Lymphoma diagnosis and treatments at City of Hope cancer research hospital near Los Angeles, CA

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Lymphomas

Why Choose City of Hope?

City of Hope is recognized internationally for its breakthrough research discoveries and clinical treatments for lymphoma and related disorders such as leukemia, myeloma and myelodysplastic syndromes.

A pioneer in the field of hematopoietic cell transplantation (HCT), we have performed more than11,000 bone marrow and stem cell transplants to date and operate one of the largest, most successful programs of its kind in the world, with many patients experiencing long-lasting remissions and even cures.

We conduct clinical trials using innovative combination chemotherapy protocols which have produced impressive results in a variety of lymphomas and leukemias.

Our team of specialists is renowned for its collaborative and compassionate approach, combining highly advanced technologies, aggressive therapies and an extensive support network to give patients the best outcomes possible.

Ancillary Services
The team at City of Hope includes many different professionals who provide important ancillary services for care and rehabilitation. Together, our specialists work to create a compassionate, nurturing, and effective environment that supports patients and families dealing with a diagnosis of lymphoma.

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.

Types of Lymphomas

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 cell s (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).

Causes
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

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

Subtypes

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.

Causes
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.

Treatment
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.

Symptoms
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.

Cause
The cause, like in many lymphomas, is unclear but it appears to be related to the Epstein-Barr virus.

Treatment
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.

Presentation
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.

Treatment
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

Risk Factors

Lymphoma Risk Factors

Hodgkin’s Lymphoma

Age between 15-40 and older than 55
HIV/AIDS
Infection with Epstein-Barr virus (EBV); individuals who have had infectious mononucleosis are over three times more likely to develop Hodgkin’s lymphoma.
Hodgkin’s lymphoma can also occur in children, and is treated differently from adult cases.

Non-Hodgkin’s Lymphoma

Age older than 55
Male gender
Caucasian

Having one of the following medical conditions:

An inherited immune disorder
An autoimmune disease
HIV/ AIDS
Infection with human T-lymphotrophic virus type I (HTLV-1) or Epstein-Barr virus
A history of infection with Helicobacter pylori (specific to MALT lymphoma type)
Infection with Borrelia burgdorferi, the causative agent of Lyme disease (specific to cutaneous marginal zone lymphoma
Receiving immunosuppressant drugs following organ transplant
Exposure to certain pesticides, herbicides, and industrial solvents, e.g. benzene, perchloroethylene and xylene
Past treatment with radiation, or treatment for Hodgkin’s lymphoma

Signs and Symptoms

The following represent symptoms typical of a variety of lymphomas. More specific symptoms may be found in descriptions of specific lymphomas.

Painless swelling of the lymph nodes in the neck, underarm, or groin
Fever
Night sweats
Tiredness
Unexplained weight loss
Itchy skin or rash
Chest pain

Diagnosing and Staging

Diagnosing and Staging Lymphoma

While establishing a diagnosis of lymphoma, doctors also need to determine its stage, meaning how advanced the disease is when first diagnosed. Staging reveals whether the cancer cells have spread within the lymphatic system, and to other parts of the body as well. Knowing the stage of a patient’s lymphoma helps in treatment planning.

Several tests and procedures may be needed, including:

History and physical exam
Blood cell counts (white blood cell, hemoglobin, platelet count)
Microscopic exam of lymph nodes and/or bone marrow biopsy samples
Blood chemistry tests

Biopsies
Because lymphomas are a diverse group of malignancies, a biopsy is needed to confirm a specific diagnosis and type of lymphoma. In this test, a tissue sample is taken and examined under a microscope. Other tests such as immunophenotyping to determine whether it is a B cell or T cell lymphoma, cytogenetics (chromosome abnormalities) and molecular tests are performed.

Biopsies may include:

Lymph node biopsyThis involves the removal of all or part of a lymph node. A pathologist then examines the tissue under a microscope to determine if lymphoma is present and what kind.
Bone marrow biopsyIn this test, a small amount of liquid and piece of bone are obtained by inserting a needle into the hipbone. Then, a pathologist examines the samples for signs of involvement by the lymphoma.

Imaging Tests
Imaging tests used in staging lymphoma include:

Chest X-ray
Ultrasound
High-energy sound waves (ultrasound) are bounced off internal tissues or organs to create an image called a sonogram
CT or CAT (Computerized Axial Tomography) Scan
This procedure uses a computer connected to an X-ray machine to obtain detailed pictures of areas inside the body. A dye may be used to help visualize organs or tissues more clearly
PET (Positron Emission Tomography) scan
This scan measures the metabolism of a tumor relative to normal tissue and can help determine where in the body there is active tumor
MRI (Magnetic Resonance Imaging)
This procedure creates a series of detailed pictures of areas inside the body, using the combination of a powerful magnet, radio waves, and computer imaging

In general, scans are performed at diagnosis to determine the extent of disease, repeated during therapy to assess response to treatment at the end to document remission, and to follow a patient to determine if the lymphoma has remained in remission or has returned (relapse).

