In this chapter, three primary groupings of lesions—reactive, developmental, and neoplastic—are considered. An important point in the discussion of lymphoid lesions involving the oral cavity and adjacent areas is that many lesions, especially those arising in lymph nodes, are capable of simulating malignancy.
It is sometimes difficult to distinguish reactive from neoplastic lymphoid proliferations, especially when they occur in unusual sites such as the peritonsillar area, palate, buccal mucosa, lymph nodes, and salivary glands. The incidence of benign cystic lymphoepithelial lesions within the parotid and submandibular glands is increasing in patients with acquired immunodeficiency syndrome (AIDS).
One of the normal sites of lymphoid tissue is the posterolateral portion of the tongue. Aggregations of lymphoid tissue within this area are part of the foliate papillae, or lingual tonsil. They may be distinguished from other lymphoid tissues by deep crypts lined by stratified squamous epithelium. These papillae occasionally become inflamed or irritated, with associated enlargement and tenderness. In such instances, patients may become symptomatic. On examination, these areas are enlarged and somewhat lobular in outline, with an intact overlying mucosa and prominent superficial vessels. In instances in which such lesions are removed for diagnostic purposes, the chief finding is reactive lymphoid hyperplasia. Within the enlarged germinal centers, mitoses and macrophages containing cellular debris may be seen. In addition to the foliate papillae, other zones where lymphoid tissue is found include the anterior floor of the mouth on either side of the lingual frenum, the anterior tonsillar pillar, and the posterior portion of the soft palate (Figures 9-1 and 9-2). Because lymphoid tissues are not always found in these areas, they are usually regarded as ectopic. The term oral tonsil also refers to this tissue.
Reactive lymphoid hyperplasia (oral tonsil) has male predominance and is noted within the second and third decades of life. In one study, a mean age of 23 years was found. Lesions range from 1 to 15 mm in diameter and may persist for years.
The buccal or facial lymph node is often the site of a reactive hyperplastic process. This is characterized as a freely movable submucosal nodule in the buccal mucosa that is usually adjacent to the second premolar and first molar teeth and can often be palpated extraorally. The cause of the process is unknown, but it may be a reaction to irritation or localized trauma. Gingivitis or periapical pathology may occasionally stimulate or initiate enlargement of this particular lymph node.
Follicular lymphoid hyperplasia may be seen in the palate. This reactive polyclonal proliferation of lymphocytes is often difficult to separate from lymphoproliferative disease of the palate, a condition that may signify lymphoma. Histologically, follicular lymphoid hyperplasia of the palate is characterized by irregularly sized, well-demarcated germinal centers with a crisply defined rim or mantle of small, mature lymphocytes. Within the germinal centers, macrophages contain phagocytosed nuclear debris. Using immunohistochemical techniques, a mixture of kappa and lambda light chains (B lymphocytes) is seen, indicating a polyclonal population of cells. In addition, the mantle zones are composed of both mature and immature B cells, whereas the extramantle zones contain both B and T lymphocytes, plasma cells, macrophages, and eosinophils. Indefinite follow-up is prudent because of possible progression to lymphoma.
Epithelioid hemangioma, also known as angiolymphoid hyperplasia with eosinophilia (ALHE), was first described in 1948 as a nodular subcutaneous benign disease in young men. Later, however, cases with the same clinical and histologic features were reported in the oral cavity. In addition to nodular aggregates of lymphocytes and eosinophils, regional lymphadenopathy and blood (peripheral) eosinophilia were noted. Similar findings were noted under the headings of Kimura’s disease, eosinophilic granuloma of soft tissue, and eosinophilic lymphofolliculosis. Because Kimura’s disease was originally described as having a distinct male predilection without associated regional lymphadenopathy, some clinicians believe that the two conditions represent different entities. Histologically, some differences have been described, adding to the tendency to split ALHE and Kimura’s disease into two separate but related entities.
Because of vascular proliferation and an intensive inflammatory infiltrate, a reactive etiology has been suggested. Increased serum immunoglobulin (Ig)E levels and deposition of IgE within the lymphoid follicles further suggest a reactive immune cause. Also demonstrated has been the presence of anti–Candida albicans antibody within the lesions and improvement after hyposensitization to this allergen.
ALHE is found predominantly in the head and neck area, accounting for approximately 85% of all cases. However, oral mucous membrane involvement is rare. The labial mucosa is the oral site most commonly affected. A wide age range from 7 to 79 years has been noted, with a mean age of 35 years. Lesions generally are solitary, with a mean size of 1.7 cm. Peripheral eosinophilia greater than 4% has been noted in 60% of cases in which peripheral blood counts have been studied. The clinical course is characterized by the presence of a painless, mobile, submucosal nodule that enlarges gradually. Multiple lesions have been reported in more than 40% of cases.
