuppressive drugs.
Burkitt’s accounts for about 30 to 40% of all childhood lymphomas. All varieties are more prevalent in males.
For children, the signs and symptoms usually depend on the site affected by the cancer. This malignancy grows very rapidly, and a child who appeared in good health 4-6 weeks prior may become rapidly ill. Often, children have a large abdominal mass with fluid buildup. Pain and vomiting may accompany this. The less common scenario has the cancerous B cells in the bone marrow causing increased anemia and bleeding.

Combined chemotherapy is standard treatment with the specific type dependent on the stage of the disease. Chemotherapy protocols may include combinations of the following:

  • cyclophosphamide
  • doxorubicin
  • vincristine
  • methotrexate
  • cytarabine
  • ifosfamide
  • etoposide
  • rituximab
T-Cell and Natural Killer Cell Lymphomas
  • Precursor T-cell neoplasm:
  • T-lymphoblastic lymphoma
  • Lymphoblastic lymphoma arising from T-cell, rather than B-cell, precursors.
  • Blastic NK lymphoma
    Blastic natural killer cell lymphoma (B-NKL) is an extremely rare form of cancer usually occurring in the middle aged or elderly (rarely children). Only a few people are diagnosed with the disease internationally each year.
    The disease can appear in the skin or other areas of the body outside of lymph nodes. The cause, like in many lymphomas, is unclear but it appears to not be related to the Epstein-Barr virus but may be related to a loss of the RB1 gene or other genetic causes.
    The cancer is extremely aggressive and can be resistant to chemotherapy used in other forms of NHL. Cases localized to skin appear to have a better prognosis. Some success has been achieved using stem cell transplantation and a chemotherapy protocol of hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate/cytarabine.
Mature (peripheral) T cell and NK-cell neoplasms
  • Leukemias
  • T-cell prolymphocytic leukemia
  • T-cell granular lymphocytic leukemia
  • Aggressive NK Cell leukemia
  • Adult T cell lymphoma/leukemia (ATLL)
Extranodal NK/T-cell lymphoma, nasal type
The extranodal nasal NK or T-cell lymphomas are rare forms of lymphoma. Nasal-type T/NK-cell lymphomas are common in Asia and in parts of Latin America but rare in the United States and in Europe. This may reflect an ethnic predisposition for the disease. Children may be affected as well as adults. Most studies have shown a male-to-female ratio of 2:1 to 3:1

NK or T cell nasal lymphomas represent about 75% of all nasal lymphomas, the rest being B-cell lymphoma. Tumors are most common in the nasal cavity but other sites may include the skin, gastrointestinal tract, testis, kidney, upper respiratory tract and rarely the eye/orbit. Commonly patients present with a nasal mass with bleeding and local bony destruction. Rarely, they may present with skin ulcer or GI perforation if these sites are primarily involved. About 10-20% of patients presenting with nasal NK/T-cell lymphoma may also have skin involvement at the same time.
The cause, like in many lymphomas, is unclear but it appears to be related to the Epstein-Barr virus.
The prognosis of extranodal NK/T-cell lymphoma is variable. Some patients respond well to chemotherapy such as CHOP, combined with local radiation, achieving complete remission. Some have suggested use of daunorubicin chemotherapy or integration of L-asparaginase into therapy. Transplants also appear to have some promise in treatment.
Cutaneous and subcutaneous T-cell lymphomas
  • Mycosis fungoides/Sezary's syndrome
  • Cutaneous T-cell lymphoma (CTCL) is an indolent (low grade) T-cell lymphoma that usually starts in or on the skin. Mycosis fungoides is the most common type and classic presentation of CTCL and usually progresses slowly over many years. In rare cases, affected individuals may develop Sezary syndrome, a leukemic variant of mycosis fungoides.
    CTCL should not be confused with peripheral T-cell lymphomas (PTL) or adult T-cell lymphoma/leukemia (ATLL), which are aggressive lymphomas which may also present themselves in the skin but require different types of treatment.
  • Diagnosis and Staging
    Once the doctors suspect a lymphoma diagnosis they will perform tests to confirm the diagnosis. This will include one or more biopsies (surgical removal of suspect tissue) which will be examined by an experienced pathologist to determine the type of cancer and how far it has spread. The determination of the spread of the disease is called staging and for CTCL it is different than for other types of non-Hodgkin's lymphoma. The TNM classification is used. The cancer is characterized by the spread of the tumors on the skin (from T1 to T4), the lymph node involvement (N0 to N3) and whether there are distant metastases (spread to visceral organs) (M1 if yes, M0 if no).
  • Treatment
    Treatment depends on the stage of the disease. Early stage (limited) disease may be treated with chemotherapy applied to the skin and ultraviolet A light exposure (PUVA). Retinoids, a class of drugs related to Vitamin A, exhibit activity against mycosis fungoides. Total skin electron beam radiation (TSEB) may be used for disease that has spread. Immunotherapy using monoclonal antibodies, interferon alfa, or interleukin-2 may be useful. Treatment with multiple agent chemotherapy may also be used, and there are clinical trials testing combinations of treatment.
Primary cutaneous anaplastic large cell lymphoma
Anaplastic large cell lymphoma (ALCL) can present itself in two forms: it can be systemic (throughout the body) in children or young adults or cutaneous (in/on the skin).