Staging

Stage I: The lymphoma cells are in one lymph node group (such as in the neck or underarm). Or, if the abnormal cells are not in the lymph nodes, they are in only one part of a tissue or organ (such as the lung, but not the liver or bone marrow).
Stage II: The lymphoma cells are in at least two lymph node groups on the same side of (either above or below) the diaphragm. Or, the lymphoma cells are in one part of an organ and the lymph nodes near that organ (on the same side of the diaphragm). There may be lymphoma cells in other lymph node groups on the same side of the diaphragm.
Stage III: The lymphoma is in lymph nodes above and below the diaphragm. It also may be found in one part of a tissue or an organ near these lymph node groups.
Stage IV: Lymphoma cells are found in several parts of one or more organs or tissues (in addition to the lymph nodes). Or, it is in the liver, blood, or bone marrow.
Recurrent: The disease returns after treatment.

In addition to these stage numbers, your doctor may also describe the stage as A or B:

A: You have not had weight loss, drenching night sweats, or fevers.
B: You have had weight loss, drenching night sweats, or fevers.

Treatment

Lymphoma Treatment Approaches

Treatments vary depending on the specific type of lymphoma, and other factors such as the patient’s age, overall health and prior therapy.

Surgery
Because lymphoma spreads throughout the lymph system, surgery plays little role. However, in primary extranodal tumors, such as those arising in the spleen or stomach, surgical removal may be useful. In localized lymphomas of the skin, surgical excision is usually first-line treatment.

Chemotherapy
Chemotherapy is often an essential component of lymphoma treatment, as a systemic approach is necessary to kill cells circulating throughout the lymphatic system .Chemotherapy is usually given in cycles, starting with treatment over several days. It is then followed by a few weeks without treatment so that the patient can recover from side effects, particularly anemia and low white blood cells. The sequence is then repeated until the disease is in remission and then continued to extend remission.

Chemotherapy drugs used for lymphoma may include combinations of the following:

bleomycin (Blenoxane®)
cyclophosphamide (Cytoxan®)
dacarbazine (DTIC-Dome®)
daunorubicin doxorubicin (Adriamycin®)
etoposide (VP-16, VePesid®)
mechlorethamine (Mustargen®, a.k.a. nitrogen mustard)
prednisone
procarbazine (Matulane®)
vinblastine (Velban®)
vincristine (Oncovin®)

Hodgkin lymphoma
The following combination chemotherapy protocols are used widely in Hodgkin lymphoma:

ABVD: doxorubicin, bleomycin , vinblastine and dacarbazine
BEACOPP: bleomycin , etoposide, doxorubicin, cyclophosphamide , vincristine , procarbazine and prednisone
MOPP: mechlorethamine , vincristine , procarbazine and prednisone

ABVD and MOPP are long-established, while BEACOPP is a newer regimen. BEACOPP, with its seven different components, may have increased side effects, but has also shown favorable treatment outcomes, particularly in higher-stage disease versus other protocols.

Non-Hodgkin Lymphoma
Perhaps the most common combination chemotherapy protocol for non-Hodgkin lymphomas is CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone). However, there are numerous other combination protocols. Because there are many varieties of non-Hodgkin lymphoma, there may be specific treatments applicable to a particular type.

Immunotherapy
Some patients with non-Hodgkin’s lymphoma, especially B cell lymphoma, are often treated with antibodies that have specific activity against the tumor. These antibodies can work alone or can be given in combination with drugs to enhance the efficacy of chemotherapy. Common monoclonal antibody treatments include:

Rituxan® (rituximab)
Bexxar® (tositumomab)
Zevalin® (ibritumomab tiuxetan)

Radioimmunotherapy
City of Hope has developed novel ways of delivering radiation utilizing monoclonal antibodies, part of the immune system, which have been combined with small amounts of radioactive substances. These radiolabeled antibodies allow doctors to target lymphoma cells directly while minimizing damage to normal tissues. City of Hope was one of the first programs to use radioimmunotherapy as part of a transplant regimen to improve the safety and efficacy of the treatment.

