Jay Tor
05-14-2002, 10:08 AM
I agree with most of Vedstone's points. Here's a cut & paste from emedicine.com describing various lymphomas. Suggest you look up this site/article.
Synonyms, Key Words, and Related Terms: Hodgkin disease, Hodgkin’s disease, HD, non-Hodgkin lymphoma, non-Hodgkin lymphoma, NHL
INTRODUCTION Section 2 of 11
Background: Otolaryngologists are often involved in the diagnosis of lymphoma. A quarter of all extranodal lymphomas occur in the head and neck, and 8% of supraclavicular fine needle aspirates are diagnosed as lymphoma. In Caucasians, lymphoma is a more common cause of cervical adenopathy than metastatic disease. Additionally, lymphoma is the second most common primary malignancy occurring in the head and neck, and incidence of aggressive non-Hodgkin lymphoma is rising in young and middle-aged patients.
Pathophysiology: Histological classification of lymphomas is now performed using the revised European American classification of lymphoid neoplasms (REAL), although this is being further revised by the World Health Organization (WHO) (see Table 1). Hodgkin disease (HD), indolent non-Hodgkin Lymphoma (NHL), and aggressive NHL are 3 broad categories, which have very different natural histories and prognoses.
Table 1. Classification of Lymphomas Based on REAL
Indolent Cellular Lineage
Follicular lymphoma /follicle center lymphoma (grades I and II) B cell
Marginal zone B-cell lymphoma of mucosa associated lymphoid tissue B cell
Nodal marginal zone lymphoma with or without monocytoid B-cells B cell
B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia B cell
Mycosis fungoides (Sézary Syndrome) T cell
Aggressive
Diffuse large B-cell lymphoma (subtype is mediastinal [thymic]) B cell
Mantle cell lymphoma B cell
Burkitt lymphoma B cell
Plasma cell myeloma B cell
Extranodal natural killer (NK)/T-cell lymphoma, nasal type (angiocentric lymphoma) NK cell/T cell
Peripheral T-cell lymphoma T cell
Angioimmunoblastic T-cell lymphoma T cell
Adult T-cell lymphoma (human T-cell lymphoma/leukemia virus type 1+ [HTLV-I+]) T cell
Enteropathy-type intestinal T-cell lymphoma T cell
Systemic anaplastic large-cell lymphoma (T- and null-cell phenotypes) T cell
Precursor T-/B-cell lymphoblastic lymphoma T cell (90%)
/B cell
Hodgkin Disease
Nodular lymphocyte predominance Hodgkin lymphoma B cell
Classic Hodgkin lymphoma: B cell
Hodgkin lymphoma, nodular sclerosis (grades I and II)
Classic Hodgkin lymphoma, lymphocyte-rich
Hodgkin lymphoma, mixed cellularity
Hodgkin lymphoma, lymphocytic depletion
HD is characterized by the presence of Reed-Sternberg (RS) cells, and the subtype diagnosis depends on the cytoarchitectural milieu in which the RS cells are found. Nodular sclerosis, mixed cellularity, and lymphocyte-depleted subtypes are collectively termed classic HD, while lymphocyte-predominant HD behaves more like low-grade NHL. Lymphocyte-predominant HD tends to affect young men and to have an asymptomatic localized presentation. Lymphocyte-depleted HD is often disseminated at presentation and occurs in older patients.
Ninety percent of NHLs are B-cell lymphomas, and most indolent NHL is follicular lymphoma thought to be derived from germinal center B cells. Other indolent histologies include lymphoplasmacytoid lymphoma, which has characteristics of B cells differentiating towards plasma cells, and marginal zone lymphoma, derived from the memory B-cell compartment, which includes the mucosa-associated lymphoid tissue (MALT) lymphomas.
Diffuse large B-cell lymphoma is the most common aggressive NHL. Its messenger RNA expression profile resembles that of either germinal center B cells or activated B cells. Mantle-cell lymphoma and Burkitt lymphoma are aggressive NHLs that have the characteristics of normal B cells residing in the mantle zone or germinal center of a lymphoid follicle, respectively.
Cutaneous T-cell lymphomas, such as mycosis fungoides, can behave in an indolent manner. However, many T-cell NHLs are aggressive malignancies.
Frequency:
In the US: In 1997, prevalence of HD was 89,000 males and 79,000 females, and its incidence was about 3 cases per 100,000 population. The incidence of HD is decreasing by 0.3% per year, and mortality is decreasing by 4.1% per year (from 1973-1997).
NHL is the fifth most common nonskin cancer in the US. Its prevalence in 1997 was 166,000 males and 166,000 females, with an incidence of 16 cases per 100,000 population. Unfortunately, NHL incidence is increasing by 2.9%per year, and mortality is increasing by 1.9%per year (from 1973-1997).
Internationally: Different histological types of NHL have a variable distribution, such as the increased frequency of NK/T-cell lymphoma in China, Taiwan, and South East Asia, or of endemic Burkitt lymphoma in Africa.
Mortality/Morbidity: For HD, overall 5-year survival rates in the US from 1989-1996 were 82.8% for Caucasians and 76.7% for blacks. For NHL, 5-year survival was 52.6% for Caucasians and 41.9% for blacks.
Race: HD, and to a lesser extent NHL, is more common in Caucasians than in blacks or Hispanics. Other races such as Asian/Pacific islander or American Indian have the lowest incidence and mortality rates.
