23

Lymphoma is commonly present in the head and neck region. It is the second most common head and neck malignancy after squamous cell carcinoma (SCC)1 and is the most common nonepithelial tumor of the head and neck.² It is imperative for the head and neck surgeon to have a good working knowledge of the various head and neck manifestations of lymphoma as he or she will often play a pivotal role in obtaining the diagnosis. Lymphoma may have diverse presentations within the head and neck, and the head and neck surgeon may be the first physician that a patient sees at the onset of symptoms. Patients may present with cervical lymphadenopathy or with a mass in one of the many extranodal sites within the head and neck. In most instances, the role of the head and neck surgeon is to provide prompt and adequate tissue specimen for diagnosis, so that the patient may begin the appropriate therapy. The otolaryngologist may be called upon to provide tissue diagnosis when a primary lymphoma is suspected or to biopsy a clinically changing node in a patient with a known indolent lymphoma so as to rule out transformation to a high-grade lesion. Beyond establishing a tissue diagnosis, the management of head and neck lymphomas is primarily nonsurgical.

Lymphomas occurring in the head and neck can be divided broadly into two categories: primary nodal lymphomas and extranodal lymphomas. Primary nodal lymphomas include Hodgkin and non-Hodgkin lymphomas. Lymphomas that originate outside lymph nodes are termed extranodal lymphomas and are mainly non-Hodgkin type.

Primary Nodal Lymphoma

Primary nodal lymphoma is divided into two forms: Hodgkin lymphoma and non-Hodgkin lymphoma. Both present with painless cervical lymphadenopathy, often involving lower cervical or supraclavicular nodes.³ The enlarged cervical nodes may wax and wane in size and appearance and may have been present for a variable amount of time. The involved nodes tend to be less firm and more mobile than metastatic lymph nodes from SCC. A complete history and physical examination is imperative in patients presenting with cervical lymphadenopathy, with careful attention to constitutional “B” symptoms such as fever, night sweats, fatigue, and weight loss. Physical examination should include a complete head and neck examination with special interest paid to all mucosal surfaces and particularly the lymphoid-rich region of the Waldeyer ring.

Any unexplained cervical lymphadenopathy warrants biopsy. Fine-needle aspiration (FNA) is usually the first step in obtaining a tissue specimen; this technique can help differentiate epithelial from nonepithelial neoplasms. In addition, cell blocks may allow for immunophenotypic and flow cytometric data to be obtained from FNA specimens. If FNA demonstrates a lymphoid tumor that cannot be further characterized, this should be followed by excisional or incisional biopsy of the mass. Excisional biopsy of an accessible cervical node is generally performed unless the complete removal would result in undue morbidity, in which case an incisional biopsy is acceptable. Often times this can be performed under local anesthesia or monitored anesthesia care. Ample tissue specimen should be provided to preserve the nodal architecture. All specimens should be sent fresh in saline rather than fixed in formalin or other preservatives. This is imperative to allow for the immunohistochemical and flow cytometric studies that are required to classify and prognosticate lymphoma subtypes.

Once the diagnosis of lymphoma has been established, further work-up is indicated to determine the patient’s stage. This work-up includes hematologic studies as well as radiologic studies to determine the extent of disease. Often, the work-up will include computed tomography (CT) scans of the head and neck, the chest, the abdomen, and the pelvis. Additional suspicious lymphadenopathy or extranodal masses that are detected on radiographic images should be biopsied. Often, bone marrow biopsies from the iliac crest are performed early in the staging process, as involvement of the bone marrow is diagnostic of stage IV disease and thus can render unnecessary other invasive diagnostic procedures.4 The Ann Arbor staging system (Table 23.1) was initially developed for Hodgkin lymphoma and is currently used for both Hodgkin and non-Hodgkin lymphoma.⁵

Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma accounts for 5% of head and neck malignancies. Non-Hodgkin lymphoma is more prevalent than Hodgkin lymphoma, with an incidence of 16 cases per 100,000 people per year in the United States.⁴ The incidence of non-Hodgkin lymphoma has been rising since the 1970s^6,7; theoretical causes for this rise include the human immunodeficiency virus (HIV) epidemic,^8–10 Helicobacter pylori infection,¹¹ autoimmune disease,^12,13 transplant-related immunosupression,¹⁴ and the increasing age of the U.S. population.⁴ Non-Hodgkin lymphoma is diagnosed most commonly in the fifth, sixth, and seventh decades of life.⁴

Several classification systems have been developed to stratify and prognosticate different types of non-Hodgkin lymphoma. The most commonly used classification schemes for non-Hodgkin lymphoma include the National Cancer Institute’s (NCI) working formulation,¹⁵ the revised European American lymphoma (REAL) classification,¹⁶ and the World Health Organization (WHO) classification.¹⁷ The NCI working formulation divides non-Hodgkin lymphomas into low, intermediate-, and high-grade lymphomas according to their clinical behavior. In contrast, the REAL classification groups lesions according to their histopathologic, immunophenotypic, and clinical features. In this classification system, lymphomas are identified according to their cell lineage as B-cell lymphomas, T-cell lymphomas, and natural killer (NK) lymphomas, with subtypes of each defined according to tumor histology. The WHO classification expands upon the REAL classification to include Hodgkin lymphoma and other lymphoproliferative lesions.

