AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Otolaryngologists are frequently involved in the diagnosis of lymphoma. A quarter of all extranodal lymphomas occur in the head and neck, and 8% of findings on supraclavicular fine-needle aspirate biopsy yield a diagnosis of lymphoma. In white populations, lymphoma is a more common cause of cervical lymphadenopathy than metastatic disease. Lymphoma is the second most common primary malignancy occurring in the head and neck and importantly, the incidence of aggressive non-Hodgkin lymphoma has risen steadily over recent decades.

Pathophysiology

Although a variety of histologic classification schemes have been used for lymphoma in the past, the World Health Organization (WHO) classification is currently used.

The WHO classification of lymphomas is as follows:

• Hodgkin lymphoma (HL)
  • Nodular lymphocyte predominant
  • Classic
  • Nodular sclerosis classic
  • Mixed cellularity classic
  • Lymphocyte-rich classic
  • Lymphocyte-depleted classic
• Non-Hodgkin lymphoma (NHL) - B-cell neoplasms
• • Precursor B-cell neoplasms
  • Precursor B lymphoblastic leukemia/lymphoma
  • Mature B-cell neoplasms
  • • Chronic lymphocytic leukemia, small lymphocytic lymphoma
    • Lymphoplasmacytic lymphoma
    • Splenic marginal-zone lymphoma
    • Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT)
    • Nodal marginal-zone lymphoma
    • Follicular lymphoma
    • Mantle-cell lymphoma
    • Diffuse large B-cell lymphoma (DLBCL)
    • Mediastinal (thymic) large B-cell lymphoma
    • Intravascular large B-cell lymphoma
    • Primary effusion lymphoma
    • Burkitt lymphoma/leukemia
  • B-cell proliferations of uncertain malignant potential
  • • Lymphomatoid granulomatosis
    • Posttransplantation lymphoproliferative disorder, polymorphic
• NHL - T-cell and natural killer (NK)–cell neoplasms
• • Precursor T-cell neoplasms
  • • Precursor T lymphoblastic leukemia or lymphoma
    • Blastic NK-cell lymphoma
  • Mature T- and NK-cell neoplasms
  • • Adult T-cell leukemia or lymphoma
    • Extranodal NK- or T-cell lymphoma, nasal type
    • Enteropathy-type T cell lymphoma
    • Hepatosplenic T-cell lymphoma
    • Subcutaneous panniculitis-like T cell lymphoma
    • Mycosis fungoides
    • Sezary syndrome
    • Primary cutaneous anaplastic large cell lymphoma
    • Peripheral T cell lymphoma, unspecified
    • Angioimmunoblastic T cell lymphoma
    • Anaplastic large cell lymphoma

HL is characterized by the presence of Reed-Sternberg (RS) cells, and the subtype diagnosis depends on the cytoarchitectural milieu in which the RS cells or their variants are found. Nodular sclerosis, mixed cellularity, lymphocyte-rich and lymphocyte-depleted subtypes are collectively termed classic HL. Nodular sclerosis is the most common subtype, especially in patients younger than 40 years, followed by mixed cellularity. Lymphocyte-predominant HL, more common in young men than in others, behaves more like a low-grade B-cell lymphoma than other tumors. In general, patients who are elderly, those who live in developing countries, and those infected with HIV are most likely to have widespread disease with systemic symptoms at diagnosis.

Approximately 85% of NHLs are B-cell lymphomas. The most common indolent NHL is follicular lymphoma, which is derived from germinal center B cells. Other indolent histologies are lymphoplasmacytoid lymphoma, which has characteristics of B cells differentiating toward plasma cells, and marginal-zone lymphoma derived from the memory B-cell compartment, which includes MALT lymphomas. DLBCL is the most common aggressive NHL. On the basis of messenger RNA microarrays, most cases have profiles that indicate an origin from a germinal center B cell or a postgerminal-center activated B cell. Mantle-cell lymphoma and Burkitt lymphoma are aggressive NHLs that have the characteristics of normal B cells residing in the mantle zone or in the germinal center of a lymphoid follicle, respectively.

Cutaneous T-cell lymphomas, such as mycosis fungoides, can be indolent. However, many T-cell NHLs are aggressive malignancies.

Frequency

United States

Lymphoma is the sixth most common cancer in the United States, with an annual incidence of 64,000 estimated cases. Approximately 88% of these cancers are NHLs. The incidence of NHL has doubled over the last 20 years because of the increase in AIDS-related lymphoma (ARL); an increase in the detection of lymphoma; and for other, poorly understood reasons.

International

The different histologic subtypes of NHL have various distributions and geographic predilections. The frequency of NK/T-cell lymphoma is increased in China, in Taiwan, in Southeast Asia and in parts of Africa where Burkitt lymphoma is endemic.

