CHAPTER 119 Lymphomas Presenting in the Head and Neck

• Surgery does not play a role in the curative treatment of lymphomas.

• An adequate biopsy is critical for rendering an accurate diagnosis and classification of lymphoma. An excisional or incisional biopsy is the preferred procedure for confirming a new diagnosis of lymphoma.

• Specimens should be submitted to the pathologist in saline, along with the patient’s clinical history and differential diagnosis, in order to perform appropriate testing such as flow cytometry.

• Highly aggressive lymphomas such as Burkitt’s or lymphoblastic lymphoma should be referred to a medical oncologist emergently.

• Limited stage Hodgkin’s lymphoma and diffuse large B-cell lymphoma presenting in the head and neck are highly curable with combined modality therapy including combination chemotherapy and involved-field radiotherapy.

• Mucosa-associated lymphoid tissue lymphomas of the thyroid and salivary glands are rarely life-threatening and should be treated with low-dose involved-field radiotherapy.

• Diffuse large B-cell lymphoma of the paranasal sinuses is associated with a high risk of central nervous system relapse.

• NK/T cell lymphoma nasal type has an aggressive clinical course and frequently causes marked tissue destruction and necrosis. Wide-field radiotherapy to a dose of at least 50 Gy is the most effective therapy.

Lymphomas are malignant neoplasms of lymphocytes and their precursor cells. Historically, lymphomas were classified merely by their histologic appearance, specifically cell size (e.g., small, large, mixed) and architecture (nodular or diffuse). The current classification system is the World Health Organization (WHO) system, which defines specific subcategories of lymphoma according to the immunologic and molecular characteristics of the lymphoma cells, as well as the morphology.¹ Most subtypes of lymphoma can potentially involve the head and neck, either as the only site of disease or as one of many sites of involvement. Because an enlarged cervical or supraclavicular lymph node is a common presentation of many lymphomas, otolaryngologists are often the first physicians to evaluate and biopsy these patients, as well as the first to inform patients of their diagnosis. Understanding the pathology, clinical features, treatment, and prognosis for each of the nodal and extranodal lymphoma subtypes that can present in the head and neck will allow for a more accurate and efficient evaluation. In addition, a brief discussion of the diagnosis and prognosis by the head and neck specialist is extremely valuable to patients and their families while they are awaiting an initial appointment with a medical oncologist.

Epidemiology

It is estimated that 74,300 new cases of lymphoma will be diagnosed in the United States in 2008, including 66,100 cases of non-Hodgkin’s lymphoma (NHL) and 8200 cases of Hodgkin’s lymphoma (HL).² The incidence of NHL rose dramatically between 1970 and 1995 but has stabilized over the past 14 years. The cause of this increase is incompletely understood. The human immunodeficiency virus (HIV) epidemic and the increase in NHL after solid-organ transplants account for only a minority of the new lymphomas. The incidence of NHL is slightly higher in men than women and increases exponentially with age. The most reproducible environmental risk factor includes exposure to certain pesticides or herbicides, and inconsistent associations have been reported with hair dyes, certain occupations, smoking, consuming foods high in animal fat, and receiving blood transfusions.³ Infectious agents including Epstein-Barr virus (EBV), HIV, human T-cell leukemia virus (HTLV)-1, Helicobacter pylori, Chlamydia psittaci, hepatitis C, HHV8, and Borrelia burgdorferi have been proposed as etiologic agents in the pathogenesis of some cases of NHL.⁴ Other factors associated with a significant increased risk of NHL include autoimmune disorders, most commonly Sjögren’s syndrome and rheumatoid arthritis, although it is difficult to separate the effects of immunosuppressive drugs used to treat these diseases and the underlying autoimmune disease.

