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. Lymphoma is the second most common primary malignancy occurring in the head and neck. Nasopharyngeal laryngoscopy, fine-needle aspiration cytology, excision lymph-node biopsy (in Hodgkin lymphoma [HL] and non-Hodgkin lymphoma [NHL]), and bone marrow aspiration and biopsy are essential in the workup of patients with head and neck lymphomas. ABVD, a regimen of doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine, is considered the standard of care in HL.
See the image below.
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CT scan of a patient with a natural killer (NK)/T-cell lymphoma of the right nasal cavity and maxillary sinus.
Signs and symptoms
Lymphoma may be nodal or extranodal. Common symptoms include the following:
Nodal presentation of Hodgkin lymphoma (HL) – 1 or more small-to-medium, rubbery lymph nodes in the neck, which may wax or wane in size but grow over time
Non-Hodgkin lymphoma (NHL) – Mass in the oropharynx or nasopharynx
Extranodal natural killer (NK)/T-cell lymphoma, nasal type – Ulcerative destructive lesion of the nose, sinuses, and face
Lymphoma in the thyroid – Neck swelling, hoarseness, dysphagia, or neck pressure/tenderness
Constitutional symptoms (B symptoms) – These may occur in up to one third of patients with lymphoma
Full otorhinolaryngologic and neck examination including fiberoptic examination, in addition to complete physical examination, is indicated. Physical findings that may be noted include the following:
Painless or mildly tender peripheral adenopathy in cervical, axillary, inguinal, and femoral regions
Superior vena cava syndrome and pleural effusions (from a mediastinal mass)
In some patients with indolent NHL, a large, asymptomatic abdominal mass
See Presentation for more detail. See also 10 Patients with Neck Masses: Identifying Malignant versus Benign, a Critical Images slideshow, to help identify several types of masses.
Diagnosis
The following laboratory studies may be warranted:
Complete blood count
Serum chemistries (including calcium, phosphate, and uric acid)
Liver function tests (including lactate dehydrogenase)
Erythrocyte sedimentation rate (in HL)
HIV and hepatitis B and C viruses (as clinically indicated)
The following imaging studies may be warranted:
Chest radiography (essential)
Computed tomography (CT) of the chest, abdomen, or pelvis (necessary for mediastinal, retroperitoneal, and mesenteric adenopathy)
CT scanning of the head and neck (mandatory for a head and neck presentation; localized disease; or cranial neuropathies, hearing loss, vertigo, or visual changes)
Magnetic resonance imaging (MRI; indicated for evaluating the brain or spinal cord)
Positron emission tomography (PET; as indicated)
Other tests to be considered include the following:
Immunohistochemical analysis of the tumor (essential)
Cytogenetic analysis (useful in select cases)
Polymerase chain reaction analysis
Fluorescent in-situ hybridization
The following procedures may be helpful:
Nasopharyngeal laryngoscopy (essential)
Fine-needle aspiration cytology (essential)
Excisional lymph-node biopsy (essential in HL and NHL)
Bone marrow aspiration and biopsy (essential).
Lumbar puncture and cerebrospinal fluid (CSF) analysis
Staging laparotomy or laparoscopy for HL
Diagnostic tonsillectomy (if lymphoma of the tonsils is suspected)
A lymphoma specialist should perform staging and treatment. The Ann Arbor staging system is used to stage lymphomas.
See Workup for more detail.