Mortality/Morbidity

For HL, overall 5-year survival rates in the United States are 83% for whites and 77% for African Americans. For NHL, the 5-year survival rate is 53% for whites and 42% for African Americans.

Race

HL and, to a lesser extent, NHL are more common in whites than in African Americans or Hispanics. Other races such as Asian/Pacific islanders or American Indians have the lowest incidence and mortality rates.

Sex

The incidence of both HL and NHL are higher in men than in women, especially among older patients.

Age

• In the United States, HL has a bimodal age distribution, with a peak incidence in people aged 20-34 years and a second peak in whites aged 75-79 years and in African Americans aged 55-64 years. In Japan, the early peak is absent, and in some developing countries, the early peak shifts into childhood.
• The mortality rate increases with age. For example, incidence and mortality rates for NHL increase with age. In addition, Burkitt lymphoma represents 40-50% of all pediatric lymphomas but is uncommon in adults without AIDS.
• Lymphoblastic lymphoma most commonly affects men aged 20-40 years who have lymphadenopathy and/or a mediastinal mass.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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History

Lymphoma may be nodal or extranodal. Extranodal lymphoma is usually NHL and worsens the patient's prognosis. HL extends by means of contiguous nodal spread; therefore, it is often localized and frequently occurs in the mediastinum. NHL tends to spread hematogenously and is often systemic at diagnosis.

• A nodal presentation of HL is typically with 1 or more small-to-medium, rubbery lymph nodes in the neck, which may wax or wane in size but grow over time.
• • Biopsy should be considered when a firm lymph node larger than 1 cm that is not associated with infection and that persists longer than 4 weeks.
  • In 2-5% of patients with HL, involved nodes can become painful after they drink alcoholic beverages.
• NHL may manifest in the cervical region and lymphoid tissue of the Waldeyer ring. It appears as a mass in the oropharynx or nasopharynx.
• • Unilateral tonsillar enlargement is highly suggestive of malignancy.
  • Extranodal disease, such as primary lymphoma, of the oral cavity is less common than other findings; this disease usually arises in the tongue base.
  • In contrast to squamous cell carcinoma, NHL is bulky, fleshy, and nonulcerating.
• Extranodal NK/T-cell lymphoma, nasal type (formerly called lethal midline granuloma), can manifest as an ulcerative destructive lesion of the nose, sinuses, and face.
• • This lesion is usually associated with Epstein-Barr virus and worsens the patient's prognosis compared with that of patients with B-cell lymphoma.
  • The disease often manifests with a nasal mass, epistaxis, and/or nasal obstruction. (See Image 5 for a video of a fiberoptic examination of an NK/T-cell lymphoma in the right nasal cavity and maxillary sinus.)
• Lymphoma in the thyroid is more common than anaplastic carcinoma of the thyroid. It manifests as a neck swelling, hoarseness, dysphagia, or neck pressure/tenderness.
• • Advanced disease can cause facial edema and Horner syndrome.
  • Extranodal marginal-zone B-cell lymphoma of MALT lymphoma occurs in the head and neck, in the ocular adnexa, and in thyroid areas.
  • Patients with Sjögren syndrome are at increased risk for MALT lymphomas in the oral mucosa.
  • Lymphoma involving the base of the skull or CNS can cause cranial nerve palsies, facial pain, hearing loss, vertigo, proptosis, or visual symptoms.
• Constitutional symptoms, designated B symptoms, may occur in up to one third of patients with lymphoma.
• • B symptoms include weight loss greater than 10% of the patient's previous body weight, temperatures higher than 38°C without evidence of infection, and/or drenching night sweats.
  • Symptoms such as bony pain, headaches, or GI discomfort may indicate 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 that occur in 10% of patients.

Physical

Full otorhinolaryngologic and neck examination including fiberoptic examination, in addition to complete physical 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 (SVC) 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 manifests 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 HL is increased 10-fold in same-sex siblings and by as much as 100-fold in identical twins. This observation implies genetic factors in the etiology.
• • Chromosomal abnormalities are common in lymphomas.
  • Aneuploidy occurs in HL, and translocations and deletions mark NHL, such as the c-myc translocation of Burkitt lymphoma and the bcl-2 translocation found in most follicular lymphomas.
• Infectious agents implicated in the pathogenesis of some lymphomas include Epstein-Barr virus, HIV-1 (aggressive NHL occurs in 10-30% of patients with AIDS), Helicobacter pylori, human t-cell lymphotropic virus-1 (HTLV-1), hepatitis B and C viruses, human herpes virus 8, Borrelia burgdorferi, Chlamydia psittaci, and Campylobacter jejuni.
• Chronic inflammation increases the risk of lymphoma, such as a MALT lymphoma arising in the salivary gland in 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 lymphoma.
• Immunosuppressive medications, for example those used following organ allotransplantation, increase 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  

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• Clinical
• Differentials
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Other Problems to be Considered

The differential diagnosis of lymphadenopathy; extranodal masses in the salivary glands; retro-orbital, thyroid and oral-pharyngeal masses or lesions encompass a wide range of benign and malignant processes other than lymphoma. Reactive lymphoid processes, which may appear as pseudolymphomas, may be difficult to distinguish from lymphoma. Indeed, clonal expansion of benign B or T-cells may occur in some reactive conditions. Adequate biopsy is essential for proper diagnosis, but pathologic interpretation must be considered in light of the patient's medical presentation and the biology of the lymphoma subtype.