HL has a bimodal age distribution in developed countries, with the first peak occurring in the third decade of life and the second peak occurring after age 50 years. Men have a slightly higher incidence than women. There is an association between HL and factors that decrease exposure to infectious agents at an early age including advanced maternal education, early birth order, decreased number of siblings, and living in a single-family residence. A history of infectious mononucleosis increases the risk of HL twofold to threefold and suggests EBV as an etiologic agent.⁵ There is a slightly increased risk of HL in patients infected with HIV and other conditions associated with chronic immunosuppression. An increased incidence among first-degree relatives, a significant concordance rate among identical but not fraternal twins, and linkage with certain HLA types suggest a genetic predisposition for HL.⁶ The incidence of HL varies significantly with geography, suggesting either an environmental or a genetic association. HL is rare in Japan, but interestingly, the incidence increases in Japanese Americans, suggesting an important environmental component.⁷

Clinical Presentation of Lymphomas of the Head and Neck

Lymphoma should be included in the differential diagnosis of any patient with adenopathy, salivary gland enlargement, or a mass in Waldeyer’s ring (WR), the nasal cavity, the paranasal sinuses, or the thyroid. Approximately 75% of lymphomas presenting in the head and neck are nodal and 25% extranodal. An accurate history and physical examination can provide important clues to the diagnosis.

Classical HL occurs most commonly in young adults and usually presents as painless lymphadenopathy in the cervical and/or supraclavicular regions. In contrast to NHL, HL spreads in a contiguous pattern and rarely involves the preauricular or occipital nodes or extranodal sites of the head and neck such as the tonsil or sinus. Infraclavicular involvement in patients with bulky supraclavicular nodes is common in HL but is rarely seen in NHL. Bulky, matted nodes are not uncommon (Fig. 119-1). Although staging studies reveal mediastinal adenopathy in more than 85% of patients with HL, symptoms of cough, chest pain, dyspnea, and superior vena cava (SVC) syndrome are uncommon, even in patients with bulky mediastinal disease. Systemic symptoms or “B” symptoms including fevers (temperature > 38° C), drenching night sweats, and weight loss occur in 30% to 40% of patients with stage III or IV disease, but in less than 10% of patients with stage I or II disease. A hallmark of HL, generalized, severe pruritus, occurs in approximately 25% of patients with HL, often precedes the diagnosis by months, can be a presenting symptom of both early and advanced-stage disease, and has no known prognostic significance. Alcohol-induced pain in involved lymph nodes is a rare symptom of HL (<1%). A rare subtype of HL, nodular lymphocyte-predominant HL (LPHL), usually presents as a solitary cervical, axillary, or inguinal lymph node. In LPHL the mediastinum is generally spared, and in contrast to the contiguous pattern of lymph node involvement in classic HL, there is no consistent pattern of spread.

Figure 119-1. Neck computed tomography scan of a 23-year-old woman with classical Hodgkin’s lymphoma showing a conglomeration of bulky, right supraclavicular lymph nodes adjacent to the right thyroid lobe.

Presenting symptoms of NHLs vary substantially depending on the pathologic subtype of NHL and the site(s) of disease. Indolent lymphomas such as follicular (FL) or small lymphocytic (SLL) lymphomas often present with painless, peripheral adenopathy. Multiple soft, mobile, bilateral cervical nodes ranging in size from 1 to 2 cm are common presentations of both FL and SLL (Fig. 119-2). Matted peripheral lymph nodes are uncommon. Isolated head and neck involvement is unusual with these subtypes of lymphoma, and examination of axillary and inguinal regions usually reveals additional enlarged nodes. SLL can involve the tonsillar regions. Because spontaneous regressions occur in up to 20% of patients with FL, the patient may describe a history of waxing and waning adenopathy, with nodes present for years in some cases. Most patients with indolent lymphoma feel well at presentation, and B symptoms including fevers, drenching night sweats, and weight loss are unusual. Patients with SLL frequently have involvement of the peripheral blood, and a complete blood count may reveal a lymphocytosis. Peripheral blood flow cytometry may provide a diagnosis and obviate the need for a tissue biopsy. Indolent lymphomas are uncommon before age 50.

Figure 119-2. Neck computed tomography scan of an 81-year-old man with small lymphocytic lymphoma showing bilateral diffuse cervical lymphadenopathy.