Sex: Especially in older patients, males have a higher incidence of both HD and NHL than females.
Age: In the US, HD has a bimodal age distribution with a peak incidence in people aged 20-34 years, and a second peak in Caucasians aged 75-79 years and in blacks aged 55-64 years. In Japan, the early peak is absent, and in some third-world countries, the early peak shifts into childhood. Mortality increases with age.
NHL has an increased incidence and mortality with age. Burkitt lymphoma represents 40-50% of all pediatric lymphomas and is uncommon in adults without AIDS. Lymphoblastic lymphoma most commonly presents in males aged 20-40 years with lymphadenopathy and/or a mediastinal mass. CLINICAL Section 3 of 11
History: Lymphoma may be nodal or extranodal. Extranodal lymphoma is usually NHL and carries a worse prognosis. HD spreads by contiguous nodal spread and hence is often localized, frequently presenting in the mediastinum. NHL tends to spread hematogenously and is often systemic at diagnosis.
A nodal presentation of HD is typically with 1 or more small to medium-sized rubbery lymph nodes in the neck, which may wax or wane in size but grow over time. A firm lymph node larger than 1 cm that is not associated with infection and that persists longer than 4 weeks should be considered for biopsy. In 2-5% of patients with HD, involved nodes can become painful after the ingestion of alcoholic beverages.
NHL may present in the lymphoid tissue of the Waldeyer ring. It appears as a mass in the oropharynx or nasopharynx. Unilateral tonsillar enlargement is highly suspicious of a malignancy. Extranodal disease such as primary lymphoma of the oral cavity is less common, usually arising in the tongue base. In contrast to squamous cell carcinoma, the lesion is bulky, fleshy, and nonulcerating.
NK/T-cell lymphoma can present as an ulcerative, destructive lesion of the nose, sinuses and face, which was formerly called lethal midline granuloma. This lesion, usually associated with Epstein-Barr virus, carries a worse prognosis than B-cell lymphoma and often presents with a nasal mass, epistaxis, and/or nasal obstruction. (Please see the video of a fiberoptic examination of an NK/T-cell lymphoma of the right nasal cavity and maxillary sinus in Picture 5.)
Lymphoma in the thyroid is more common than anaplastic carcinoma of the thyroid. It presents as a neck swelling, hoarseness, dysphagia, or neck pressure/tenderness. Advanced disease can cause facial edema and Horner syndrome. The salivary glands and ocular adnexa (8% of all extranodal lymphomas occur in the conjunctiva, orbit or lacrimal gland) are other sites of primary lymphoma presentation. Lymphoma involving the base of the skull or central nervous system can present with cranial nerve palsies, facial pain, hearing loss, vertigo, proptosis, or visual symptoms.
For all lymphomas, up to a third of patients have systemic symptoms used in staging that are designated B symptoms. Examples of B symptoms include a weight loss greater than 10% of body weight for no apparent reason, a fever higher than 38°C without evidence of infection, and/or drenching night sweats.
In addition, note any complaints such as bony pain, headaches, or gastrointestinal discomfort as possible indicators of generalized disease. A persistent cough can be the presenting feature of mediastinal lymphadenopathy, as can chest pain, shortness of breath, or hypertrophic osteoarthropathy. Pruritus, malaise, fatigue, and weakness are nonspecific symptoms occurring in 10% of patients.
Physical: A full otorhinolaryngological and neck examination including fiberoptic examination is indicated.
Examine patients for painless or mildly tender peripheral adenopathy in cervical, axillary, inguinal, and femoral regions. Less typically, enlargement of epitrochlear nodes is associated with enlargement of the Waldeyer ring.
Superior vena cava syndrome and pleural effusions may be due to a mediastinal mass.
Some patients with indolent NHLs may have large asymptomatic abdominal masses. Splenic or hepatic enlargement may be detected. The endemic (African) form of Burkitt lymphoma presents as a jaw or abdominal tumor that spreads to extranodal sites, but the nonendemic (American) form has an abdominal presentation with massive disease.
Causes:
Incidence of HD is increased 10-fold in same-sex siblings, implying genetic factors in its etiology. Chromosomal abnormalities are common in lymphomas. Aneuploidy occurs in HD, and translocations and deletions mark NHL, such as the c-myc translocation of Burkitt's lymphoma and the bcl-2 translocation found in most follicular lymphomas.
Infectious agents implicated in the pathogenesis of some lymphomas include Epstein-Barr virus, human immunodeficiency virus 1 (aggressive NHL occurs in 10-30% of patients with AIDS), Helicobacter pylori, HTLV-I, hepatitis B, and human herpes virus 8.
Chronic inflammation increases the risk of developing lymphoma, such as a MALT lymphoma arising in the salivary gland of a patient with Sjögren syndrome. Hashimoto disease increases a patient's risk of thyroid lymphoma, usually aggressive NHL, about 70-fold. In general, patients with autoimmune diseases such as rheumatoid arthritis have an increased risk of developing lymphoma.
Immunosuppressive medication, for example used following organ allotransplantation, increases the risk of Epstein-Barr virus–associated NHL. A percentage of these lymphomas regress spontaneously when the immunosuppressive medication is discontinued.
Farming, welding, and work in the lumber industry are associated with an increased risk of lymphoma.