Common differential diagnoses to be considered are listed below.

Other neoplasms

Squamous cell carcinoma
Nasopharyngeal carcinoma
Thyroid carcinoma

Generalized lymphadenopathy from infectious etiologies, such as bacteria, viruses (eg, Epstein-Barr virus [infectious mononucleosis], cytomegalovirus, HIV), and parasites (eg, 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  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Laboratory studies of the following are indicated.
• • Complete blood cell count
  • Serum chemistries including calcium, phosphate, and uric acid levels
  • Liver function, including lactate dehydrogenase values (An elevated level of lactate dehydrogenase is an adverse prognostic biomarker.)
  • ESR in HL
  • HIV and hepatitis B and C viruses, as clinically indicated

Imaging Studies

• Chest radiography is essential.
• CT scanning of the chest, abdomen, and/or pelvis is necessary for the evaluation of mediastinal, retroperitoneal, and mesenteric adenopathy. CT scans miss splenic involvement in 20-30% of cases of limited stage HL.
• CT scanning of the head and/or neck is mandatory for patients with a head and neck presentation; localized disease; or symptoms such as cranial neuropathies, hearing loss, vertigo, or visual changes.
• MRI is indicated for evaluating the brain and/or spinal cord as indicated.
• Positron emission tomography (PET) scanning should be ordered as indicated.

Other Tests

• Immunohistochemical analysis of the tumor is essential for diagnosis and may aid in identifying monoclonal antibody targets such as CD20 (rituximab) or CD52 (alemtuzumab). Cytogenetic analysis may be useful in select cases.
• Polymerase chain reaction analysis helps in evaluating for B- or T-cell clonality or for minimal residual disease, eg, t(14;18).

Procedures

• Nasopharyngeal laryngoscopy is essential. Perform this as the initial investigation to evaluate for a neoplasm of the upper aerodigestive tract that is accessible for biopsy.
• Fine-needle aspiration cytology is also essential. This test is useful for the initial investigation of neck lymphadenopathy for differentiating squamous cell carcinoma from lymphomas, thyroid tumors, and salivary gland tumors.
• Excisional lymph-node biopsy is essential in HL and NHL.
• • Needle aspiration and/or biopsy are not adequate for the primary histologic diagnosis because the architectural features of the tissue are important.
  • A biopsy sample should be obtained from the lump through an incision that can itself be excised and incorporated into a radical neck dissection if the histology indicates squamous cell carcinoma. In most cases, the unfixed node should be sent immediately to the laboratory for analysis.
• Bone marrow aspiration and biopsy are also essential. Results are positive in as many as 70% of patients with indolent NHL. In disseminated disease, malignant cells may be found in the bone marrow, spinal fluid, ascites fluid, or pleural fluid.
• Lumbar puncture may be indicated.
• • Lumbar puncture should be performed routinely in all patients with HIV infection in addition to patients with specific histologic subtypes such as Burkitt lymphoma and lymphoblastic lymphoma.
  • Lumbar puncture is also used when possible symptoms of CNS disease are present after head CT or MRI shows no evidence of mass effect.
  • In addition to cytology, the CSF should be evaluated with flow cytometry, as recent evidence has demonstrated that cytology may not help in detecting some cases with positive results on flow cytometry.
• Staging laparotomy or laparoscopy for HL may be needed. CT and other imaging modalities are not reliable in diagnosing occult splenic and nodal disease.
• • Historically, staging laparotomy was often included in the initial evaluation of patients with HL, as this was the only way to detect occult splenic disease. Because chemotherapy is usually incorporated into the initial treatment of HL, it is rarely done now, and really indicated only in patients in whom the assessment is required to optimize treatment.
  • Staging laparotomy includes biopsy of selected lymph nodes in the retroperitoneum, splenectomy, and several needle and wedge biopsy procedures in the liver. Laparoscopy with laparoscopic sonographic probes can be used to detect small intrahepatic and lymph-node metastases, with a sensitivity and specificity that approaches those of laparotomy.
  • In the past, the initial clinical stage changed in nearly one third of all patients with HL because of staging laparotomy. About one third of normal-sized spleens were found to be infiltrated with tumor, and 35% of patients with clinical splenomegaly had no histologic evidence of disease. However, a randomized study did not demonstrate a survival advantage in patients with surgically staged disease compared with those with clinically staged disease.
  • The use of prognostic factors is replacing staging laparotomy in identifying HL patients suitable for radiotherapy alone.
• Diagnostic tonsillectomy may be indicated if lymphoma of the tonsils is suspected.
• • Risk factors for malignancy in the tonsils are tonsillar asymmetry, a history of cancer, palpable firmness or a 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 1 of the risk factors listed above had malignancy on pathologic evaluation of the tonsils.