Mucosa-associated lymphoid tissue (MALT) lymphomas, indolent lymphomas occurring in extranodal sites, can present as an isolated swelling in the thyroid or a salivary gland, most commonly the parotid gland. Bilateral parotid involvement can occur and occasionally a history of stable enlargement over months or years is elicited. Cases of MALT lymphoma have also been reported in the sinuses, oral cavity, and nasal cavity. MALT lymphomas of the head and neck are often associated with autoimmune disorders, such as Hashimoto’s thyroiditis and Sjogren’s syndrome, and occasionally precede the diagnosis of the autoimmune disorder.

Many aggressive lymphomas, the most common being diffuse large B-cell (DLBC), also often occur as painless cervical or supraclavicular adenopathy, without other associated symptoms. Fevers, night sweats, or weight loss occur in about 20% of patients with advanced-stage disease. Primary extranodal large cell lymphomas are common, accounting for 15% to 20% of all large cell lymphomas and can present in the tonsils, nasopharynx, oropharynx, thyroid, salivary glands, or sinuses. The presentation of extranodal lymphomas of the head and neck is discussed in more detail later in this chapter.

The very aggressive lymphomas, lymphoblastic and Burkitt’s, are rare in the adult population, but can occur with acute symptoms and can be life threatening without rapid intervention. In adults, lymphoblastic lymphomas occur most commonly in young men, and frequently occur with acute respiratory compromise due to bulky mediastinal adenopathy, and pleural or pericardial effusions. Occasionally supraclavicular adenopathy is present and the otolaryngologist will be called upon to obtain diagnostic tissue emergently.

Biopsy Techniques and Specimen Handling

Because surgery does not play a role in the curative treatment of lymphomas, the goal of biopsy is to provide enough material for an accurate diagnosis, while minimizing the cosmetic effect of the biopsy. If the biopsy involves a nodal site, sample the largest node or any node growing out of proportion to other nodes in order to rule out transformed lymphoma. Sampling a single site is usually adequate.

Tissue biopsy is essential in the diagnosis and management of patients with lymphomas. Recent advances in the immunology and molecular biology of lymphomas, as well as new diagnostic reagents and methods, have resulted in more precise diagnoses. The most recent WHO classification includes more than 25 subtypes of NHL, with B-cell neoplasms representing 80% to 90% of NHLs (Table 119-1). When the clinical history is suggestive of lymphoma, but initial histologic review and immunohistochemistry by flow cytometry or on paraffin-embedded tissue sections are nondiagnostic, molecular testing for T-cell receptor and immunoglobulin heavy-chain gene rearrangements should be considered. Cases in which the pathologic diagnosis seems inconsistent with the clinical history should be reviewed by an expert hematopathologist.

Table 119-1 Proposed World Health Organization Classification for NHL

B-cell neoplasms

Precursor B-cell lymphoblastic leukemia/lymphoma^*

Mature B-cell neoplasms

B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma

B-cell prolymphocytic leukemia

Lymphoplasmacytic lymphoma

Mantle-cell lymphoma

Follicular lymphoma^†

Marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type

Nodal marginal zone lymphoma ± monocytoid B cells

Splenic marginal zone B-cell lymphoma

Hairy cell leukemia

Diffuse large B-cell lymphoma^†

Subtypes: mediastinal (thymic), intravascular, primary effusion lymphoma

Precursor T-cell lymphoblastic leukemia/lymphoma^*

Mature T-cell and NK-cell neoplasms

T-cell prolymphocytic leukemia

T-cell large granular lymphocytic leukemia

NK-cell leukemia

Extranodal NK/T-cell lymphoma, nasal-type

Mycosis fungoides^†

Sézary syndrome

Angioimmunoblastic T-cell lymphoma

Peripheral T-cell lymphoma (unspecified)^†

Adult T-cell leukemia/lymphoma (HTLV1⁺)^†

Systemic anaplastic large-cell lymphoma (T- and null-cell types)^†

Primary cutaneous anaplastic large-cell lymphoma^†

Subcutaneous panniculitis-like T-cell lymphoma

Enteropathy-type intestinal T-cell lymphoma

Hepatosplenic γ/δ T-cell lymphoma

NHL, non-Hodgkin’s lymphoma; NK, natural killer.

