Lymphomas Presenting in the Head and Neck: Current Issues in Diagnosis and Management

Chan Yoon Cheah

Fredrick B. Hagemeister

Lymphoma is the fifth most common cancer in Western countries, with 80,000 new cases estimated in the United States in 2014.¹ Up to a quarter of extranodal lymphomas present in the head and neck, and 8% of supraclavicular node fine needle aspiration (FNA) are lymphoma.² The 2008 World Health Organization (WHO) classification recognizes 54 distinct subtypes of lymphoma, which can be broadly classified as Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) with the latter category further divided according to their postulated normal cell of origin being of B- or T-cell lineage.³ Although lymphoma typically presents with lymphadenopathy, extranodal involvement is common with the most frequently involved extranodal site in the head and neck area being the tonsil, followed by the nasopharynx, oral cavity, salivary glands, paranasal sinuses, and base of the tongue. HL rarely presents with extranodal disease; however, in NHL, extranodal sites of involvement may be the primary (or exclusive) disease manifestation. Lymphomas are typically both chemo- and radiosensitive tumors and may be cured in a significant proportion of patients, even when presenting with disseminated disease. Therefore, the distinction of lymphomas from carcinomas and other malignancies is critical. The purpose of this chapter is to review the clinical presentation, diagnosis, staging, and treatment of this group of diseases with emphasis on patient treatment when presentation includes localized nodal or extranodal disease in the head and neck region.

CLINICAL PRESENTATION

The clinical presentation of lymphoma varies considerably depending on the anatomic site and underlying subtype; however, painless nodal enlargement is typical. Aggressive lymphomas with rapid proliferation may result in painful nodes due to central necrosis. Constitutional or “B” symptoms (unintentional weight loss, night sweats, unexplained fevers) are usually associated with aggressive lymphomas with advanced stage and are uncommon in patients with indolent or localized disease. An overview of typical presentations of lymphomas in the head and neck is presented in Table 26.1. In addition to standard evaluation for other lymphadenopathy and enlargement of the liver and spleen, physical examination should also specifically focus on evidence of superior vena cava obstruction, which may indicate a large mediastinal mass.

CLASSIFICATION

The classification of lymphoid neoplasms has evolved over time from a morphologic classification system (Rappaport, Kiel) into the current WHO classification, which incorporates molecular, immunophenotypic, cytogenetic, morphologic, and clinical features.³ Lymphomas can broadly be classified according to their normal hematopoietic counterpart (B-cell malignancies, T- and NK-cell malignancies, or HL) and the point of maturation of the cells (precursor or mature). Generally speaking, there is an inverse correlation between degree of maturation and proliferation rate. For example, the most immature (lymphoblastic lymphoma) is considered a nodal variant of acute lymphoblastic leukemia and is rapidly fatal if untreated. At the other end of the spectrum, indolent subtypes such as follicular lymphoma (FL) may sometimes be observed safely without treatment for more than 10 years. It is important to note that even within histologic subtypes, there exists considerable heterogeneity in disease biology, clinical behavior, and outcome. Tables 26.2 and 26.3 list the current (2008) WHO classification of B-cell and T- and NK-cell lymphomas, respectively.

ETIOLOGY

For any given individual patient with lymphoma, the precise etiology is usually unknown. However, risk factors for developing lymphoma have been identified. There is evidence for genetic susceptibility in lymphoma. Siblings of younger patients (<40) with HL have a 7-fold increased risk, and identical twins have a 100-fold risk.⁴^,⁵^,⁶ Relatives of patients with NHL also appear to be at 4- to 10-fold increased risk of developing NHL.⁵ Exposure to various substances including phenytoin, phenoxy herbicides (Agent Orange), hair dyes, dioxin, and benzenes has been found to have some correlation with an increased incidence of lymphoma.⁷^,⁸^,⁹^,¹⁰ Occupations in which exposure to these agents may occur are associated with a higher-than-normal risk for lymphoma; these include woodworking industries, agriculture, rubber and petrochemical industries, and dry-cleaning occupations. In contrast, exposure to ultraviolet sunlight (but not dietary vitamin D intake) and diets rich in fruits and vegetables have found to be associated with a reduction in the risk of developing lymphoma.¹¹^,¹²^,¹³ Exposure to prior radiation is also associated with increased risks of lymphoma, although the risk appears to be mainly in men.¹⁴