Histologic Findings

Accurate histologic diagnosis is the main guide for the modality of treatment to be used in NHL. A pathologist experienced in lymphoma diagnosis uses immunophenotyping by immunocytochemistry and/or flow cytometry 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. Of interest, 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 is used to stage lymphomas. Although it was originally designed for HL and based on the contiguous lymphatic mode of spread of HL, it is used for cases of NHL in which hematogenous dissemination is prevalent. The Ann Arbor staging classification is as follows:
• • 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 and possibly the spleen
  • Stage IV - Disseminated involvement of 1 or more extralymphatic organs with or without lymph node involvement and/or involvement of the bone marrow or liver
• Other designations are as follows:
• • Letter designations
    • A - Asymptomatic, or B constitutional symptoms: This type is characterized by unexplained, persistent or recurrent fever with temperature higher than 38°C or by recurrent and drenching night sweats within 1 month, or by unexplained loss of more than 10% the person's body weight within 6 months.
    • E - Extranodal: This form is characterized by limited and direct extension into extralymphatic organ from an adjacent lymph node.
    • X - Bulky disease: In this form, the width of the mediastinal tumor is greater than one third the transthoracic diameter at T5/6, or the diameter of the tumor diameter is larger than 10 cm.
  • Suffices
    • Suffix B indicates the presence of systemic symptoms.
    • Suffix A indicates the absence of systemic symptoms.
    • E indicates the presence of localized extralymphatic disease.
  • Stage IV indicates disseminated disease, or multifocal extranodal, bone marrow, or liver involvement. Bone involvement must be separated from bone marrow involvement because the latter is always defined as disseminated disease.
• The clinical stage is defined by the extent of disease based on physical findings and findings on other noninvasive studies. The pathologic stage is defined by data obtained from invasive tests, including biopsy of specimens obtained from different sites, usually during staging laparotomy.
• Treatment and prognosis in both HL and NHL depends on the disease stage, on biomarkers, and on tumor biology. In NHL and in some types of HL, the histologic subtype dictates therapy.
• In the past, early-stage HL was usually treated with radiotherapy alone, but now, it is generally treated with a combination of radiotherapy and chemotherapy. Disseminated disease is treated by using chemotherapy with or without radiotherapy.
• In some patients with indolent NHL who have early stage localized disease, radiotherapy alone may be an option. For aggressive lymphomas, chemotherapy is standard, but may be used in conjunction with radiotherapy. Radiotherapy is the primary treatment modality in early stage NK/T-cell lymphomas.

TREATMENT

Section 6 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

In the past, the standard chemotherapeutic regimen used for HL was mechlorethamine (nitrogen mustard), vincristine, procarbazine, and prednisolone (MOPP). However, this regimen was associated with infertility, a 2% incidence of myelodysplasia/acute leukemia at 4-6 years after treatment, and a 3% incidence of fatal febrile neutropenia. ABVD is a regimen of doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine. ABVD is superior to MOPP alone and now considered the standard of care in HL. The incidence of infertility is lower with ABVD than with MOPP, but fatal pulmonary toxicity can occur with bleomycin.

In advanced HL, intensified regimens such as the escalated BEACOPP (ie, cyclophosphamide, doxorubicin, etoposide, procarbazine, prednisolone, vincristine, and bleomycin with granulocyte colony-stimulating factor) are being investigated. However, ABVD remains the standard of care.

• Hodgkin lymphoma - Initial therapy
• • Classic HL: For the purpose of selecting therapy, the European Organization for Research and Treatment of Cancer (EORTC) divides patients with early-stage (I or II) classic HL into favorable or unfavorable groups based on the presence of at least 1 of the following adverse factors: large mediastinal mass, age > 50 years, elevated ESR, and involvement of 4 or more lymph-node regions. Advanced stages are III and IV.
  • • Stage I or II favorable disease: Although extended-field radiotherapy alone was the standard of care for several years, most groups now favor combined chemotherapy and radiation, eg, 4 cycles of ABVD with radiation of 20-30 Gy to the involved field. Some groups advocate radiation alone and chemotherapy alone for low-risk stage I neck disease.
    • Stage I and II unfavorable disease: Chemotherapy with or without radiation is standard of care.
    • Stage III or IV disease: For advanced disease, combination chemotherapy, such as ABVD, is the standard of care. Patients generally receive 2 cycles of therapy beyond complete remission (for a minimum of 6 and maximum of 8 cycles). Patients with bulky mediastinal disease often receive consolidative irradiation. Radiation therapy is sometimes omitted in select patients who have complete remission and negative PET scans.