* The classification of acute lymphoid leukemias will expand on the classification of precursor B-cell and T-cell malignancies, incorporating both immunophenotypic and genetic features.

† Morphologic and/or clinical variants of these diseases are not listed, for the purpose of clarity and ease of presentation.

The proper handling of specimens for adjunctive diagnostic tests is critical whenever lymphoma is suspected. Specimens should not be transported on dry towels or surgical sponges; they should be submitted to the pathologist in saline along with the patient’s clinical history and differential diagnosis. Specimens should not be held overnight or for extended periods before processing by the pathology laboratory. If there will be a delay in processing the specimen, preserve a portion of the specimen in formalin to maintain the architecture. Crushed specimens are extremely difficult to evaluate for lymphoma.

The pathologist usually reserves fresh cells or frozen tissue for immunophenotyping and molecular diagnostics as needed. Immunophenotyping is performed, either by flow cytometry or using immunohistochemical methods, on slides prepared from frozen tissue or paraffin-embedded fixed tissue, on nearly all new cases of NHL or HL. Flow cytometry requires a fresh cell suspension, but it offers the advantage of preservation of antigens. Although fewer antigens are preserved in fixed and embedded tissues, immunohistochemical staining of paraffin-embedded specimens allows analysis of archival specimens and offers the benefit of correlation with architectural and cellular details.

Application of the World Health Organization classification system requires the integration of clinical, morphologic, cytogenetic, molecular, and immunophenotypic features to accurately characterize lymphoproliferative disorders. Therefore it is essential that all available clinical and diagnostic information related to a specimen be made available to the hematopathologist including any prior diagnosis of lymphoma.

Fine-Needle Aspiration

Because of the improved diagnostic methods previously discussed, a less invasive procedure such as fine-needle aspiration (FNA) or core-needle biopsy may lead to a precise diagnosis without the need for surgery in some cases of lymphoma. Although FNA is a rapid and cost-effective method, it provides only cytologic material. Cytology alone is less useful for the initial diagnosis of lymphomas because the architectural pattern is often necessary for accurate subclassification. In addition, FNA often does not provide adequate tissue for immunophenotyping, especially when the lymphoma is associated with extensive fibrosis, limiting the ability to aspirate cells. However, if an adequate number of cells can be aspirated, many pathologists agree that FNA may be adequate in the setting of relapsed disease because it is often easier to confirm a previous diagnosis than to render an initial diagnosis on the basis of limited material.

Due to the lack of fibrosis and a unique cytologic appearance and immunophenotype, small lymphocytic lymphoma and lymphoblastic lymphoma can often be accurately diagnosed solely on the basis of a fine-needle biopsy. Lymphoblastic lymphoma (LL), a high-grade lymphoma, often presents with SVC syndrome or severe dyspnea and progresses extremely rapidly. The ability of pathologists to provide a preliminary diagnosis within hours on the basis of an FNA of a supraclavicular or mediastinal node may allow earlier initiation of therapy. In one report of eight children with LL, FNA was employed as the initial diagnostic procedure.⁸ Immunophenotyping established the T cell derivation in all cases, and treatment was initiated only on the basis of FNA results in six cases. Two patients had subsequent surgical biopsies that confirmed the FNA diagnosis of LL. In a separate retrospective study, nine out of nine cases of lymphoblastic lymphoma were correctly identified on the basis of specimens obtained by FNA.⁹