In addition to environmental factors, a variety of infectious agents have been associated with lymphomagenesis. In particular, chronic antigenic stimulation is thought to play an important role in the pathogenesis of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma).¹⁵ Of particular relevance to the head and neck setting, Chlamydophila psittaci DNA has been found in 47% to 80% of patients with ocular adnexal MALT
lymphoma,¹⁵ and eradication with doxycycline has been shown to be effective in some patients.¹⁶ Other infectious agents associated with MALT lymphoma include hepatitis C (splenic), Helicobacter pylori (gastric), and Borrelia burgdorferi (cutaneous). Patients with chronic hepatitis B also appear to carry an approximately threefold increased risk of development of NHL.¹⁷ Other viruses associated with lymphoma include human T-cell leukemia/lymphoma virus (HTLV)-1, Epstein-Barr virus (EBV), human herpes virus (HHV) 8, and HIV.¹⁸^,¹⁹ Immunosuppression, whether acquired (HIV infection, 11-fold),²⁰ congenital (combined variable immunodeficiency, 12-fold),²¹ or iatrogenic (organ transplant recipients, up to 240-fold),²² is probably among the most potent risk factors for the development of lymphoma. Finally, other disorders characterized by dysregulation of the immune system have been associated with development of lymphoma. An increased incidence of NHL has been noted in patients with rheumatoid arthritis, celiac disease, Sjögren syndrome, dermatitis herpetiformis, inflammatory bowel disease, and acquired angioedema.²³^,²⁴ Lymphoma of the thyroid has been associated with either antecedent diagnosis or concomitant histologic finding of Hashimoto thyroiditis in more than 90% of cases, although <1% of patients with Hashimoto thyroiditis will develop lymphoma.²⁵

Table 26.1 Anatomic Sites, Common Histologic Subtypes, and Clinical Manifestations of Lymphoma of the Head and Neck

Anatomic Location	Common Histologic Subtypes	Clinical Presentation
Cervical and supraclavicular nodes	Hodgkin lymphoma Diffuse large B-cell lymphoma Follicular lymphoma	With a rubbery/nodal enlargement Alcohol-induced node pain (<5% HL only)
Tonsils	Diffuse large B-cell lymphoma Follicular lymphoma Lymphoplasmacytic lymphoma Mantle cell lymphoma	Fleshy, nonulcerated unilateral tonsillar mass, odynophagia, globus sensation, dysphagia, and hearing loss secondary to otitis media
Salivary glands	Marginal zone lymphoma	Asymmetric swelling
Nasopharynx and paranasal sinuses	Extranodal NK-cell lymphoma Diffuse large B-cell lymphoma	Nasal obstruction, epistaxis, sinusitis, bloody drainage, or pain
Orbits, ocular adnexal tissue	Extranodal marginal zone lymphoma Diffuse large B-cell lymphoma	Facial swelling, ocular discomfort, diplopia, proptosis, conjunctival lesions, lacrimal duct blockage
Thyroid	Diffuse large B-cell lymphoma Marginal zone lymphoma	Swelling of the neck, dysphagia, dysphonia or hoarseness, or facial edema
Base of the skull, leptomeninges, brain	Diffuse large B-cell lymphoma Mantle cell lymphoma Burkitt lymphoma Lymphoblastic lymphoma Double-hit lymphomas Intravascular large B-cell lymphoma	Cranial nerve palsies, headache, pyramidal weakness, dysphasia, ataxia, vertigo

EPIDEMIOLOGY

The incidence of lymphoma has been increasing, and lymphomas account for 3% to 4% of cancers worldwide.²⁶ Lymphoma is the leading cause of cancer death in adolescents and young adults.¹ HL has a bimodal incidence curve, the first peak occurring in teenagers to young adults and the second peak in older adults (>55 years).²⁷ There is a higher frequency among males than females. The incidence of NHL varies by histologic subtype: highly aggressive histologic subtypes (e.g., lymphoblastic and Burkitt lymphoma) are more common in children and adolescents, but most other forms of NHL are diseases of older adults, in particular, elderly adults (>60 years). NHL is more common in men than women, though the size of the discrepancy varies between subtypes.³ HL accounts for around 10% of lymphoma diagnoses; in developed countries, 70% are nodular sclerosing, 20% are mixed cellularity, 5% are lymphocyte rich, and 1% are lymphocyte depleted, a group of diseases known collectively as classical HL, and 5% are nodular lymphocyte predominant, a disease that has a morphologic appearance that is distinct from the classical variants.³ Among NHL, B-cell lymphomas are vastly more common and constitute 85% to 90% of NHL with T- and NK-cell lymphoma constituting the remainder.³