      Although the outcome with ABVD in these stages is good (event-free survival of about 70%) and though it remains the standard of care, intensive regimens are being investigated. The Stanford V regimen, which combines chemotherapy (mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone) with consolidative radiotherapy to bulky sites produces a progression-free survival of over 80%. The German Hodgkin Lymphoma study group investigated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP). Although this therapy was associated with increased toxicity, elevated-dose BEACOPP has shown promising results in terms of reducing induction failures and decreased rates of treatment failure.

  • In contrast to classic HL, nodular lymphocyte predominant HL is a rare subtype that is biologically similar to indolent B-cell lymphoma.
  • • The 10-year survival rate for patients with early-stage disease without treatment is greater than 80%; therefore, the role of therapy in asymptomatic patients is unclear, nevertheless radiation or rituximab alone is often used.
    • Advanced-stage disease is usually treated like HL in patients with an unfavorable prognosis, though regimens for aggressive NHL may be considered.
    • Rituximab has demonstrated good activity in this disease.
• Hodgkin lymphoma - Therapy for relapsing or refractory disease
• • For patients who have had early-stage disease and relapse after receiving radiation therapy alone, regimens such as ABVD are highly effective and result in high relapse-free survival rates of about 70% at 10 years.
  • For patients who have relapse after receiving combined-modality therapy or chemotherapy alone, the same or another combination chemotherapeutic regimen can be used if the duration of remission exceeds 12 months. The relapse-free survival at 5 years is 50%.
  • Regimens used for salvage therapy in HL include ABVD; etoposide, methylprednisolone, high-dose cytarabine, and cisplatin (ESHP); ifosfamide, cisplatin, and etoposide (ICE); and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and hydroxyl-daunomycin (DA-EOPCH).
  • For patients in whom induction fails or who have a relapse within a year of initial chemotherapy, the outcome with standard chemotherapy is poor. High-dose chemotherapy (with or without radiotherapy) followed by autologous hematopoietic stem-cell transplantation is the standard therapy for patients with responsive disease.
  • Autologous stem-cell transplantation should also be seriously considered for patients with sensitive disease who have a relapse after 12 months.
  • Patients with disease after curative options have been exhausted are often still responsive to chemotherapy. Such patients may achieve long-term benefit from chronic treatment with single agents, such as vinblastine, gemcitabine, or etoposide. In addition, investigational therapies for HL include use of monoclonal antibodies, radioimmunoconjugates, tumor vaccines, or immunotherapy and also allogeneic stem-cell transplantation.
• Non-Hodgkin lymphoma
• • Indolent B-cell lymphoma: These lymphomas include multiple subtypes, such as follicular and small lymphocytic lymphoma, and they are generally considered incurable with conventional therapy. The tumors are characterized by an indolent course, and because patients can remain well for several years without therapy, a watch-and-wait strategy is often used. When this is the case, indications for therapy include symptomatic or aggressive disease, bulky lymphadenopathy, hypersplenism, or bone-marrow infiltration causing cytopenias. Recently, evidence has shown that patients who are symptomatic and have untreated advanced stage follicular lymphoma, may benefit from receiving the combination of CHOP chemotherapy with rituximab. 
  • • In select patients with early-stage follicular lymphoma, irradiation alone is associated with a 10-year disease-free survival rate of over 60%. Although no prospective study has been performed to compare irradiation with observation, findings from a recent retrospective analysis from Stanford University suggest that irradiation may not improve the survival of patients with early disease over observation alone.
    • Several drugs are effective. Fludarabine has high response rates and is useful in untreated and previously treated patients, as are alkylating agents such as cyclophosphamide and prednisone. Anti-CD20 monoclonal antibody is increasingly used; it is effective in treated patients and in up to 73% of untreated patients. In combination with fludarabine or regimens such as cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone (CHOP), rituximab is effective and may have a role in maintenance therapy. A phase III study showed that rituximab and CHOP (R-CHOP) improved survival compared with CHOP, raising the issue of whether R-CHOP should be the new standard.
    • Radioimmunotherapy is a relatively new treatment for relapsing follicular lymphoma. It involves radiotherapy targeted to tumor tissue by conjugating anti-CD20 antibody to yttrium-90 or iodine-131. Ibritumomab tiuxetan (Zevalin) and tositumomab (Bexxar) are approved for relapsing or refractory follicular lymphoma and have an overall response rate of up to 80%. Their role in previously untreated disease has still not been established and remains under investigation.
    • Both autologous and allogeneic stem-cell transplantation are being evaluated in follicular lymphoma. Idiotype vaccination, made by conjugating and immunologically manipulating tumor-specific antigen for in vitro and bcl-2 antisense therapy is aimed at decreasing bcl-2 oncoprotein. 
  • Aggressive B-cell lymphomas: These include DLBCL, Burkitt lymphoma, mantle-cell lymphoma, and lymphoblastic lymphoma. With the exception of mantle-cell lymphoma, these tumors are potentially curable.
  • • DLBCL is the most common histologic subtype. All stages of disease require systemic chemotherapy; irradiation alone is inadequate. Early-stage (I or II) disease may be treated with combined modalities, though the benefit of irradiation is controversial and it adds the problem of long-term toxicities which can be very serious.
    • Chemotherapy followed by consolidation radiotherapy has 5-year overall survival and progression-free survival rates of up to 80%. Rituximab-based chemotherapy and the observation that radiation does not improve overall survival strengthen the case for immunochemotherapy alone.