Treatment of non-Hodgkin lymphoma consists of chemotherapy and radiation therapy as determined by the clinical stage and tumor classification. Other important factors that determine treatment options include the patient’s age, comorbidities, and degree of symptomatology.⁴ Low-grade non-Hodgkin lymphomas tend to be widespread at the time of diagnosis. Though remission can be achieved, relapse is common.¹⁸ The current recommendation is to delay treatment of low-grade non-Hodgkin lymphomas until the patient becomes symptomatic, as treatment provided at the time of diagnosis does not lengthen long-term survival compared with treatment started at the time of symptom onset.^19,20 Treatment consists of chemotherapy with a single agent.¹⁹ Relapses can often be treated with the same regimen that induced initial remission.⁴ The mean survival for patients diagnosed with low-grade lymphomas is 10 to 15 years.²¹

Intermediate- and high-grade aggressive lymphomas are treated with a goal of complete remission and cure. Localized lesions are treated with radiation alone, which can induce complete remission in more than 80% of patients.^22,23 Chemotherapy is integral in treating advanced stage disease or bulky localized disease. The most effective chemotherapy regimen is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).⁴ Immunotherapy with monoclonal antibodies, such as rituximab, is currently evolving as adjuvant therapy.^24–28

Table 23.1 Ann Arbor Staging System for Lymphoma

Hodgkin Lymphoma

Hodgkin lymphoma has an incidence of 3 cases per 100,000 people per year. Hodgkin lymphoma presents with a bimodal age distribution, peaking in the second and fifth decades of life. Hodgkin lymphoma is more likely to be accompanied by constitutional symptoms than non-Hodgkin lymphoma.29 The majority of patients are male, and higher socioeconomic class has been associated with the development of Hodgkin lymphoma.^30,31

The histopathological diagnosis of Hodgkin lymphoma is made by the presence of the classic Reed-Sternberg cells in a characteristic background of reactive lymphocytes, neutrophils, plasma cells, and eosinophils.⁴ The WHO system is the most commonly used classification scheme; it categorizes Hodgkin lymphomas into six subtypes. Nodular sclerosing is the most common subtype, representing almost 80% of cases. The prognosis for nodular sclerosis is generally good. Mixed cellularity is the second most common subtype, accounting for 15 to 20% of cases. The mixed-cellularity subtype is the most commonly found type in HIV-positive patients. Lymphocyte-rich classic Hodgkin lymphoma accounts for approximately 6% of cases. The lymphocyte-predominant subtype is considered a nonclassical subtype of Hodgkin lymphoma. It makes up approximately 4 to 5% of Hodgkin lymphomas and has an excellent prognosis. The lymphocyte-depleted subtype is the least common, making up only 1% of the diagnoses of Hodgkin lymphoma. This subtype has the worst prognosis, often presenting at an advanced stage. The final subtype, unclassifiable Hodgkin lymphoma, includes lesions that do not otherwise fit into one of the aforementioned categories.^4,32

Treatment of Hodgkin lymphomas consists of combined modality therapy including both chemotherapy and radiation therapy. The most commonly used chemotherapeutic regimen is doxorubicin, bleomycin, vinblastine, and dacarbazine. Radiation is given to the involved field only; doses are in the range of 3600 to 4000 cGy.³³ Survival outcomes are superior in Hodgkin lymphoma than in non-Hodgkin lymphoma. In one comparative study, 12% of patients with Hodgkin lymphoma died of their disease, contrasted with 41% of patients with non-Hodgkin lymphoma.²⁹ Unfortunately, many patients with Hodgkin lymphoma are young, and, in addition to the standard side effects and complications of chemotherapy and radiotherapy, up to 5% of patients may develop a secondary malignancy as the result of combined modality treatment.³⁴

Primary Extranodal Head and Neck Lymphomas

Lymphoma arising primarily from a site other than a lymph node is a relatively common occurrence within the head and neck. One-third of extranodal lymphomas are localized to the head and neck region,³⁵ and 23 to 28.4% of all head and neck non-Hodgkin lymphomas are extranodal.^29,36 Extranodal lymphomas are almost exclusively non-Hodgkin type. Anatomic sites include the Waldeyer ring, the salivary glands, the nose and paranasal sinuses, the thyroid gland, the larynx and trachea, the orbit, the temporal bone, and the skin. Tumors tend to be submucosal rather than ulcerative.³⁷ The diagnosis may not be readily apparent at the time of initial evaluation, and, in children, extranodal tumors may mimic other disease processes such as inflammatory disease, Langerhans cell histiocytosis, or rhabdomyosarcoma.³⁸ It is therefore important that the head and neck surgeon maintains a good working knowledge of the diverse presentations of extranodal lymphomas. As a group, extranodal non-Hodgkin lymphomas have a better prognosis than their nodal counterparts, but tumors of each anatomic site have characteristic clinicopathological features and varying levels of aggressiveness and response to treatment.