DIAGNOSTIC EVALUATION

Fine Needle Aspiration

When a patient presents with lymphadenopathy in the head and neck region, FNA is helpful only as a minimally invasive test that can distinguish carcinoma or some other malignant process from lymphoma. If a diagnosis of lymphoma is favored by FNA findings, either excisional biopsy or image-guided core biopsy (if excisional biopsy is considered unfeasible) is needed, as the classification of lymphomas relies heavily on the histologic pattern of the malignancy in the lymph node. FNA may also result in both false negatives (e.g., concurrent reactive hyperplasia may occur as a response to the lymphoma in the lymph node) and false positives (e.g., infectious mononucleosis in which individual cells may appear aberrant). Therefore, a patient with a negative FNA but a clinically enlarging lymph node should undergo definitive excisional biopsy before a final diagnosis can be verified.

Table 26.2 WHO Classification of Mature B-Cell Lymphomas

Mature B-Cell Lymphomas
Diffuse large B-cell lymphoma (DLBCL), not otherwise specified
	T-cell/histiocyte-rich large B-cell lymphoma DLBCL associated with chronic inflammation EBV + DLBCL of the elderly Primary mediastinal B-cell lymphoma Intravascular large B-cell lymphoma Primary cutaneous DLBCL, leg type ALK+ large B-cell lymphoma Plasmablastic lymphoma Primary effusion lymphoma Large B-cell lymphoma arising in HHV-8-associated multicentric Castleman disease
Follicular lymphoma Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) Chronic lymphocytic leukemia/small lymphocytic lymphoma
	Splenic marginal zone lymphoma Lymphoplasmacytic lymphoma Nodal marginal zone B-cell lymphoma (MZL) Primary cutaneous follicle center lymphoma Mantle cell lymphoma Lymphomatoid granulomatosis Burkitt lymphoma B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical HL
Hodgkin Lymphoma Nodular lymphocyte-predominant HL Classical HL
	Nodular sclerosis classical HL Lymphocyte-rich classical HL Mixed cellularity classical HL Lymphocyte-depleted classical HL
Bold text denotes entities commonly presenting in the head and neck. © Copyright World Health Organization (WHO), 2016. All Rights Reserved.

Biopsy

Biopsy of a representative lymph node is still the optimal procedure for establishing the diagnosis and subclassification of lymphomas. The selection of node for biopsy depends on the safety and accessibility of lymph nodes and the availability of baseline PET-CT imaging. The latter is valuable as the standardized uptake value (SUV) has some correlation with proliferation index in NHL,²⁸^,²⁹ and thus, the targeted biopsy of a node with SUV significantly higher than other involved nodal areas can be used to establish the presence of histologic transformation of an indolent lymphoma.³⁰ A prospective study of 38 patients with indolent lymphoma undergoing PET-CT-directed biopsy used ROC analysis to identify an optimum SUV cutoff of 14, which resulted in a positive predictive value of 93.9% and specificity and negative predictive value of 95.3% for detecting histologic transformation.³¹ As the presence of histologic transformation may have significant treatment and prognostic implications, in cases where there is heterogeneous nodal ¹⁸F-flurodeoxyglucose (FDG) avidity present, the area with highest SUV should be biopsied if feasible. Excisional biopsy is preferred; however, in cases where excisional biopsy is not feasible, CT-guided core biopsy is an acceptable alternative. Rebiopsy is usually necessary in patients who have residual FDG-avid masses at the completion of therapy, particularly if escalation of therapy is planned as the finding of nonmalignant pathologies, such as necrosis, foamy macrophages, or sarcoidosis, is not unusual in this setting.³²^,³³ Rebiopsy is also needed at time of relapse as it is possible for indolent lymphomas to undergo transformation to aggressive lymphomas such as diffuse large B-cell lymphoma (DLBCL) and vice versa.³⁴^,³⁵ The entire lymph node should be removed in one piece and its capsule maintained intact. The lymph node must be handled gently during surgery to minimize crush artifact, and the tissue should be placed fresh in saline and transported to the laboratory immediately to minimize deterioration of the sample. Biopsies of the tonsil, base of the tongue, and nasopharynx are done in the same manner as biopsy in diagnosis of squamous cell carcinoma.