Adoptive T-Cell Therapy
T-cells are a powerful part of the immune system. A new approach being studied at City of Hope involves redirecting T-cells to recognize cancer cells specific to lymphoma. Researchers are taking normal T-cells from patients with lymphoma, and genetically modifying them to target and destroy the malignant cells. Studies are focusing on patients with recurrent diffuse large cell lymphoma who are undergoing ASCT.

Stem Cell Transplantation
Hematopoietic Cell Transplantation (HCT) and Peripheral Blood Stem Cell Transplantation (PBSCT) are therapies that use stem cells (immature blood cells) to treat a patient's malignancy, or to repair diseased or defective bone marrow. Transplants are sometimes performed early in the course of treatment to improve long-term results. In some patients, it is utilized when other treatments are not working.

Transplant procedures include intensive chemotherapy with or without radiation therapy to destroy (ablate) the cancerous cells, followed by an infusion of healthy new cells.

Autologous Stem Cell Transplantation (ASCT)
The greatest concern for patients with lymphoma is the chance that the disease will return (relapse). The Department of Hematology and Hematopoietic Cell Transplantation at City of Hope pioneered the use of early autologous stem cell transplantation (ASCT) in patients with poor-risk, aggressive NHL to avoid relapse after initial treatment. It is also the most effective treatment for most patients who suffer a recurrence of their lymphoma or Hodgkin disease.

In autologous transplants, a patient donates and receives back his or her own stem cells, typically collected from peripheral (circulating) blood.

ASCT in AIDS-related Lymphoma and Hodgkin Lymphoma
At City of Hope, patients with AIDS-related lymphoma and Hodgkin lymphoma are sometimes candidates for ASCT and the results of treatment at City of Hope are excellent. We are also conducting studies of autologous stem cells that have been genetically engineered to provide additional resistance to HIV infection in patients undergoing ASCT. This approach is being studied here at City of Hope to help improve the control of the virus after transplant.

Allogeneic Transplantation
In certain situations, a patient’s lymphoma is very advanced, and the blood or bone marrow is extensively involved. In these cases, an allogeneic transplant strategy is preferred, using stem cells from a matched donor, using related, unrelated or cord blood.

In allogeneic transplants, the donor is preferably a sibling. Alternatively, a matched unrelated donor (MUD) who has a similar genetic type may be used. In fact, 45 percent of all allogeneic transplants at City of Hope come from volunteer donors who are unrelated to the patient.

Researchers now understand that the response from the immune system carried in transplanted donor stem cells helps fight the cancer. This is known as a graft versus tumor effect.

Efforts to decrease allogeneic transplant-related complications are being explored, including the use of less intensive "non-myeloablative" transplant conditioning regimens (also called “mini-HCT”) which have a reduced risk of side effects and can be used to treat older patients with lymphoma, leukemia and myeloma.

Radiation Therapy
Radiation therapy uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. Traditionally, lymphoma treatment required the use of whole-body irradiation, which unnecessarily exposes healthy tissues.

City of Hope was the first in the Western U.S. to provide treatment for lymphoma using the helical TomoTherapy System®. This system combines radiation delivery with real-time imaging, allowing doctors to create a higher dose of energy that more precisely targets the bone marrow. The system not only provides more effective treatment, it reduces the unwanted exposure of normal tissues and reduces potential complications.

Research/Clinical Trials

Research and Clinical Trials

City of Hope has long been a leader in lymphoma research. With our extensive program of clinical trials investigating promising new treatments, we can provide our patients access to novel therapies that are not yet available elsewhere for the treatment of lymphoma. Our Developmental Therapeutics Program has a very active portfolio of trials for patients with recurrent lymphoma.

To learn more about our clinical trials program and specifically about trials for lymphoma, click here.

Lymphoma Resources

All of our patients have access to the Sheri & Les Biller Patient and Family Resource Center, which offers a wide array of support and educational services. Patients and loved ones may work with a coordinated group of social workers, psychiatrists, psychologists, patient navigators, pain management specialists and spiritual care providers at the center, as well as participate in programs such as music therapy, meditation and many others.

Additional Resources

Lymphoma Research Foundation
(800) 500-9976
(212) 349-2910
The Lymphoma Research Foundation was formed in 2002 by the merger of the Lymphoma Research Foundation of America and the Cure for Lymphoma Foundation. This group has awarded millions of dollars in over a hundred lymphoma research grants. Not just devoted to research, they are there to help patients and happy to answer questions and help those looking for information. They also have a good patient support resource listing.