Waldeyer Ring

The Waldeyer ring is an anatomic region of the oropharynx and nasopharynx that is heavily populated with lymphoid tissue. This area is composed of the palatine tonsil, the pharyngeal tonsil, the tubal tonsils of Gerlach, and the lingual tonsil on the base of tongue. The Waldeyer ring is the most common site of primary extranodal lymphoma in the head and neck, accounting for more than half of the cases.^39,40 The tonsil is the most common site of lymphoma within the Waldeyer ring and is the most common single anatomic site of primary extranodal non-Hodgkin lymphoma overall. Tonsillar lymphomas have been cited as comprising 40 to 79% of the Waldeyer ring lymphomas, with the next most frequent location being the nasopharynx, followed by the base of tongue and the soft palate.^39,41–46 Within the broader context of head and neck malignancies, however, tonsillar lymphoma is still relatively rare, representing less than 1% of head and neck cancers.⁴⁷

The median age of patients diagnosed with primary lymphoma of the Waldeyer ring is 45 to 60 years,^{35,39,41,42,44,45} and there is a slight male predominance of 1.3 males for every female affected.³⁵ The Waldeyer ring lymphomas may present with observable tonsillar enlargement, or they may present with symptoms of obstructive sleep apnea. Tonsillar lymphoma is a common presentation of posttransplant lymphoproliferative disorder (PTLD); this entity will be discussed in detail later in the chapter. The incidental diagnosis of tonsillar lymphoma is exceedingly rare in the absence of clinical suspicion. In a study examining the cost-effectiveness of routine pathologic evaluation of pediatric tonsillar specimens, zero cases of unsuspected pathology were found in 4186 routine tonsil specimens.48

The vast majority of primary Waldeyer ring lymphomas are B-cell lymphomas, with diffuse large B-cell lymphomas being the most common type.^35,39,47 In a recent literature review, B-cell lymphomas were found to make up 82% of tonsillar lymphomas. They are often of intermediate- to high-grade, but tend to be localized at the time of presentation.³⁵ Diagnosis is made by tissue biopsy, usually via tonsillectomy. Surgery does not play a role in the management of the Waldeyer ring lymphomas except in the rare incidence of upper airway obstruction from severe lymphoid hypertrophy necessitating surgical intervention.

The accepted treatment of primary lymphoma of the Waldeyer ring is combined chemotherapy and radiation therapy. In a randomized, prospective clinical trial of 316 patients with stage I primary lymphoma of the Waldeyer ring, combined modality treatment with chemotherapy and radiation therapy achieved superior failure-free survival and overall survival rates than the chemotherapy-alone and radiation therapy-alone study arms. Failure-free survival was 83% for patients treated with combined modality treatment compared with 48% for patients treated with radiation therapy alone and 45% for patients treated with chemotherapy alone. Overall survival was 90% for the combined-treatment arm compared with 56% in the radiation-only group and 58% in the chemotherapy-only group.⁴² Other studies have similarly found an advantage with combined chemotherapy and radiation therapy over single-modality treatment.^{35,39–41,49–53} Tonsillar lymphomas have a better prognosis than their analogs occurring in the nasopharynx or base of tongue.³⁹ Even though the Waldeyer ring lymphomas are often histologically intermediate- or high-grade tumors, the prognosis is generally favorable³⁵ and is better than for their more prevalent SCC counterparts.⁵⁴

Salivary Gland Lymphoma

Primary lymphoma of the salivary glands is rare, accounting for only 1.7% of all salivary gland neoplasms.⁵⁵ Patients most commonly present with painless, firm enlargement of a salivary gland, although occasionally the lesion may be painful. Patients may have bilateral swelling and may give a history of relapsing and remitting swelling consistent with recurrent sialadenitis.^55,56 Often, patients will not have accompanying systemic symptoms.⁵⁷ The parotid gland is most frequently affected, occurring in 65% of cases. This is followed in descending order of frequency by the submandibular glands, the minor salivary glands, and the sublingual glands. The median age at diagnosis is 50 to 70 years, and there is a female predominance.^55–61