DIFFERENTIALS Section 4 of 11
Squamous Cell Carcinoma of the Skin
Wegener Granulomatosis
Other Problems to be Considered:
Other neoplasms
Squamous cell carcinoma
Nasopharyngeal carcinoma
Thyroid carcinoma
Generalized lymphadenopathy from infectious etiologies
Bacteria
Viruses (eg, infectious mononucleosis, cytomegalovirus, HIV)
Parasites (toxoplasmosis)
Nasal granulomatous disease
Wegener granulomatosis
Lymphomatoid granulomatosis
Infections (eg, leishmaniasis, syphilis)
Mediastinal presentation
Infections (eg, histoplasmosis, tuberculosis)
Sarcoidosis
Other neoplasms
Benign lymphoid hyperplasias
B-cell predominant: Cutaneous lymphoid hyperplasia (CLH), angiolymphoid hyperplasia with eosinophilia, Kimura disease, and Castleman disease
T-cell predominant: T-cell CLH, lymphomatoid contact dermatitis, and lymphomatoid drug eruption
Differentiation from lymphomas requires the use of clinical features, histology, immunophenotyping, and gene rearrangement studies for monoclonal population detection.
WORKUP Section 5 of 11
Lab Studies:
All of the following lab studies are indicated.
Complete blood count
Serum chemistries including calcium, phosphate, and uric acid levels
Liver function tests including lactate dehydrogenase: High levels are associated with a poorer prognosis.
Erythrocyte sedimentation rate: High levels are associated with a poorer prognosis.
Serum protein electrophoresis for circulating monoclonal polyprotein
Serum beta2-microglobulin: High levels are associated with a poorer prognosis.
Imaging Studies:
Chest x-ray (essential)
CT scan of chest/abdomen/pelvis (essential) - Necessary in order to evaluate mediastinal, retroperitoneal, mesenteric, and retrocrural areas but fails to detect unsuspected splenic involvement in 20-30% of cases of early HD
CT scan of head/neck - Mandatory for a head and neck presentation, for localized disease, or in presence of symptoms, such as cranial neuropathies, hearing loss, vertigo, and visual changes
Magnetic resonance imaging - For evaluating the brain/spinal cord
Gallium scanning (planar or with single-photon emission computed tomography) - Positive in almost all aggressive and half of indolent NHLs and useful for monitoring response to therapy
Barium studies and/or endoscopy of the gastrointestinal tract - Waldeyer ring involvement often associated with intestinal involvement, but studies only undertaken if their results would alter treatment
Thyroid scintiscan - For a thyroid lump
Lymphangiography - Rarely used; only to look for infiltrated but normal-sized or mildly enlarged paraaortic, common internal, and external iliac nodes and only indicated if the results would alter treatment
Other Tests:
Immunohistochemical and cytogenetic analysis - Useful in the diagnosis of all lymphomas
Specific staining - For antibody-based treatments, which may be used directly in therapy or for purging tumor from autologous stem cells
Polymerase chain reaction analysis - For minimal residual disease
Procedures:
Nasopharyngeal laryngoscopy (essential): Perform this as the initial investigation to evaluate for an upper aerodigestive tract neoplasm that is accessible for biopsy.
Fine needle aspiration cytology (essential): This test is useful for the initial investigation of neck lymphadenopathy in differentiating squamous cell carcinoma from lymphomas, thyroid tumors, and salivary gland tumors.
Excisional or incisional lymph node biopsy (essential): This is essential in HD and NHL. Needle aspirations/biopsies are not adequate for the primary histological diagnosis because the architectural features of the tissue are important. The lump should be biopsied through an incision that can itself be excised and incorporated into a radical neck dissection if the histology in fact turns out to be squamous cell carcinoma. Usually, the unfixed node should be sent immediately to the laboratory for analysis.
Bilateral percutaneous bone marrow biopsies (essential): Up to 70% are positive in patients with indolent NHL. In disseminated disease, malignant cells may be found in the bone marrow, spinal fluid, ascites, or pleural fluid.
Percutaneous liver biopsy: Perform this test if blood tests or liver CT scan results are abnormal and histology of the liver biopsy would alter treatment.
Lumbar puncture: All patients with AIDS should have this routinely. Lumbar puncture is also used when there are possible symptoms of central nervous system disease after head CT scan shows no evidence of mass effect.
Staging laparotomy or laparoscopy
This is only useful for patients in whom radiotherapy alone is being considered, such as those with clinically early-stage localized disease. It is now only rarely indicated in patients with HD.
Staging laparotomy includes biopsy of selected lymph nodes in the retroperitoneum, splenectomy, and several needle and wedge biopsies of the liver. Laparoscopy with laparoscopic sonography probes can be used to detect small intrahepatic and lymph node metastases with a sensitivity and specificity that approaches that of laparotomy.
Historically, nearly one third of patients had their initial clinical stage changed as a result of the staging laparotomy because one third of normal-sized spleens were found to be infiltrated with tumor and 35% of patients with clinical splenomegaly had no histological evidence of disease. However, a randomized study failed to demonstrate a survival advantage for surgically staged patients compared to those managed on the basis of clinical staging.
Use of prognostic factors is replacing staging laparotomy in identifying patients suitable for radiotherapy alone.
Diagnostic Tonsillectomy: Indicated if lymphoma is suspected in the tonsils.
