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New Treatments for Malignant Lymphomas

Hodgkin's Disease

1) Pathology

Hodgkin's disease is diagnosed when Reed-Steinberg cells are present in an appropriate background of other cells and stroma. Reed-Steinberg cells are a feature of Hodgkin's disease but are not pathognomonic. The origin of the cell is still not established.

The four histologically recognized types of Hodgkin's disease are:

1. Lymphocyte predominant

2. Nodular sclerosing

3. Mixed cellularity

4. Lymphocyte depleted

Although there are clinical features associated with the subtypes (eg, nodular sclerosing tends to occur in women with involvement of mediastinal nodes), they do not determine prognosis with

2) Clinical Features

Most patients present with adenopathy. Some come because of systemic symptoms such as fever, night sweats or weight loss.

3) Staging

The accurate staging of patients is crucial since it determines therapy. The Ann Arbor staging system is generally used. It has four main categories:

Stage I -Involvement of a single nodal group.

Stage II -Involvement of more than one nodal group on one side of the diaphragm.

Stage III -Involvement of nodal groups on both sides of the diaphragm.

Stage IV -Extra-nodal involvement.

Some investigators include an E category when there is direct extension into visceral structures from a nodal area (eg, Stage IE). The spleen is considered lymphoid tissue and does not advance the stage. Splenic involvement is noted with a subscript (eg, Stage IIIs). Patients with systemic symptoms (fever, night sweats, loss of more than 10% of body weight in preceding six months) are known to have a poorer prognosis and are designated.

The evaluation should be planned to establish the stage as efficiently as possible. The work-up should begin with a complete history and physical examination. Blood work should include a complete blood count and liver function tests. The alkaline phosphatase might be elevated due to hepatic or bone involvement and imaging tests may be required to determine the source. CT scans of the chest and abdomen/pelvis will be necessary on most patients. An abdominal lymphangiogram demonstrates the internal architecture of the pelvic and retroperitoneal lymph nodes, information not obtained on the CT scan which shows only the size of the nodes. However, few institutions have radiologists with the expertise to carry out the procedure. A bone marrow biopsy is indicated in many patients. Further biopsies of other tissue may be necessary to determine.

The role of the staging laparotomy in the evaluation of patients with Hodgkin's Disease is becoming more limited as the proportion of patients who are treated with chemotherapy increases. Patients who have B symptoms or who have strong clinical evidence for being in Stage III or IV are unlikely to have their management altered by a laparotomy. A laparotomy may not be necessary in some patients with a clinical stage IA who have a very low likelihood of intra-abdominal involvement. Such patients include women with a supraclavicular or axillary presentation and men with high neck node presentations, especially if the histological type is lymphocyte predominant. If a laparotomy is done, it should be performed by an experienced surgeon who will carefully explore the abdomen, do a splenectomy, biopsy the liver (a wedge from the flee edge as well as core needle biopsies) and biopsy multiple lymph nodes, particularly any that appear.

4) Therapy

As indicated above, the treatment of Hodgkin's disease depends on the stage. The general approaches to therapy are:

Stage IA and IIA -Radiotherapy is the primary treatment and should be curative for the great majority of patients. Patients with "bulky" Stage II disease (eg, large mediastinal mass) are usually treated with a combination of chemotherapy followed by radiotherapy.

Because of the significant long-term complications of radiation therapy (discussed below), clinical trials have been started comparing the outcome of patients with these limited stages of Hodgkin's Disease treated with chemotherapy compared to radiation therapy.

Stage IB, IIB, III or IV -Chemotherapy is the primary treatment for these patients. The combination of Adriamycin, bleomycin, vinblastine and DTIC (ABVD) provides the same outcome as nitrogen mustard, vincristine, prednisone and procarbazine (MOPP) with less toxicity, especially in terms of fertility and possibly second malignancies.

Patients who relapse following chemotherapy may enter a second remission with conventional dose chemotherapy, especially if at least one year elapsed between the end.

5) Long-Term Side Effects of Therapy

The success in treating Hodgkin's Disease means that patients now live long enough to develop complications related to the treatment. Patients who have had radiation to the neck may become hypothyroid and may develop thyroid cancer. The former should be detected by regular measurement of TSH and replacement therapy initiated promptly.