    • Primary mediastinal DLBCL (PMBCL) is a potential exception in that consolidation radiotherapy appears to be necessary after standard chemotherapy. However, results with DA-EPOCH and rituximab (DA-EPOCH-R) suggest that this regimen may obviate the need for radiation treatment in most patients. This is particularly important in this disease, considering that it typically occurs in young women who have a much higher risk of developing breast and other cancers after receiving mediastinal radiation.
    • Stage III or IV DLBCL is treated with combination chemotherapy. CHOP, developed more than 25 years ago, remains the standard combination and cures about one third of all cases. In a randomized study, the addition of rituximab improved event-free and overall survival and has led to the emergence of R-CHOP as the de facto standard in DLBCL.
    • Several other regimens are used to treat DLBCL. In patients with a poor prognosis over 60 years, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ADVBP) is associated with improved overall and event-free survivals compared with CHOP. DA-EPOCH-R has progression-free and overall survival rates of approximately 80% at 2-year follow-up. Modified CHOP regimen, such as dose-dense CHOP (given every 2 wk) and etoposide plus CHOP (CHOEP) have also been evaluated, but no definitive and convincing evidence suggests that they should replace standard R-CHOP given on a 21-day schedule. Autologous stem-cell transplant consolidation in untreated DLBCL is under investigation, but most previous results do not suggest any benefit over standard approaches.
    • Relapsing DLBCL should be treated with salvage chemotherapy, such as rituximab and ICE (R-ICE), ESHAP, or DA-EPOCH-R. Patients with responsive disease are often treated with autologous stem-cell transplantation, though cure rates are relatively low. In patients who have a chemosensitive relapse without marrow involvement of the bone, high-dose therapy usually offers the best opportunity for a response and remission. The value of autologous transplantation at relapse may diminish because more patients are being cured with R-CHOP (compared with CHOP in the past) given as initial therapy.¹
    • Primary CNS lymphoma (PCNSL) is a rare DLBCL usually confined to the CNS. Although they have DLBCL histology, their clinical behavior is distinct from systemic DLBCL, a feature that indicates different biology. Several important drugs used for the treatment of systemic DLBCL achieve low CNS concentrations because they do not cross the blood-brain barrier. Methotrexate, which has excellent CNS penetration, is the core of chemotherapeutic regimens for PCNSL; alone, it produces response rates up to 50%. Irradiation is also effective, but responses are short lived. New treatment paradigms combine several drugs with good CNS penetration and rituximab, with or without irradiation.
  • Other aggressive B-cell lymphomas
  • • Burkitt lymphoma is a highly aggressive B-cell lymphoma that can cause disease in the head and neck region. It is curable with systemic chemotherapy. Intensive regimens are typically used and include intrathecal chemotherapy. Lymphoblastic lymphoma is usually of the T-cell phenotype and usually affects the mediastinum; this is curable with aggressive chemotherapy.
    • Mantle-cell lymphoma is a B-cell lymphoma that has a moderately aggressive clinical course. Current treatments are rarely curative, and patients have a median survival of 3-5 years. Treatments range from aggressive combination chemotherapy to allogeneic transplantation. In asymptomatic patients, particularly in older patients, a watch-and-wait approach is reasonable. The disease has a high predilection for the GI tract, though it may involve the tonsils and head and neck nodes. Recently, bortezomib was found to be very effective in the treatment of relapsed and refractory mantle cell lymphoma and is being evaluated in the up-front setting.
  • Aggressive B-cell lymphomas in patients with immunocompromise
  • • Patients with HIV infection have a significantly increased incidence of lymphoma. The risk is increased approximately 1000-fold for Burkitt lymphoma and 400-fold for aggressive lymphoma. Many of these lymphomas are highly curable and should be treated with systemic chemotherapy. Although adding rituximab to chemotherapy to treat these tumors is controversial, rituximab with chemotherapy does appear to improve tumor response, and the authors recommend its inclusion.
    • The infusional EPOCH regimen is effective in this setting, and produced a 72% overall survival at a median follow-up time of 53 months.
    • Lymphomas are also seen after solid-organ transplantation, when they are generally associated with an infection with Epstein-Barr virus (EBV).
    • The spectrum of disease is wide, and treatment options include the withdrawal of immunosuppression, rituximab, and chemotherapy. Whether highly active antiretroviral therapy (HAART) should be suspended during chemotherapy is controversial
• T-cell lymphomas: Patients with T-cell lymphoma can present with disease in the head and neck region, but these tumors are less common than B-cell lymphomas. In general, T-cell lymphomas involve the nodal regions, but skin involvement with cutaneous T-cell lymphomas can also occur. Extranodal NK/T-cell lymphomas specifically involve the nasal sinuses. These lymphomas are derived from mature T-cells and have been subdivided into a number of distinct pathologic entities. However, a portion does not fit into a specific subtype and are classified as peripheral T-cell lymphoma unspecified (PTCL-U).
• • Extranodal NK/T-cell lymphoma, nasal type: The sites of predilection for this particular disease are the nasal cavity, nasopharynx, and palate. Patients with this are variable, but localized disease can be treated very effectively with radiation. The prognosis for those with disseminated disease is poor.
  • Other peripheral T-cell lymphomas: Anaplastic large-cell lymphoma (ALCL) tends to occur in young patients, and the outcome with systemic chemotherapy is good. The long-term survival rate is approximately 70% with chemotherapy. Angioimmunoblastic T-cell lymphoma is usually associated with immunodeficiency. It tends to be aggressive, and results of standard therapy are poor. Those with PTCL-U also have poor outcomes, with a low incidence of cure. T-cell lymphoblastic lymphomas are highly aggressive and treated with regimens that include intrathecal chemotherapy.