Risk factors for malignancy in the tonsils are: tonsillar asymmetry, history of cancer, palpable firmness or visible lesion of the tonsil, neck mass, unexplained weight loss, and constitutional symptoms.
In a study of 476 consecutive adults undergoing tonsillectomy, no patient without at least one of the above risk factors was found to have malignancy on pathologic evaluation of the tonsils.
Histologic Findings: Accurate histological diagnosis is the main guide for the modality of treatment to be used in NHL. A pathologist experienced in lymphoma diagnosis uses immunophenotyping by flow cytometry or immunocytochemistry to aid diagnosis. Special stains can be used, such as staining for follicular dendritic cells to highlight residual architecture in differentiating MALT from non-MALT lymphoma. It is interesting to note that 80% of lymph node infarctions are associated with a final diagnosis of lymphoma.
Staging: A lymphoma specialist should perform staging and treatment.
The Ann Arbor staging system (see Table 2) is used to stage lymphomas, although it was originally designed for HD and hence was based on the contiguous lymphatic mode of spread of HD rather than the hematogenous dissemination prevalent in NHL.
Table 2. Ann Arbor Staging Classification
Stage I Involvement of a single lymph node region or lymphoid structure
Stage II Involvement of 2 or more lymph node regions on the same side of the diaphragm or localized contiguous involvement of only 1 extralymphatic site and lymph node region
Stage III Involvement of lymph node regions or lymphoid structures on both sides of the diaphragm; can include spleen
Stage IV Disseminated involvement of one or more extralymphatic organs with or without lymph node involvement and/or involvement of the bone marrow or liver
A Asymptomatic
B Unexplained persistent or recurrent fever higher than 38°C or recurrent drenching night sweats within 1 month, or unexplained loss of more than 10% body weight within 6 months
E Limited direct extension into extralymphatic organ from adjacent lymph node
X Bulky disease - Mediastinal tumor width greater than one third transthoracic diameter at T5/6, or tumor diameter larger than 10 cm
Clinical stage is defined by the extent of disease based on physical examination and other noninvasive studies. The pathologic stage is defined by data obtained from invasive tests including biopsy specimens obtained from different sites, usually during a staging laparotomy.
Presence of systemic symptoms is designated by the suffix B and their absence by the suffix A. Presence of localized extralymphatic disease is designated by the suffix E. Multifocal extranodal, bone marrow, or liver involvement is disseminated (stage IV) disease. Bone involvement must be separated from bone marrow involvement, as the latter is always defined as disseminated disease.
Treatment and prognosis in HD is dependent on the stage, but treatment in NHL is based on both stage and histological subtype.
Early-stage HD traditionally is treated by radiotherapy, and disseminated disease is treated by chemotherapy with or without adjuvant radiotherapy.
Fewer than 20% of patients with NHL have early-stage localized disease suitable for treatment with radiotherapy alone. Hepatic infiltration is present in 25-50% of NHL cases, and in indolent NHL this figure approaches 75%. For aggressive NHL, even those with localized disease receive chemotherapy, usually in conjunction with radiotherapy. Radiotherapy is used for NK/T-cell lymphomas.
TREATMENT Section 6 of 11
Medical Care:
Chemotherapy is the major modality of treatment in the management of many lymphomas.
In HD, the standard chemotherapy regimen used was MOPP (ie, mechlorethamine [nitrogen mustard], vincristine, procarbazine, and prednisolone), but this is associated with a 2% incidence of myelodysplasia/acute leukemia 4-6 years after treatment, a 3% incidence of fatal febrile neutropenia, and infertility. ABVD is a regimen using doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine, which has the advantage of sparing fertility but has a 3% risk of fatal pulmonary toxicity. The choice of therapy therefore involves trade-offs of toxicity risk. ABVD-containing regimens have been found to be superior to MOPP alone and are now considered to be the standard of care.
In advanced-stage HD, more intensified regimens such as the escalated BEACOPP (ie, cyclophosphamide, doxorubicin, etoposide, procarbazine, prednisolone, vincristine, and bleomycin with granulocyte colony-stimulating factor) are being investigated. As the majority of chemotherapy relapses occur at the sites of initial disease, particularly nodal sites and sites of bulky tumor, adjuvant radiation therapy in the 15- to 25-Gy range is advocated in selected cases of bulky disease. Combining chemotherapy with radiotherapy forms the basis of combined-modality regimens such as Stanford V.
Patients with HD in whom chemotherapy fails can be divided into 3 groups.
Patients who never achieved a complete remission
Patients who have a complete remission that lasts less than a year
Patients who have a complete remission that lasts longer than a year
Even in this third group of patients, who have a 44% 5-year survival rate using conventional dose salvage chemotherapy, projected 20-year survival rate is only 24% because of secondary neoplasias and other treatment-related mortality.
In HD, salvage therapy is very successful. Nearly half of those not cured with primary treatment are cured with salvage therapy. If patients relapse more than a year after completion of primary chemotherapy, they can be retreated with the original treatment regimen. If they relapse in less than a year, some authorities suggest that they be treated with an alternative treatment regimen such as ABVD where the original treatment was MOPP, MOPP for ABVD, or mini-BEAM ie, (carmustine, etoposide, cytarabine, and melphalan) for MOPP/ABVD or MOPP/ABV hybrids. Relapses within a year are less frequently controlled without high-dose therapy and peripheral stem-cell transplantation.