Table 26.3 WHO Classification of Mature T- and NK-Cell Neoplasms

Mature T- and NK-Cell Lymphomas
Extranodal NK-/T-cell lymphoma, nasal type
Anaplastic large cell lymphoma (ALCL), ALK+
Anaplastic large cell lymphoma (ALCL), ALK-
Peripheral T-cell lymphoma, not otherwise specified
Angioimmunoblastic T-cell lymphoma
Systemic EBV⁺ T-cell lymphoproliferative disease of childhood (associated with chronic active EBV infection)
Hydroa vacciniforme-like lymphoma
Adult T-cell leukemia/lymphoma
Enteropathy–associated T-cell lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Mycosis fungoides
Sézary syndrome
Primary cutaneous CD30⁺ T-cell lymphoproliferative disorder
	Lymphomatoid papulosis Primary cutaneous anaplastic large-cell lymphoma
Primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma
Primary cutaneous gamma-delta T-cell lymphoma
Primary cutaneous small/medium CD4⁺ T-cell lymphoma
Bold text denotes entities commonly presenting in the head and neck. © Copyright World Health Organization (WHO), 2016. All Rights Reserved.

Pathologic Studies

Histology

Histologic evaluation of a lymph node involved by lymphoma should include an assessment of tumor cell morphology, growth pattern of the lymphoma (diffuse or follicular), and the presence of composite lymphomas (where two histologically distinct lymphomas exist in a single lymph node or in different nodes contemporaneously in the same patient). Immunohistochemistry can confirm hematopoietic origin of the tumor (CD45 or LCA), distinguish tumor cells from normal
or reactive lymphoid tissue, determine B-cell (CD20, PAX5) or T-cell (CD3, CD5) lineage and proliferation index (Ki 67), assist in the determination of specific subtype (e.g., cyclin D1 expression in mantle cell lymphoma or CD10, BCL6, and MUM1 to determine cell of origin in DLBCL),³⁶ and give prognostic information (coexpression of MYC and BCL2 or BCL6 in the highly aggressive double-hit lymphoma).³⁷ Additional surface marker studies such as keratin, mucin stain, or S100 may also be useful in excluding squamous cell carcinoma, adenocarcinoma, and melanoma, respectively.

Table 26.4 Important Chromosomal Translocations in Lymphoma

Histologic Subtype	Gene	Cytogenetic Abnormalities	Utility
Diffuse large B-cell lymphoma	MYC	MYC/8q24	MYC and BCL2 and/or BCL6 = double- or triple-hit lymphoma, adverse prognosis
	BCL2	BCL2/18q21
	BCL6	BCL6/3q27
Burkitt lymphoma	MYC-IGH	t(8;14) (q24q32)	Diagnosis
	MYC-IGK	t(2;8)(p12q24)
	MYC-IGL	t(8;22)(q24q11)
Follicular lymphomas; some large-cell lymphomas	IGH-BCL2	t(14;18) (q32q21)	Diagnosis
Mantle cell lymphoma	CCND1-IGH	t(11;14) (q13q32)	Diagnosis
Marginal zone lymphomas	FOXP1-IGH	t(1;14) (p22q32)	BIRC3-MALT resistant to antibiotic therapy
	IGH-MALT1	t(3;14)(p14.1q32)
	BIRC3-MALT1	t(11;18)(q12q21)
Anaplastic large-cell lymphoma, ALK+	NPM1-ALK	t(2;5) (p23q35)	Diagnosis, prognosis (ALK+ better than ALK-)
Extranodal NK-cell lymphoma, nasal type		del(6)(q21q25)	Uncertain

Flow Cytometry

Flow cytometric analysis is a useful complementary tool in the diagnosis of lymphomas as it allows for the detection of two or more markers simultaneously (e.g., concurrent expression of CD19 and CD5 in small lymphocytic and mantle cell lymphoma), has rapid turnaround, and can provide a more quantitative assessment of the intensity of antigen expression than immunohistochemistry. However, it gives no information about cellular morphology and is not useful in the diagnosis of HL as the neoplastic Reed-Sternberg cells constitute <1% of the cellular population in involved lymph nodes. In the setting of NHL, when performed on FNA specimens, it can distinguish B-cell or T-cell lineage, although in most cases accurate subtyping is still contingent on evaluation of an adequate biopsy sample. It is also more sensitive than cytology alone in detecting lymphoma cells in cerebrospinal fluid (CSF) in patients with leptomeningeal disease and should always be requested in addition whenever lumbar puncture is performed.³⁸^,³⁹^,⁴⁰

Cytogenetic Analysis

Cytogenetic analysis by conventional karyotype or fluorescence in situ hybridization (FISH) may be required in specific lymphoma subtypes or clinical presentations. These studies can be performed on both fresh and formalin-fixed paraffinembedded tissue and will usually be requested as needed by the reporting pathologist or treating hemato-oncologist. FISH can identify a range of chromosomal abnormalities including deletions, gains, translocations, and duplications and can be used to provide both diagnostic and prognostic information. Table 26.4 summarizes clinically relevant chromosomal abnormalities in lymphoma.