Stewart and colleagues ¹⁰ reported that FNA of palpable lymph nodes correctly identified 61 of 67 (91%) malignant lymphomas, with 27% of the cases representing recurrent lymphomas. However, in a more recent study, Hehn and colleagues¹¹ found that a specific and complete histologic diagnosis of lymphoma was obtained in only 27 of 93 FNA attempts (29%) at initial diagnosis, and in only 9 of 22 FNA attempts (41%) done in the setting of recurrent disease. Importantly, these 115 needle aspirations were interpreted by 70 different pathologists in the community setting and only 43% had concurrent ancillary studies such as flow cytometry. Howlett and colleagues¹² reported results of an audit of 276 patients who underwent FNA and subsequent surgery for evaluation of a “neck lump” at one of five hospitals in the Sussex cancer network in the United Kingdom during 2004. Of the 276 aspirations, 105 (38%) were nondiagnostic, 54 of 104 (52%) in the neck node group, 23 of 54 (43%) in the salivary gland group, and 28 of 118 (24%) in the thyroid group. Only patients in the thyroid group had ultrasound guidance for the procedure. Interestingly, 15 of the 54 nondiagnostic FNAs in the neck node group were NHL at surgery, as well as 3 of the 23 cases in the salivary gland group and 1 of the 28 thyroid cases. Additionally, 2 of 12 neck node aspirations and 2 of 24 salivary gland aspirations diagnosed as benign revealed NHL at surgery.

An accurate diagnosis of lymphoma by FNA requires an experienced sampling team, an expert cytopathologist, and the facilities to perform and interpret appropriate ancillary tests. The continued identification of unique immunophenotypic and molecular changes associated with many subtypes of lymphoma is likely to make this procedure more promising as the sole method of diagnosis in the future.

Core-Needle Biopsy

The use of percutaneous core-needle biopsies can sometimes overcome the limitations of FNA by retaining the architecture of the tissue and providing serial sections for histochemical and immunocytochemical stains. If a core-needle biopsy is technically feasible, use the largest-gauge needle possible (12 to 16 gauge) and obtain multiple cores. In general, both the peripheral and central portion of the mass should be sampled to avoid obtaining only necrotic tissue.

Several studies evaluating core-needle biopsy for lymphoma diagnosis have been published.¹³^–¹⁶ In one study, 241 patients with lymphoma underwent core-needle biopsy as their initial biopsy.¹³ Overall, an 82.5% success rate was observed. Several studies included both patients undergoing initial evaluation, as well as patients with suspected relapse or progressive disease.¹⁴^–¹⁶ Core-needle biopsy procedures yielded sufficient material for formulation of a treatment plan in 83% to 93% of patients. A recent report of 88 patients undergoing ultrasound-guided core-needle biopsy for head and neck masses included 16 patients with a final diagnosis of lymphoma.¹⁷ In 3 of 16 patients inadequate tissue was obtained by core-needle biopsy, and the patients had subsequent excisional biopsies. In 12 of 13 with “adequate” tissue to make a diagnosis of lymphoma, full subclassification of the lymphoma was possible and treatment initiated on the basis of the core-needle biopsy. Importantly, these 12 patients did not have an open biopsy to confirm the results of the needle biopsy. Gong and colleagues¹⁸ compared results of FNA and core-needle biopsy in 74 patients with lymphoma. FNA with flow cytometry was insufficient in 47% of patients and core-needle biopsy was insufficient in 28% of patients.

Open Biopsy

Despite encouraging results with limited needle biopsies, both oncologists and hematopathologists prefer an excisional or incisional biopsy as initial diagnostic tissue in nearly all cases of lymphoma. Because head and neck masses can usually be biopsied with less invasive procedures than intrathoracic or intra-abdominal lymph nodes, there should be no reason to potentially compromise the diagnosis due to limited material.