Lymphoma Foundation
(212) 831-5332
The Lymphoma Foundation promotes basic research and clinical studies with regard to the causes, treatment and cure of all patients with Hodgkin's disease and the non-Hodgkin's lymphomas as well as the allied disorders that plague the lymphoma patient in the form of leukemia, second primary cancers of the breast, colon, ovary, lung, neurofibroma and other malignant tumors and immunological syndromes such as multiple myeloma. The Lymphoma Foundation supports and informs practicing physicians, clinical investigators, basic research scientists and the general public in matters concerning all forms of cancer and promotes the education and application of the latest and most effective forms of medical science.

Cutaneous Lymphoma Foundation
(248) 644-9014
The Cutaneous Lymphoma Foundation (formerly the Mycosis Fungoides Foundation) is dedicated to all forms of lymphoma of the skin.

Other Helpful Lymphoma Websites:
www.lymphomation.org
www.lymphomainfo.net

American Cancer Society
800-ACS-2345
866-228-4327 for TYY
The American Cancer Society has many national and local programs, as well as a 24-hour support line, to help cancer survivors with problems such as travel, lodging and emotional issues.

National Bone Marrow Transplant Link
248-358-1886

National Comprehensive Cancer Network (NCCN)
888-909- NCCN (6226)
The National Comprehensive Cancer Network, an alliance of 21 of the world's leading cancer centers, is an authoritative source of information to help patients and health professionals make informed decisions about cancer care.

National Cancer Institute (NCI)
800-4-CANCER
The National Cancer Institute, established under the National Cancer Act of 1937, is the federal government's principal agency for cancer research and training.

SPORE

Lymphoma SPORE

Stephen, J. Forman, M.D.
Principal Investigator

Andrew Raubitschek, M.D.
Co- Principal Investigator

The overall goal of the City of Hope Lymphoma Specialized Program of Research Excellence (SPORE) is to develop translational studies to improve the detection and therapy of Hodgkin’s and non-Hodgkin’s Lymphoma. This grant consists of four translational research projects and five cores developing novel approaches that are derived from molecular and immunologic studies of T-cell and antibody based therapies. An important theme of the translational studies in this grant is to develop lymphoma therapies that will reduce toxicities associated with current treatment regimens for Hodgkin’s and non-Hodgkin’s Lymphoma which can then be translated to the older patient population.

Main Research Projects
The major goal ofProject 1is to develop anti-CD30 based radioimmunotherapy for both Hodgkin’s and CD30+ non-Hodgkin’s Lymphoma.

Project 2will study the effectiveness of cellular immunotherapy to eradicate B-lineage lymphoma using genetically modified CD4+ and CD8+ T-cells expressing a CD19-specific chimeric immunoreceptor, which recognizes CD19 malignant B-cells.

Because epidemiologic studies indicate that stem cell damage from pretransplant therapeutic exposures may play a role in the development of myelodysplasia,Project 3will longitudinally study a population of patients with Hodgkin’s and non-Hodgkin’s Lymphoma to investigate the cellular and molecular factors that are predictive for development of myelodysplasia, and to determine the molecular sequence of events that lead to myelodysplasia.

InProject 4, investigators will develop molecularly engineered constructs for anti-CD20 directed therapeutics to improve imaging, radioimmunotherapy, and novel immunocytokines for the treatment of patients with CD20+ lymphoma. An important component of this project will be to delineate the immunologic effector mechanisms operative in immunocytokine-mediate anti-lymphoma in vivo activity.

This Lymphoma SPORE also supports aDevelopmental Research Programand aCareer Development Programto foster the advancement of pilot translational research projects and young investigators focused on lymphoma.

Lymphoma Team

People

TeamMembers

http://forms.cityofhope.org/directorysearch/

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Clinics, Treatments and Services

City of Hope Master Calendar

Lymphoma SPORE

Treatments and Clinics

A national leader in cancer treatment and prevention, City of Hope is steadfast in its drive to offer more positive outcomes to patients everywhere. Our research innovations become advances in patient care without delay, because people fighting cancer need better options – now.

How to Become a Patient - the first steps

To make an appointment for yourself, a family member or a friend, please complete and submit our Become a Patient Request Form, or call City of Hope at

800-826-HOPE (4673).

Supportive Care for Patients and Caregivers

The Sheri & Les Biller Patient and Family Resource Center embodies the heart and soul of City of Hope’s mission to care for the whole person.

Clinical Trials

Our aggressive pursuit to discover better ways to help patients now – not years from now – places us among the leaders worldwide in the administration of clinical trials. Last year, City of Hope conducted more than 300 studies enrolling almost 5,000 patients. Find out more about City of Hope's Clinical Trials.

Visiting City of Hope

Situated just northeast of Los Angeles, City of Hope combines the best science and the most innovative and highly compassionate patient care. Stretched across more than 100 acres in the City of Duarte, lushly landscaped gardens surround state-of-the-art facilities.

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