Non-Hodgkin's Lymphoma

1) Pathology

No classification system for the non-Hodgkin's lymphomas has been developed which has been generally accepted by pathologists and oncologists. The Rapoport classification was developed in the 1960s and was based on the interpretation of hematoxylin and eosin stained tissue sections of lymph nodes. A number of other classifications were subsequently developed. In the early 1980s, the Working Formulation was promulgated. In Europe, a system called the Kiel Classification became widely used. More recently (1995), an international consensus meeting was held and proposed a system called the "REAL" classification (Revised European American Lymphoma). As with other systems, it generally permits patients to be placed in groups with prognostic

2) Clinical Features

Patients usually present with lymphadenopathy. The nodes of the upper aerodigestive tract (Waldeyer's ring), the epitrochlear area and the mesentery are more commonly involved by non-Hodgkin's lymphoma than by Hodgkin's disease. Some of the lymphomas tend to involve extra-nodal sites such as the gastric mucosa.

a) Follicular lymphomas.

These are a common type of non-Hodgkin's lymphoma, making up about 30% of all cases. The histological features include the follicular architecture with the individual lymphoid cells being small cleaved or a mixture of small cleaved and large cells.

An important aspect of the follicular lymphomas is the presence of a reciprocal translocation between chromosome 14 and 18 in most cases. The Bcl-2 gene is on chromosome 18 and the

b) Diffuse large B-cell lymphomas.

This is another of the common types of lymphoma, accounting for about 30% of cases. As the name implies, the pathologist will describe effacement of the normal nodal architecture by large lymphoid cells which are of B cell origin. Translocations involving the Bcl-6 oncogene have been reported in patients with diffuse large cell lymphomas. Patients with this lymphoma have a

c) Mantle cell lymphomas

Mantle cell lymphomas were recognized as a specific entity in the REAL classification. They account for 3 to 6% of the non-Hodgkin's lymphomas. Only experienced hematopathologists will recognize it from the histological sections. Cell surface marker studies show a typical pattern with expression of pan-B cell antigens (CD 19, CD 20 and CD 22) with surface IgM and IgG. The

d) MALT Lymphomas - Mucosal Associated Lymphoid Tumors

This entity has been recognized over the last few years. A classic site of involvement is the gastric mucosa. Infection with H. pylori has been postulated to play a causative role and in some case reports, the lymphoma has regressed following anti-bacterial therapy.

e) High-Grade Lymphomas

i. Lymphoblastic lymphoma

The cells are of T-cell derivation and are positive for terminal transferase. The disease affects young men and they often have a mediastinal mass. Combination chemotherapy regimens that are used in treating acute lymphoblastic lymphoma are employed. Prophylactic treatment of the central nervous system is routinely included in the therapy.

ii. Burkitt's lymphoma

The malignant cells in Burkitt's lymphoma are B-cells. Children are more commonly affected than adults. The African form is related to infection with EB virus whereas cases in the United States lack evidence for viral involvement. Burkitt's lymphoma is one of the AIDS related malignancies. Most patients have a chromosomal translocation involving the c-myc oncogene on chromosome 8. It is most frequently translocated to the region of chromosome 14 coding for the DNA sequences controlling synthesis of the heavy chain gene. In other cases translocations occur to the regions of chromosome 2 or 22 that code for light chain regulatory sequences. Combination chemotherapy is indicated with prophylactic therapy of the central nervous system.

f) AIDS related lymphomas

An increased incidence of non-Hodgkin's lymphoma has been described in patients with AIDS. Primary central nervous system lymphoma is much more common in AIDS patients than in patients with lymphoma in the general population. EB virus is associated with almost all the CNS cases. The lymphomas are usually of B cell origin and are in the high grade (poor prognosis) group. The common histological types are immunoblastic lymphoma and diffuse small, non-cleaved (Burkitt's or non-Burkitt's). The patients do poorly, often because of the advanced state of

Cutaneous T Cell Lymphoma

The cutaneous T cell lymphomas are derived from T4 cells. The two major clinical forms are mycosis fungoides and Sezary's syndrome. In the latter disease the patient may have diffuse skin erythema. The peripheral blood smear will show lymphoid cells with cerebriform nuclei. The illness is often chronic with median survivals exceeding five years. A range of treatments are