Prebiopsy Corticosteroids

Historical teaching dictates that patients with suspected lymphoma should not receive corticosteroids before biopsy because of the theoretic risk of obscured results because of rapid tumor response. In reality, except in the rare case of lymphoblastic lymphoma, steroids are unlikely to have a significant detrimental effect if tissue is obtained within 24 to 48 hours of the first dose. In one study of 86 children with mediastinal lymphoma, 23 received prebiopsy corticosteroids. In five (22%) an adverse effect on the pathologic diagnosis was observed, one patient with HL and four with probable lymphoblastic lymphoma.¹⁹ However, the only indication for prebiopsy steroids should be severe, life-threatening airway compromise. Although patients with SVC syndrome can be quite symptomatic, these symptoms are not life threatening over the short term and steroids should not be administered until diagnostic tissue is obtained. If lymphoblastic lymphoma is suspected, every effort should be made to obtain tissue within 1 day of presentation and before administration of steroids.

Nodal Lymphomas of the Head and Neck

Hodgkin’s Lymphoma

As described earlier, most patients with HL present with asymptomatic peripheral adenopathy, most commonly cervical and supraclavicular. The incidence peaks between 15 and 40 years of age. Severe, generalized pruritus is common in HL, rare in NHL, and often precedes the diagnosis by months. Systemic symptoms including fever of greater than 38° C for 3 consecutive days, drenching night sweats, or unexplained weight loss of more than 10% of body weight in the preceding 6 months occur in about 25% of patients with HL, but they are uncommon in early-stage disease.²⁰ Pruritus, systemic symptoms, and many of the laboratory abnormalities seen in HL are probably a result of cytokine production by Reed-Sternberg cells.

HL is a neoplastic proliferation of Reed-Sternberg (R-S) cells or R-S variants, large cells with abundant cytoplasm and multiple or multilobed nuclei. R-S cells are surrounded by host inflammatory cells including lymphocytes, plasma cells, neutrophils, and eosinophils. R-S cells are derived, in most cases, from germinal center B cells.²¹ The World Health Organization classifies HL as either “classic” HL or nodular LPHL. LPHL and classic HL have different natural histories, prognoses, and treatments.²¹ Immunohistochemical studies accurately distinguish LPHL from classical HL and should be performed if histology is equivocal. In classical HL, the large atypical cells generally express CD15 and CD30, whereas other T- and B-cell–associated antigens are usually negative. In contrast, the tumor cells of LPHL are CD20⁺ (a pan-B-cell antigen), CD45⁺ (leukocyte common antigen), CD15⁻, and variably reactive for CD30, an immunophenotype often seen in B-cell NHL. Flow cytometry is nondiagnostic in HL.

Staging

The Ann Arbor staging system for HL and NHL is detailed in Table 119-2. The designation E applies to extranodal involvement, which is limited in extent and contiguous with lymph node disease. Extranodal involvement of HL of head and neck sites is extremely rare. Proper staging requires computed tomography (CT) scans of the chest, abdomen, and pelvis. CT scans of the neck are optional and probably add little to a thorough physical examination but may aid in designing radiotherapy portals if radiotherapy is planned. The mediastinal mass ratio (MMR), defined as the ratio of the maximal transverse diameter of the mediastinal mass to the maximal transverse intrathoracic diameter, is an important prognostic factor and should be calculated in all patients with significant mediastinal adenopathy. An MMR greater than 0.33 by chest radiograph (CXR) or 0.35 by CT portends a worse prognosis and may influence treatment recommendations. Positron emission tomography (PET)/CT upstages and potentially alters treatment in 10% to 20% of patients with HL compared with CT alone and should be considered in the initial staging of patients with early-stage disease.^22,²³

Table 119-2 Ann Arbor Staging System for Lymphoma *

Stage I	Involvement of a single lymph node region or lymphoid structure, or involvement of a single extralymphatic site (I_E)
Stage II	Involvement of 2 or more lymph node regions on the same side of the diaphragm, which may be accompanied by localized contiguous involvement of an extralymphatic site or organ (II_E)
Stage III	Involvement of lymph node regions on both sides of the diaphragm, which may also be accompanied by involvement of the spleen (III_S) or by localized contiguous involvement of an extralymphatic site or organ (III_E)
Stage IV	Diffuse or disseminated involvement of 1 or more extralymphatic organs or tissues, with or without lymph node involvement