Disease limited to the skin is quite slow growing (indolent). Primary cutaneous ALCL manifests as a solitary nodule or ulcerating tumor in patients without a history of or concurrent mycosis fungoides (MF) or lymphomatoid papulosis (LyP) and no evidence of disease outside the skin. Lymph nodes in the same region are involved 25% of the time.

The disease tests positive for the CD30 antigen. Staging is required per other non-Hodgkin lymphomas. Patients may experience spontaneous remissions with relapses. If no spontaneous remission occurs, radiation and/or surgical excision are preferable. Chemotherapy is reserved for patients who have generalized lesions - low dose methotrexate has been shown to be an effective treatment. Cutaneous ALCL in patients with a prior history of mycosis fungoides or lymphomatoid papulosis has a poorer prognosis. When ALCL secondarily involves the skin from nodes, the prognosis is worse. Primary cutaneous-type ALCL does not appear to have the gene translocation t(2;5).

Systemic ALCL can involve lymph nodes and extranodal sites acting aggressively, but responds to chemotherapy used to treat other large cell lymphomas. The systemic form is associated with a t(2;5) chromosomal abnormality, leading to the production of the anaplastic lymphoma kinase (ALK) protein. This so-called "classic" ALCL is most common in children and adolescents.

Both types of ALCL can be from T-cell lymphocytes or cell type unknown (null).
Subcutaneous panniculitis-like T-cell lymphoma
This is a rare, highly aggressive lymphoma of the subcutaneous fatty tissues. It appears often as red nodules on the skin, which may be painful and tender. Women in their fourth and fifth decade of life are more commonly affected.

Systemic symptoms include fevers, chills, weight loss and hepatosplenomegaly. The primary treatment for this disease is chemotherapy with CHOP. Stem cell transplant may be considered if chemotherapy fails.
Primary systemic anaplastic large cell lymphoma - See cutaneous anaplastic large cell lymphoma.
Angioimmunoblastic T cell lymphoma
Angioimmunoblastic lymphoma (AIL) is an aggressive T-cell lymphoma representing about 1-2% of all types of non-Hodgkin's lymphoma in the United States. It has in the past been called angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). Initially, it was thought to represent an abnormal reaction of the immune system but it is now known to be a form of lymphoma. It is now a distinct entity under the newer WHO classification system.
AIL is a type of peripheral T-cell lymphoma that is clinically characterized by high fever, night sweats, weight loss, skin rash, a positive Coombs test, polyclonal hypergammaglobulinemia, and generalized lymphadenopathy that sometimes has cutaneous involvement. The skin is involved in approximately 40-50% of patients.
This malignancy usually occurs in adults. Patients are usually aged 40-90 years (median around 65) and are more often male.

As AIL progresses, hepatosplenomegaly (enlargement of the liver and spleen) and hemolytic anemia may develop.
Although steroid therapy initially is beneficial in many patients, the disease usually progresses to another form of lymphoma (e.g. to high-grade T-cell immunoblastic lymphoma or Epstein-Barr virus-positive diffuse large b-cell lymphoma).
Stem cell transplantation has been selectively used for advanced cases.
  • Other rare lymphomas
  • Peripheral T cell lymphoma, unspecified
  • Enteropathy-type T-cell lymphoma
  • Hepatosplenic gamma-delta T-cell lymphoma