Asymptomatic indolent NHL may be observed without treatment for an average of 3-4 years, as early treatment has shown no survival advantages. Although disease is disseminated in 80% of patients, local radiation therapy or surgery may provide long-term remissions or possible cure in those with early-stage disease, such as in many MALT lymphomas or early follicular lymphomas.
Median survival in indolent NHL is 8-10 years. When patients develop systemic symptoms or cytopenia, they are often treated with single agents such as chlorambucil. In advanced-stage follicular lymphoma, the more aggressive combination chemotherapy CHOP (ie, cyclophosphamide, doxorubicin, vincristine, and prednisolone), purine analogues such as fludarabine, or the humanized anti-CD20 antibody rituximab may be used.
Histological transformation to aggressive NHL occurs in 7% of patients with indolent NHL each year, and most patients who die from follicular lymphoma have evidence of histological progression, probably due to the acquisition of additional genetic abnormalities.
Patients diagnosed with aggressive NHL should be initially treated with curative intent. Choice of therapy may be influenced by the presence of comorbid diseases that affect end-organ toxicity. For most patients, combination chemotherapy consists of 2 cycles beyond achieving complete remission, for a usual total of 6 cycles. Fifteen percent of patients require 8 cycles. Initiation of successive cycles of treatment upon hematopoietic recovery appears beneficial when compared with traditional fixed-cycle durations. Central nervous system prophylaxis is recommended for patients with elevated LDH and multiple extranodal site involvement, as well as all high-grade NHL such as Burkitt or lymphoblastic lymphoma. It usually involves 4-6 injections of intrathecal methotrexate.
In treatment of aggressive NHL, a trial comparing CHOP to more recent regimens (m-BACOD [ie, methotrexate, bleomycin, cyclophosphamide, and etoposide], ProMACE/CytaBOM [ie, prednisone, methotrexate, Adriamycin, cyclophosphamide, and etoposide; cytarabine, bleomycin, vincristine, and mechlorethamine] and MACOP-B [ie, methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin]) found no difference in overall survival, response rate, or time to treatment failure between the 4 treatment arms. Prolonged maintenance therapy has not improved survival. However, the cure rate of less than 40% in unselected cases underscores the need for development of more effective treatment strategies. Stimulation of the CD20 receptor by the rituximab monoclonal antibody may be synergistic with cytotoxic agents; a recent study showed that combining rituximab with chemotherapy improved 12-month overall survival to 83% versus 68% with CHOP alone.
Salvage chemotherapy regimens used for aggressive NHL have included drugs such as cytosine arabinoside, cisplatin, etoposide, and ifosfamide given as single agents or in combination. Approximately 20-30% of patients achieve complete remission, with another 30% attaining partial remission, but these remissions only last a few months with a 2-year median survival of 10-30%. Recent studies have utilized infusional regimens where the original up-front chemotherapy agents are used. This is based on in vitro evidence that tumor cells display less resistance to prolonged exposure to low concentrations of the natural product class of drugs compared with brief higher-concentration exposure. One such infusional regimen is EPOCH (infused etoposide, doxorubicin, and vincristine with bolus cyclophosphamide and prednisolone), which has achieved a 41% overall survival at 3 years.
A steep dose-response curve persists even after relapse in NHL and HD; very high doses of chemotherapy can be used if supported by stem cell transplantation (SCT). Bone marrow as a source of hematopoietic stem cells can be infused from an identical twin (syngeneic), an HLA-matched relative (allogeneic), or from the patient (autologous). Bone marrow may be purged to remove residual disease. Stem cells can also be isolated from peripheral blood, and these have been found to be superior to standard bone marrow support when obtainable in adequate number, as is usually possible after chemotherapy and/or cytokine mobilization.
Using recombinant hematopoietic growth factors to hasten myeloid cell recovery has reduced the morbidity associated with SCT, as has the movement toward earlier transplantation and away from preparative programs with fractionated total-body irradiation (FTBI). The mortality rate from treatment is now less than 5% for autologous SCT using non-FTBI regimens such as CBV (cyclophosphamide, carmustine, and etoposide) or BEAM. Adjuvant involved-field irradiation may be used either before or after SCT.
Autologous SCT has been the most commonly used form of SCT. Allogeneic SCT has higher treatment-related mortality (up to 40% often due to pulmonary toxicity) but is associated with lower lymphoma recurrence rates, probably due to a graft-versus-lymphoma (GVL) effect. Nonmyeloablative conditioning regimens (fludarabine and cyclophosphamide) have been used with allogeneic SCT. Donor lymphocyte infusions (DLI) can augment the GVL response and are used for relapses after allogeneic SCT. Severe life-threatening complications of DLI are clinical graft-versus-host disease (as opposed to the therapeutic GVL response) and myelosuppression. Escalating doses of cells and T-cell depletion can be used to reduce the morbidity of DLI.
The benefit of high-dose therapy is greatest in patients with the most favorable prognostic factors. However, a high incidence of leukemia/myelodysplasia (9-18% actuarially calculated at 5-7 years) is present following SCT.
In HD, high-dose therapy and SCT have been used for failure of induction chemotherapy and for early relapse following chemotherapy to realize an event-free survival of 40-50% at 4-5 years.