Surgical Care

Surgery is only performed in select cases.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

For a general discussion of chemotherapeutic regimens, see Treatment. See also the following articles: For adults, see Lymphoma, Non-Hodgkin and Lymphoma, B-Cell, and for children, please see Non-Hodgkin Lymphoma and Hodgkin Disease.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• Otolaryngologists are required to perform regular nasopharyngeal laryngoscopy in patients whose initial presentation involved findings in the nasopharyngeal cavity, mouth, or sinuses.
• In addition, otolaryngologists may be required to perform biopsy when suspicious lesions are present in these areas. They may also need to perform biopsy for suspicious neck nodes during follow-up to obtain a histopathologic specimen to examine for recurrence.

Deterrence/Prevention

• For patients with HL anticipating mantle irradiation, abstinence from smoking is essential to minimize their risk of lung carcinoma.
• In addition, patients who receive bleomycin are at risk for lung toxicity.
• When possible, mantle irradiation should be avoided in people who smoke and in young women because of the risks of lung and breast cancer, respectively, as secondary neoplasia is the most common cause of long-term treatment-related mortality.

Complications

• Because of the high cure rates with lymphoma, particularly in HL, the long-term adverse effects of therapy are important considerations. Mortality from causes other than HL overtakes HL deaths at 15 years after diagnosis, and because the median age at diagnosis is 44 years, most are treatment-related deaths. Deaths from second malignancies become the most important cause of death other than HL itself.
• • The risk of leukemia is maximal at 5-10 years after treatment. Leukemia rarely occurs after the second decade. Although it is observed after irradiation alone, the relative risk is an order of magnitude less than the risk after therapy with alkylating agents.
    • The addition of involved-field irradiation increases the risk only marginally if at all, but extended-field irradiation with chemotherapy increases the risk from 2-3% to 6-9% at 10-15 years.
    • The risk of leukemia is linearly related to the total dose of alkylating agents. Repeated courses of drug, as in the treatment of relapses with the same amount of alkylating agent over 2 or more periods, may increase the risk 40-fold.
    • The risk of leukemia after ABVD is less than that after MOPP therapy.
  • The risk of NHL is increased after treatment for HL, even in the first 5 years, and the cumulative risk is 4.1% after 20 years and levels off by the middle of the second decade after treatment.
    • The incidence of GI involvement is high.
    • Increasing age at treatment of HL is correlated with an increasing risk of secondary NHL or leukemia.
  • After patients are cured of HL, second neoplasms other than leukemia or NHL are the most common challenge in achieving a normal life span.
    • The risk of solid cancer 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 in or at the edge of treatment fields.
  • The risks of other cancer may increase.
    • The risk of lung cancer increases 2- to 8-fold after radiotherapy or combined regimens containing alkylating agents.
    • The excess risk of breast carcinoma predominantly affects women undergoing irradiation before the age of 30 years. Breast carcinomas begin to appear at the end of the first decade after HL irradiation and continue at increased frequencies for at least 3 decades (longest observation period so far). Calculations in women with HL who were treated before the age of 20 years predict a 34% incidence of breast cancer at 25 years after irradiation.
    • The absolute risk of carcinomas of stomach, pancreas, and thyroid; sarcomas of the bone and soft tissue; and melanomas continues to increase in the third decade after treatment.
    • An increase in colorectal cancer has also been reported in pediatric patients who had HL.
  • Cardiovascular complications of mantle irradiation are second only to new neoplasms as the most frequent cause of treatment-related mortality in patients with HL.
    • The relative risk of cardiac death is modest (2.2-3.1), but the absolute risk is high (9.3-28 cases per 10,000 patients per year), with a cumulative risk of cardiac mortality after 22 years of 23% for men and 8% for women.
    • Myocardial infarction accounts for more than two thirds of these deaths (15.5% of treated men and 3.5% of treated women at 22 y).
    • Refinement of irradiation techniques, such as the introduction of equal anterior and posterior fractions, reduced fraction size, and routine left ventricular and subcarinal blocking to limit doses to the entire cardiac silhouette, has led to almost quartering of the risk of radiation damage to the pericardium, myocardium, and heart valves. However, the number of deaths from myocardial infarction has not decreased.