The vast majority of salivary gland lymphomas are non-Hodgkin lymphomas, predominantly B-cell lymphomas. Approximately 60% of cases are mucosa-associated lymphoid tissue (MALT) lymphomas. Follicular lymphoma and diffuse large B-cell lymphomas are next in order of frequency, with the remainder composed of mantle cell lymphoma, lymphoblastic lymphoma, peripheral T-cell lymphoma, and Hodgkin lymphoma.^55,57,58 MALT lymphomas tend to be low grade, though rare transformation to high-grade tumors has been described.^58,62 It is debated whether primary lymphomas of the salivary glands are truly extranodal lymphomas or if they arise from intraparenchymal or adjacent lymph nodes, as extranodal lymphoid tissue is not normally present in the salivary glands. It is proposed that chronic inflammation in the form of myoepithelial sialoadenitis leads to the reactive infiltration of the gland with lymphoid tissue, which has the potential to transform into MALT lymphoma.^62–64 Hyman and Wolff proposed three criteria to diagnose a primary salivary gland lymphoma; the lesion had to be confirmed histologically to be malignant and had to involve the gland parenchyma rather than only adjacent soft tissue or lymph nodes. In addition, the presentation in the salivary gland had to be the first clinical manifestation of the disease.⁶⁵

Patients who carry the diagnosis of Sjögren syndrome deserve special mention. Sjögren syndrome is a chronic autoimmune disease whereby prolonged infiltration of salivary and lacrimal glands with lymphocytes and histiocytes leads to symptoms of xerostomia and keratoconjunctivitis sicca. Sjögren syndrome may be associated with other autoimmune phenomena in which case it is referred to as secondary Sjögren syndrome. Patients affected by Sjögren syndrome have a 6- to 44-fold increased risk of developing non-Hodgkin lymphoma compared with the general population.^66–68 About 4 to 10% of patients affected by Sjögren syndrome go on to develop non-Hodgkin lymphoma,^69–72 and approximately 20% of patients with primary salivary gland lymphoma have Sjögren syndrome.⁵⁷ The salivary glands are involved in 37% of these cases of non-Hodgkin lymphoma, and the majority are MALT lymphomas.⁶⁹ Tonami et al did not find an association between time of onset or severity of disease and the development of non-Hodgkin lymphoma.⁶⁹ Several studies have demonstrated a worse prognosis in patients with Sjögren syndrome who develop primary salivary gland lymphoma,^59,73 but others have not found this to be the case.⁵⁶

A tissue sample should be obtained on any patient with a salivary gland mass. FNA cytology has a reported sensitivity of 73% for identifying specimens as benign or malignant in the salivary glands, though the accuracy of FNA for correctly identifying a specific pathologic diagnosis is as low as 48%. In a multi-institutional study of 6249 pathologic salivary specimens, the diagnosis of lymphoma on FNA had the highest false-negative rate of any malignancy at 57%.⁷⁴ The authors stress the importance of immunophenotyping studies with flow cytometry. If enough tissue for flow cytometry cannot be obtained by FNA, surgical biopsy should be considered to make the diagnosis. Excisional biopsy in the parotid gland often requires superficial parotidectomy.

Salivary gland lymphoma is believed to have a superior prognosis compared with lymphoma of other extranodal sites.57,59,73,75 Tumors tend to remain localized with slow regional progression and low rates of local relapse.⁵⁸ The median survival is 49 months.⁵⁵ MALT lymphomas of the salivary gland have been found to have improved prognosis over other B-cell salivary gland lymphomas,^58,76 although follicular lymphoma of the salivary gland may have equally good prognosis to MALT.⁵⁷ Overall 5-year survival for salivary gland lymphoma has been quoted at 83%, with 5-year disease-free survival of 71.5%.⁵⁸ Recommended treatment is radiotherapy for stage I non-Hodgkin lymphomas and chemotherapy plus or minus radiotherapy for stage II through IV disease.^56,77 All patients with non-Hodgkin lymphomas other than MALT type should receive systemic chemotherapy.⁵⁸ Some advocate delaying treatment in the case of low-grade histology in an asymptomatic patient.^20,56 There is no role for definitive surgical management of salivary gland lymphomas after the diagnosis has been established.⁵⁶

Nasal and Paranasal Sinus Lymphoma

Nasal and paranasal sinus lymphomas are a rare entity in Western populations, composing only 0.17% of all lymphomas.⁷⁸ Now collectively referred to as sinonasal lymphomas, they have previously been included under various nomenclatures such as lethal midline granuloma, midline malignant reticulosis, polymorphic reticulosis, and angiocentric immunoproliferative lesions.^16,79–89 Sinonasal lymphomas make up a diverse group of non-Hodgkin lymphomas and have been classified according to the WHO classification.⁹⁰

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