High-dose chemotherapy and SCT may offer curative opportunities to a small number of patients with indolent NHL, but most centers accept it as the treatment of choice for relapse of aggressive NHL.
The cure rate for relapsed aggressive NHL is about 20% overall and 36% for those whose tumors are still somewhat responsive to a standard salvage polychemotherapy regimen. When intensive salvage chemotherapy with DHAP (ie, dexamethasone, high-dose aracytine, cisplatin) plus involved-field radiotherapy (IFRT) was used, either with or without SCT, transplanted patients had higher event-free survival (46% vs 12%) and overall survival (53% vs 32%).
When high-dose regimens with SCT were used as first-line therapy for aggressive NHL, significant improvements were seen in event-free survival (76% versus 49%), although this remains controversial. In patients in whom chemotherapy failed by never achieving a complete remission of their aggressive NHL, high-dose chemoradiotherapy and SCT compared to continuation of CHOP showed no difference in event-free, disease-free, or overall survival at 4 years. Therefore, the role of transplantation strategies in the management of aggressive NHL awaits the results of additional ongoing randomized trials.
Future developments in the treatment of aggressive NHL could involve the use of low-dose interleukin 2 (IL-2) after SCT, recombinant interferon alpha, or semisynthetic flavone derivatives such as flavopiridol.
Radiotherapy is the other major modality of treatment.
Radiation fields used in the treatment of lymphoma were devised to cover likely sites of contiguous disease. The Mantle field includes the submandibular, cervical, supraclavicular, infraclavicular, axillary, mediastinal, and hilar lymph nodes. It can be extended to cover the Waldeyer ring and the skull base with lateral portals for lymphomas involving the skull base. The paraaortic field covers the transverse processes of the abdominal vertebral bodies and the spleen if it has not been removed. Pelvic irradiation includes the common iliac, hypogastric, external iliac, and inguinal nodes. When gross pelvic nodal involvement is present, the femoral nodes are also treated. The "inverted Y" field covers the paraaortic and pelvic fields.
Radiation can be reduced to sites of known disease. IFRT is often used for bulky disease in combination with systemic chemotherapy, and the combination is called combined modality therapy (CMT). Fractionated stereotactic radiation therapy (FSRT) given as a boost or as a sole modality has been found to be effective and safe for extracranial head and neck tumors.
Patients with HD may receive Mantle and paraaortic irradiation, called subtotal lymphoid irradiation (STLI), in doses of 3000-3600 cGy with an additional "cone down" dose for a total of 4000 cGy to areas of bulk disease. In Europe, the Mantle field alone has been used to treat selected cases of HD. This takes 1 month versus the 3 months that STLI involves.
Patients with early-stage HD who are treated with STLI have an 80% chance of long-term disease-free survival. Failure rates within treated fields should be 7% or lower. A one-third reduction in treatment failure in early-stage HD treated with STLI is noted compared with limited (Mantle or IFRT) radiotherapy, but overall 10-year survival is identical because of successful salvage chemotherapy. CMT generally has no survival advantage in early-stage disease because salvage therapy is so efficacious in HD.
CMT is being investigated for patients with early-stage HD who have poor prognostic factors. IFRT and extended-field irradiation have been equally effective. CMT is used for the 25-30% of patients with HD who present with a mediastinal mass of greater than one third of the chest diameter at the T5-6 level. A recent metaanalysis found that tumor control was improved by 11% by adding radiation to chemotherapy, but overall survival was unchanged because chemotherapy-only patients had fewer late treatment-related deaths. A high incidence of second solid malignancies was observed in those whose recurrence after radiotherapy was treated with CMT (41% at 20 years compared to 12% in patients with no prior treatment).
Radiotherapy alone for localized aggressive NHL has poor results, and the preferred treatment option is 3-4 cycles of chemotherapy such as CHOP with IFRT. In patients with disseminated aggressive NHL, combination chemotherapy alone is the treatment of choice. The exception is nasal NK/T-cell lymphoma, which requires radiotherapy as the primary treatment modality, with or without chemotherapy. NK/T-cell lymphoma should be treated at higher doses of radiation in the 4- to 5-Gy range, with adjusted margins.
Cutaneous T-cell lymphomas such as mycosis fungoides can be treated with electron beam radiation therapy if limited to the skin, in combination with topical chemotherapeutic agents such as nitrogen mustard. Oral psoralens combined with ultraviolet light can also induce partial remission.
Surgical Care: Surgery is only performed in select cases.
Excision of necrotic tissue may be necessary in nasal NK/T-cell lymphoma. This lymphoma warrants monitoring by an otolaryngologist, as it usually recurs locally.
MALT lymphomas are often treated surgically with or without local radiotherapy. (Primary gastric MALT lymphomas associated with H pylori gastritis can respond to amoxicillin and omeprazole.)
Localized extranodal NHL has been successfully treated with surgery alone, such as selected cases of primary lymphoma of the bone, thyroid and gastrointestinal tract, but surgery is not normally recommended as the sole treatment.
Lymphomas of the central nervous system and skull base have been treated with surgical decompression when necessary, but chemotherapy and/or radiotherapy rather than operative intervention has been the treatment of choice.