Molecular Analysis

In some cases, the distinction of malignant lymphoma from a reactive lymphoid proliferation can be difficult, and molecular analysis for polymerase chain reaction for immunoglobulin gene rearrangements (in B-cell NHL) or T-cell receptor gene rearrangements (in T-cell NHL) to demonstrate clonality can be helpful in some cases.⁴¹ Perhaps the defining milestone in medicine in the last decade has been the advent of highthroughput whole-exome sequencing. The increasing availability and decreasing cost of this technology have resulted in definition of the mutational landscape of many lymphoma subtypes.⁴²^,⁴³^,⁴⁴^,⁴⁵ These advances will fundamentally change the way lymphomas (and for that matter, all cancers) are classified, diagnosed, and treated. However, at the present time, technologies such as next-generation sequencing, nanostring, and whole-exome sequencing remain largely research tools and are not widely available in diagnostic pathology laboratories.

Staging

For the last 40 years, the Ann Arbor classification system has remained the most widely used staging system for lymphomas (Table 26.5).⁴⁶ Originally designed for HL (which spreads in a pattern of anatomic contiguity), the system classifies patients as having limited (I/II) or advanced (III/IV) stage—a division that remains critically important for prognostic and therapeutic purposes for many (but not all) types of lymphoma. Although widely used in NHL, it is not ideally suited to describe disease extent due to frequent involvement of extranodal sites. Furthermore, in both HL and many subtypes of NHL, specific prognostic indices have been developed, which may incorporate stage as only one of several factors (Table 26.6).

Table 26.5 Ann Arbor Staging Classification

Stage I	Involvement of a single lymph node region (I) or a single extralymphatic organ or site (I_E)
Stage II	Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site (II_E)
Stage III	Involvement of lymph node regions on both sides of the diaphragm (III) or localized involvement of an extralymphatic organ or site (III_E) or spleen (III_S) or both (III_SE)
Stage IV	Diffuse or disseminated involvement of one or more extralymphatic organs with or without associated lymph node involvement
A	Absence of B symptoms
B	Unexplained fever (>38°C), night sweats, unintentional weight loss >10% of body weight
From Carbone PP, Kaplan HS, Musshoff K, et al. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res. 1971;31:1860-1861.

Table 26.6 Prognostic Scoring Systems in Selected Lymphoma Subtypes

Histologic Subtype	Prognostic Index	Components (Points)	Risk Groups	Outcome
Diffuse large B-cell lymphoma	NCCN-IPI⁴⁷	Age, normalized serum LDH		5-y OS
Diffuse large B-cell lymphoma	NCCN-IPI⁴⁷	Involvement of marrow, GIT/liver, lung, or CNS, stage III/IV, ECOG ≥2	Low Low intermediate High intermediate High	96% 77% 56% 38%
Follicular lymphoma	FLIPI-2⁴⁸	Age, elevated serum LDH, hemoglobin <12 g/dL, marrow involvement, longest diameter of largest involved node 6 cm	Low Intermediate High	5-y PFS 80 51 19
Mantle cell lymphoma	MIPI⁴⁹	Age, ECOG, normalized LDH, WBC	Low Intermediate High	5-y OS 60 35 20
Classical Hodgkin lymphoma (stage III/IV only)	IPS⁵⁰	Albumin <4 g/dL, hemoglobin <10.5 g/dL, male, age >45, stage IV, white-cell count >15 × 10⁹/L, lymphocyte <8% of total WBC	Number of factors 0 1 2 3 4 5+	5-y FFP 84% 77% 67% 60% 51% 42%
Nodular lymphocytepredominant Hodgkin lymphoma	NLPHL score⁵¹	Variant histology, albumin, gender	Low Intermediate High	5-y PFS 95% 87% 69%
NK-/T-cell lymphoma	NKPI⁵²	B symptoms, stage III/IV, elevated LDH, regional nodal involvement	Number of factors 0 1 2 3-4	5-y OS 81 64 34 7
NCCN, National Comprehensive Cancer Network; IPI, International prognostic index; FL, follicular lymphoma; M, mantle cell lymphoma; NK, natural killer cell; IPS, international prognostic score; NLPHL, nodular lymphocyte-predominant Hodgkin lymphoma; LDH, lactate dehydrogenase; GIT, gastrointestinal tract; CNS, central nervous system; ECOG, eastern cooperative oncology group; WBC, white blood cell count; OS, overall survival; PFS, progression-free survival; FFP, freedom from progression.