Management
Initial therapy for HL typically includes the following:
Stage I or II favorable disease – Combined chemotherapy and radiation or combined chemotherapy alone
Stage I or II unfavorable disease – Chemotherapy with or without radiation
Stage III or IV disease – Combination chemotherapy (eg, ABVD); more intensive regimens (eg, Stanford V and BEACOPP) are being investigated
Nodular lymphocyte predominant HL – Radiation or rituximab alone is often used; advanced-stage disease is usually treated like HL in patients with an unfavorable prognosis
Therapy for relapsing or refractory HL typically involves the following:
Early-stage disease and relapse after radiation therapy alone – ABVD
Relapse after combined-modality therapy or chemotherapy alone – The same or other combination chemotherapy (if remission duration > 12 months)
Salvage therapy – ABVD, ESHP, ICE, or DA-EPOCH
Failed induction or relapse within a year of initial chemotherapy – High-dose chemotherapy (with or without radiotherapy) followed by autologous hematopoietic stem-cell transplantation
Therapy for NHL may include the following:
Indolent B-cell lymphoma (eg, follicular and small lymphocytic lymphoma) – Watch-and-wait strategy initially; fludarabine, anti-CD20, CHOP, rituximab, or rituximab plus CHOP (R-CHOP); on an investigational basis, radioimmunotherapy or stem-cell transplantation
Stage I or II DLCBL – Combined modalities; use of rituximab, DA-EPOCH, or both may eliminate the need for irradiation
Stage III or IV DLBCL – Combination chemotherapy (eg, CHOP and, subsequently, R-CHOP)
Relapsing DLBCL – Salvage chemotherapy (eg, rituximab and ICE [R-ICE], ESHAP, or rituximab and DA-EPOCH [DA-EPOCH-R}; responsive disease is often treated with autologous stem-cell transplantation
Primary central nervous system (CNS) lymphoma – Methotrexate, rituximab, irradiation
Other aggressive B-cell lymphomas – Burkitt lymphoma is treated with intensive systemic chemotherapy; mantle-cell lymphoma is treated with measures ranging from aggressive combination chemotherapy to allogeneic transplantation; bortezomib may prove effective
Therapy for T-cell lymphomas may include the following:
Extranodal NK/T-cell lymphoma, nasal type – Irradiation (for localized disease)
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.
The image below depicts a lymphoma of the head and neck.
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CT scan of a patient with a natural killer (NK)/T-cell lymphoma of the right nasal cavity and maxillary sinus.
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 classical
Mixed cellularity classical
Lymphocyte-rich classical
Lymphocyte-depleted classical
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
Primary cutaneous follicle center lymphoma
Mantle-cell lymphoma
Diffuse large B-cell lymphoma (DLBCL)
Primary mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma
ALK positive large B-cell lymphoma
Plasmablastic lymphoma
Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease
Primary effusion lymphoma
Burkitt lymphoma
Lymphomatoid granulomatosis
NHL - T-cell and natural killer (NK)–cell neoplasms
Lymphoproliferative diseases associated with primary immune disorders
Other iatrogenic immunodeficiency-associated lymphoproliferative disorders
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.
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.
A study by Han et al using the Surveillance, Epidemiology, and End Results (SEER) database found overall survival rates in the United States for nasopharyngeal lymphoma to be 70%, 57%, and 45% at 2, 5, and 10 years, respectively, and determined median overall survival to be 8.2 years. Multivariate analysis indicated that overall and disease-specific survival rates are worse in patients with advanced age or NK/T-cell NHL and are improved in association with radiation therapy.[1]
A study by Anderson et al found that in adolescents and young adults aged 15-39 years, noncancer-related deaths rates were higher in NHL, HL, and head and neck cancer than in the general US population, with the standardized mortality ratios for these rates being 6.33, 3.12, and 2.09, respectively. The ratio was high for certain other cancers as well.[2]
Lymphoma is the fifth most common cancer in the United States, with an annual incidence of 74,490 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)[3] ; an increase in the detection of lymphoma; an increase in the elderly population; 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.
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 is 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.
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 the video below of a fiberoptic examination of an NK/T-cell lymphoma in the right nasal cavity and maxillary sinus.)
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Fiberoptic nasal examination of a patient with natural killer (NK)/T-cell lymphoma of 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.
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.
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.
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. The images below depict CT scan changes.
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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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CT scan 6 months after treatment with 4 cycles of DA-EPOCH (ie, infused etoposide, doxorubicin, and vincristine with bolus cyclophosphamide and predni....
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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 ProMA....
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CT scan 2 years after salvage therapy.
MRI is used as indicated for evaluation of the brain and/or spinal cord. Positron emission tomography (PET) scanning should also be ordered as indicated.
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).
In diffuse large B-cell lymphoma, fluorescent in-situ hybridization (FISH) for t(8;14)/MYC translocation should be considered. Up to 10% of DLBCLs have a MYC translocation and have a poor outcome with standard therapy.[4]
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
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.
A study by Crous et al found the combination of fine-needle aspiration cytology and flow cytometry to be effective in diagnosing NHL but less so in detecting HL. According to the investigators, in NHL the combined diagnostic means had a sensitivity of 95.5%, a specificity of 99.9%, a positive predictive value of 99.5%, and a negative predictive value of 99.2%, being 99.3% accurate. However, fine-needle aspiration cytology/flow cytometry missed 6 out of 13 HL cases (46.2%).[5]
Excisional lymph-node biopsy
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
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
Lumbar puncture may be indicated. This 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 evidence has demonstrated that cytology may not help in detecting some cases with positive results on flow cytometry.