The incidence of lymphoepithelial lesions has risen, and many of the recent cases are associated with HIV infection. In HIV positive patients, these lesions may be a manifestation of AIDS-related complex, which consists mainly of lymphadenopathy. Hence, surgical excision of the salivary glands in patients with HIV is not usually warranted. A proposed diagnostic and treatment algorithm is as follows:
Initially do a fine needle aspiration biopsy (FNAB) on patients with HIV risk factors or multiple cystic lesions of the salivary glands.
If the FNAB is not suggestive of a benign lymphoepithelial lesion, surgery is recommended, as there is an increased risk of lymphoma in HIV positive patients.
If FNAB does suggest benign lymphoepithelial lesion, and the patient is HIV positive but has not developed AIDS, treatment with Zidovudine has been advised. Patients can become unresponsive to this over time, so surgery may be necessary if this occurs or the lesions do not respond to the Zidovudine.
For patients who have AIDS, treatment with radiotherapy has been recommended.
Although most lymphoepithelial lesions of the salivary glands in patients without HIV are benign, some can progress to or be difficult to differentiate from malignant lymphoma, so surgery has been advised for all patients without risk factors for HIV. Should the pathology specimen from the superficial parotidectomy or submandibular gland resection reveal a malignant lymphoma, further treatment using chemotherapy or radiotherapy is recommended.
MEDICATION Section 7 of 11
For a general discussion of chemotherapy regimens, see Treatment. See also the following articles:
For adults
Lymphoma, Non-Hodgkin
Hodgkin Disease
For pediatric patients
Non-Hodgkin Lymphoma
Hodgkin Disease
FOLLOW-UP Section 8 of 11
Further Outpatient Care:
Otolaryngologists will be required to perform regular nasopharyngeal laryngoscopy on patients whose initial presentation was within the nasopharyngeal cavity, mouth, or sinuses, and may be required to perform biopsies for suspicious lesions in these areas. They may also be required to perform biopsies for suspicious neck nodes during the follow-up period in order to obtain a histopathological specimen to examine for any recurrence.
Deterrence/Prevention:
For patients with HD anticipating Mantle irradiation, abstinence from smoking is essential to minimize the risk of lung carcinoma. Mantle irradiation should be avoided when possible in people who smoke and young women because of lung and breast cancer risks respectively, as secondary neoplasia is the most frequent cause of long-term treatment-related mortality.
Complications:
Mortality from causes other than HD overtakes HD deaths at 15 years after diagnosis, and as the median age at diagnosis is 44 years, most of these are treatment-related deaths. Deaths from second malignancies become the most important cause of death other than HD itself.
Leukemia risk is maximal 5-10 years after treatment. It rarely occurs beyond the second decade. Although it is observed after radiation alone, the relative risk is an order of magnitude less than that following alkylating agents. Addition of involved-field irradiation increases the risk only marginally if at all, but using extended-field irradiation with chemotherapy results in a 3-fold increase of risk from 2-3% to 6-9% at 10-15 years. The leukemia risk is linearly related to the total dose of alkylating agents. Repeated courses of drug, as in the treatment of relapses, may produce a 40-fold increase in leukemia risk associated with the same amount of alkylating agent administered over 2 or more separate time periods. The leukemia risk after ABVD is much less than that following MOPP.
NHL risk is increased following treatment for HD even in the first 5 years, and cumulative risk reaches 4.1% after 20 years, leveling off by the middle of the second decade after treatment. The gastrointestinal tract has a high incidence of involvement. Increasing age at treatment of HD is correlated with an increased risk of secondary NHL or leukemia.
Second neoplasms other than leukemia or NHL are the most frequent challenge to patients cured of HD realizing their normal life span. The solid cancer risk continues well beyond the second decade with no indication of when, if ever, it diminishes. The 20-year cumulative risk of solid tumors is 13.1% compared with 8.1% for leukemia and NHL combined. The major carcinogenic role is attributed to irradiation because approximately two thirds of the second solid tumors arise within or at the edge of treatment fields.
Lung cancer has a 2- to 8-fold excess risk after radiotherapy or combined regimens containing alkylating agents. The excess risk of breast carcinoma presents predominantly in women undergoing irradiation before age 30 years. Breast carcinomas begin to appear at the end of the first decade after HD irradiation and continue to present at increased frequencies for at least 3 decades (the longest observation period so far). A 34% incidence of breast cancer 25 years after irradiation has been predicted by actuarial calculation for female patients having HD treated before the age of 20 years. Other neoplasms such as carcinomas of stomach, pancreas, and thyroid; sarcomas of bone and soft tissue; and melanoma also have an absolute risk that is still rising in the third decade following treatment. An increase in colorectal cancer has also been reported for pediatric patients who had HD.
Cardiovascular complications of Mantle irradiation are second only to new neoplasms as the most frequent cause of treatment-related mortality in patients with HD. The relative risk of cardiac death is modest (2.2-3.1), but the absolute risk is high (9.3-28 per 10,000 patients per year), with a cumulative risk of cardiac mortality after 22 years of 23% for males and 8% for females. Myocardial infarction accounts for more than two thirds of these deaths (15.5% of treated males and 3.5% of treated females at 22 years). Refinement of radiation technique, such as the introduction of equal anterior and posterior fractions, reduced fraction size, and routine left ventricular and subcarinal blocking to limit dosage to the entire cardiac silhouette, has led to almost quartering the risk of radiation damage to the pericardium, myocardium, and heart valves. However, there has been no reduction in deaths from myocardial infarction.