• Other complications of radiation therapy are hypothyroidism (after mantle irradiation), xerostomia, pharyngitis, fatigue, and weight loss.
  • 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.
  • Para-aortic irradiation is rarely associated with clinically significant adverse effects.
  • Pelvic irradiation induces acute, transient diarrhea and bladder irritation associated with urinary frequency.
  • Long-term effects include a potential for long-term bone-marrow suppression and sterility.
• Patients treated for NHL can have late relapses at 7-10 years.
  • Patients receiving standard chemotherapy have an increased risk of acute nonlymphoblastic leukemia or other malignant neoplasms, such as melanoma, HL, lung cancer, brain tumor, renal cancer, and bladder cancer.
  • In patients with NHL, the late effects of radiation therapy are similar to those of HL (as described above).
• Common toxicity-related effects of chemotherapy are nausea and vomiting, marrow suppression, alopecia, mucositis, pneumonitis, and neuropathy. Delayed effects of chemotherapy can include a risk of premature menopause and infertility and a small risk of anthracycline-induced cardiac toxicity.
• After autologous stem-cell transplantation, late, nonrelapse mortality is primarily due to 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%. The incidence of leukemia in patients receiving transplantation is similar to the incidence in those receiving conventional chemotherapy, but the risk of secondary solid tumors is higher than with chemotherapy alone.

Prognosis

• In early-stage HL, factors associated with adverse outcomes are large mediastinal involvement, age older than 40 years, B symptoms, involvement at multiple sites, high ESR, high beta2-microglobulin, mixed-cellularity and lymphocyte-depleted histologies, and treatment with involved-field radiation.
• For advanced HL, the International Prognostic Factors Project for Advanced Hodgkin's Lymphoma identified 7 adverse factors at diagnosis: initial hemoglobin level of less than 10.5 g/dL, albumin value less than 4 g/dL, stage IV disease, male sex, WBC count greater than 15,000 cells/mm³, absolute lymphocyte count of less than 600 cells/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 B-cell NHL (eg, DLBCL), the prognosis depends on age (<60 or >60 y), serum LDH levels, performance status, stage, and extranodal involvement. Response to treatment is also an important prognostic indicator.

Patient Education

• For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. See also eMedicine's patient education articles Brain Cancer and Cancer of the Mouth and Throat.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Because lymph nodes can wax and wane in size while the disease progresses, early diagnosis of unexplained lymphadenopathy and appropriate referral is advised.

Special Concerns

• In elderly patients 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. However, in aggressive NHL, the addition of doxorubicin significantly improves the likelihood of overall survival. In such patients, a regimen such as DA-EPOCH may be preferred because the infusion of doxorubicin reduces cardiac toxicity. Hematopoietic growth factors may be especially useful in this patient population.
• Patients who have AIDS and who develop NHL usually have immunodeficiency combined with leukopenia and therefore do not tolerate chemotherapy as well as HIV-negative patients.
• • Because of frequent CNS relapses, prophylactic intrathecal chemotherapy is the rule.
  • DA-EPOCH (with or without rituximab) is a standard regimen for AIDS-related lymphomas.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 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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Media type:  CT

Media file 2:  CT scan of the same patient as in Image 1, 6 months after treatment with 4 cycles of DA-EPOCH (ie, infused etoposide, doxorubicin, and vincristine with bolus cyclophosphamide and prednisone).
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Media type:  CT

Media file 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 prednisone) and 3960 cGy of radiation.
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Media type:  CT

Media file 4:  CT scan of the same patient as in Image 3, 2 years after salvage therapy.
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Media type:  CT

Media file 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 Images 1 and 2.
	View Full Size Image
Media type:  Video

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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