Staging laparotomy or laparoscopy
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
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 one of the risk factors listed above had malignancy on pathologic evaluation of the tonsils.
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.
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.
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 or combined chemotherapy alone, and a recent study has demonstrated a better overall survival for patients who receive chemotherapy alone.[6]
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 hydroxy-daunorubicin (DA-EPOCH).
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. Recently, brentuximab, which targets CD30, was approved for the treatment of patients with relapsed HL and has high response rates.[7] 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.[8]
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. Recent studies show excellent outcomes with EPOCH-R chemotherapy.[9, 10]
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 combination antiretroviral therapy (cART) 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-NOS 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.
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.
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.
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.
Because of the high cure rates with lymphoma, particularly in HL, the long-term adverse effects of therapy are important considerations and these effects have recently been realized in long-term follow-up of patients with HL.[11, 12] 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).
A study by Seland et al indicated that in patients with NHL treated with radiation of the head and neck, those with untreated hormone dysfunction are at greater risk of subsequently developing chronic fatigue. The study’s results also suggested that patients whose dysfunction has been treated with hormone substitution are at no greater risk of chronic fatigue than are patients with normal hormone status. The study included 98 NHL survivors who had been treated with radiation to the head and neck region, 29% of whom had chronic fatigue.[13]
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.
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.
A study by Teckie et al indicated that in patients with early stage extranodal marginal-zone lymphoma, those with lymphoma of the stomach or the head and neck have the highest likelihood of relapse-free survival following treatment with curative-intent radiation therapy alone. The study utilized the records of 490 patients (median follow-up 5.2 y) with stage IE or IIE marginal-zone lymphoma, located most frequently in the stomach, orbit, skin, breast, or nonthyroid head and neck.[14]
Kieron M Dunleavy, MD, Professor of Medicine, Director of Lymphoma Program, Co-Director of Microbial Oncology Program, Division of Hematology and Oncology, GWU Cancer Center
Disclosure: Nothing to disclose.
Coauthor(s)
Erik Kass, MD, Chief, Department of Clinical Otolaryngology, Associates in Otolaryngology of Northern Virginia
Disclosure: Nothing to disclose.
Wyndham Wilson, MD, PhD, Senior Investigator, Division of Clinical Sciences, National Institutes of Health National Cancer Institute
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Karen H Calhoun, MD, FACS, FAAOA, Professor, Department of Otolaryngology-Head and Neck Surgery, Ohio State University College of Medicine
Disclosure: Nothing to disclose.
Chief Editor
Arlen D Meyers, MD, MBA, Professor of Otolaryngology, Dentistry, and Engineering, University of Colorado School of Medicine
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cerescan;RxRevu;Cliexa;The Physicians Edge;Sync-n-Scale;mCharts<br/>Received income in an amount equal to or greater than $250 from: The Physicians Edge, Cliexa<br/> Received stock from RxRevu; Received ownership interest from Cerescan for consulting; .
Additional Contributors
Daniel J Kelley, MD, Consulting Staff, Eastern Shore ENT and Allergy Associates and Peninsula Regional Medical Center
CT scan of a patient with a natural killer (NK)/T-cell lymphoma of the right nasal cavity and maxillary sinus.
CT scan of a patient with a natural killer (NK)/T-cell lymphoma of the right nasal cavity and maxillary sinus.
Fiberoptic nasal examination of a patient with natural killer (NK)/T-cell lymphoma of the right nasal cavity and maxillary sinus.
CT scan of a patient with a natural killer (NK)/T-cell lymphoma of the right nasal cavity and maxillary sinus.
CT scan 6 months after treatment with 4 cycles of DA-EPOCH (ie, infused etoposide, doxorubicin, and vincristine with bolus cyclophosphamide and prednisone).
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.
CT scan 2 years after salvage therapy.
CT scan of a patient with a natural killer (NK)/T-cell lymphoma of the right nasal cavity and maxillary sinus.
CT scan 6 months after treatment with 4 cycles of DA-EPOCH (ie, infused etoposide, doxorubicin, and vincristine with bolus cyclophosphamide and prednisone).
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.
CT scan 2 years after salvage therapy.
Fiberoptic nasal examination of a patient with natural killer (NK)/T-cell lymphoma of the right nasal cavity and maxillary sinus.
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