Patients treated for NHL can suffer late relapses at 7-10 years. An increased risk of developing acute non-lymphoblastic leukemia or other malignant neoplasms such as melanoma, HD, lung cancer, brain tumor, renal cancer, or bladder cancer has been observed with standard chemotherapy.
Depending upon the site of irradiation, acute adverse effects of radiotherapy include transient xerostomia, pharyngitis, fatigue, and weight loss.
Within a few months, patients can develop Lhermitte syndrome (paresthesia in the lower extremities upon flexion of the neck or thighs), which usually resolves spontaneously.
Pulmonary complications are radiation pneumonitis, which is severe in fewer than 5% of patients, and symptomatic pulmonary fibrosis, which occurs in fewer than 1% of patients.
Hypothyroidism develops in up to 30% of patients following Mantle irradiation.
Paraaortic irradiation is rarely associated with significant adverse effects.
Pelvic irradiation acutely induces transient diarrhea and bladder irritation associated with frequency. Chronic effects include potential long-term bone marrow suppression and sterility.
Common toxicities from chemotherapy include nausea and vomiting, marrow suppression, alopecia, mucositis, pneumonitis, and neuropathy. ABVD has an acute treatment-related mortality of 1%. Delayed effects of chemotherapy can include a risk of premature menopause and infertility, and a small risk of anthracycline-induced cardiac toxicity.
Following autologous stem cell transplantation, late nonrelapse mortality results primarily from chronic lung damage, infection, and secondary malignancies. Late pulmonary fibrosis occurs in up to 6% of patients, and late fatal infections occur in 1-2% of patients. The incidence of leukemia is similar to those receiving conventional chemotherapy, but the risk of secondary solid tumors is higher than in chemotherapy alone.
Prognosis:
In early-stage HD, factors that are associated with an adverse outcome include large mediastinal involvement, age older than 40 years, B symptoms, multiple sites, high erythrocyte sedimentation rate, high beta2-microglobulin, mixed-cellularity and lymphocyte-depleted histologies, and treatment with involved-field radiation.
For advanced HD, The International Prognostic Factors Project for Advanced Hodgkin's Disease has identified 7 adverse factors at diagnosis. These are an initial hemoglobin of less than 10.5 g/dL, albumin less than 4 g/dL, stage IV disease, male sex, white blood cell count greater than 15,000/mm3, absolute lymphocyte count of less than 600/mm3, and age older than 45 years. Each of these factors decreases the 5-year progression-free survival rate by 7-8%.
In patients with aggressive NHL, prognosis depends on age (older or younger than 60 years), serum LDH, performance status, stage, and extranodal involvement. Patients with 2 or more of these risk factors have a 50% or worse chance of 5-year overall survival. Response to treatment is also one of the most important prognostic indicators.
Patient Education:
n/a
MISCELLANEOUS Section 9 of 11
Medical/Legal Pitfalls:
As lymph nodes can wax and wane in size while the disease is progressing, early diagnosis of unexplained lymphadenopathy and appropriate referral is advised.
Special Concerns:
In elderly patients diagnosed with NHL, a CHOP regimen may be too toxic for patients with underlying coronary artery disease. Therefore, a doxorubicin-free regimen is preferred for indolent NHL, but in aggressive NHL the addition of doxorubicin significantly improves the chances of overall survival. Regimens with too much reduction in toxicity, such as CVP, have a lower efficacy when compared to CHOP. Hematopoietic growth factors may be especially useful in this patient population.
Patients who have AIDS and develop NHL usually have immunodeficiency combined with leukopenia and therefore tolerate chemotherapy poorly. Because of frequent CNS relapses, prophylactic intrathecal chemotherapy is the rule. Combining chemotherapy with colony-stimulating factors and antiretroviral therapy is being addressed.
PICTURES Section 10 of 11
Caption: Picture 1. CT scan of a patient with a natural killer (NK)/T-cell lymphoma of the right nasal cavity and maxillary sinus
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Caption: Picture 2. CT scan of the same patient as in Picture 1, 6 months after treatment with 4 cycles of EPOCH (ie, infused etoposide, doxorubicin, and vincristine with bolus cyclophosphamide and prednisolone)
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Caption: Picture 3. CT scan of a patient with a recurrence of stage I-AE angiocentric lymphoma of the left maxillary sinus, treated 7 years earlier with 4 cycles of ProMACE-MOPP (ie, prednisone, methotrexate, Adriamycin, cyclophosphamide, etoposide–mechlorethamine [nitrogen mustard], vincristine, procarbazine, and prednisolone) and 3,960 cGy of radiation
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Caption: Picture 4. CT scan of the same patient as in Picture 3, 2 years later after salvage therapy
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Caption: Picture 5. Fiberoptic nasal examination of a patient with natural killer (NK)/T-cell lymphoma of the right nasal cavity and maxillary sinus, whose CT scans are shown in Pictures 1 and 2
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BIBLIOGRAPHY Section 11 of 11
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NOTE:
Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this journal have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this article do not warrant the information in this article is accurate or complete, nor are they responsible for omissions or errors in the article or for the results of using this information. The reader should confirm the information in this article from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert. FULL DISCLAIMER
eMedicine Journal, September 11 2001, Volume 2, Number 9
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