Lesions are circumscribed and usually are grossly separable from surrounding tissue. A nodular mass of hyperplastic lymphoid tissue with well-developed lymphoid follicles containing germinal centers may be seen. Proliferating capillaries with plump endothelial cells are found in a dense, patchy infiltrate of lymphocytes, with eosinophils and fewer numbers of macrophages noted. Toward the periphery, this infiltrate may extend into surrounding soft tissue. Arterial intimal proliferation and disruption of the internal elastic lamina may be seen. Early lesions or those in an active growth phase may be dominated by a vascular element; older or quiescent lesions may contain a larger percentage of inflammatory cells.
When it involves the labial mucosa, the characteristic nodule of ALHE may be indistinguishable from a minor salivary gland neoplasm or a mucus retention cyst or mucocele. Other benign soft tissue neoplasms, such as lipoma and schwannoma, might be included in the differential diagnosis.
Because of the presence of eosinophils within tissue, a microscopic differential diagnosis should include Langerhans cell disease (eosinophilic granuloma), traumatic (eosinophilic) granuloma, and possibly a drug reaction (hypersensitivity) or parasitic infection.
Lymphoepithelial cyst is an uncommon lesion of the mouth, major salivary glands, or neck that is thought to arise from an entrapment of epithelium within lymph nodes or lymphoid tissue during development. Subsequent epithelial proliferation results in a clinically evident mass.
Oral lymphoepithelial cysts (see also the discussion on ectopic lymphoid tissue in Chapter 3) present as asymptomatic mucosal elevations that are well defined and yellowish pink (Figure 9-3). The site most commonly affected is the floor of the mouth, where approximately 50% of cases are found. Ventral and posterolateral portions of the tongue constitute an additional 40% of cases; the balance is shared among the soft palate, the mucobuccal fold, and anterior facial pillars. A wide age range is noted, from adolescence to the seventh decade of life. The gender distribution is essentially equal. Except for the small central cystic space, these lesions are identical to ectopic lymphoid aggregates.
A marked increase in the incidence of lymphoepithelial cysts of the major salivary glands has been noted recently, particularly in those testing positive for the human immunodeficiency virus (HIV). The mechanism of cyst formation is unclear.
The lymphoepithelial cyst is lined by stratified squamous epithelium that often is parakeratotic. Focal areas of pseudostratified columnar cells or mucous cells may be present. The epithelial lining is surrounded by a discrete, well-circumscribed lymphoid component, often with germinal center formation and a sharply defined zone of mantle lymphocytes. In addition, the cyst wall may contain variable proportions of lymphocytes, macrophages, and plasma cells, with occasional multinucleated giant T cells (Figure 9-4). Continuity of the cyst lining with the surface oral epithelium may be noted occasionally.
In the anterior floor of the mouth, a sialolith may have a similar clinical appearance. However, a history of pain and swelling of the associated salivary gland would be expected with a salivary duct stone. Developmental anomalies such as teratomas or dermoid cysts, benign mesenchymal neoplasms, and salivary gland tumors might also be considered in a differential diagnosis for a floor-of-mouth soft tissue mass. When it involves the parotid gland, a lymphoepithelial cyst must be distinguished from salivary lymphoma, Warthin’s tumor, and cystic neoplasm of salivary origin.
Lymphomas are malignant neoplasms of component cells of lymphoid tissues. Broad division of the group into Hodgkin’s and non-Hodgkin’s lymphomas is widely accepted. Hodgkin’s lymphoma is primarily a disease of lymph nodes characterized by the presence of large binucleated cells called Reed-Sternberg cells and a lymphoid stroma composed of large numbers of non-neoplastic cells. Hodgkin’s lymphoma is very rare in the oral cavity.
Non-Hodgkin’s lymphomas (NHLs) are a relatively common group of neoplasms (more than 50,000 cases per year) that often occur in extranodal head and neck sites, especially in HIV-infected (AIDS) patients. NHLs are heterogeneous with a spectrum of behaviors. Some cases are indolent but ultimately fatal; others are aggressive and if left untreated kill the patient rapidly. NHL can arise in lymph nodes (nodal) and extranodal sites. Up to 40% of all NHLs arise at extranodal sites, with the most common site being the gastrointestinal tract. In the West, they most commonly occur in the stomach, but in the Middle East, the intestine is the most common location. The head and neck is the second most common site for extranodal NHL; most cases arise in Waldeyer’s ring.
Similar to lymphomas arising in lymph nodes, B-cell lymphomas are the most common phenotype in extranodal sites. A wide histologic and biological spectrum of B-cell lymphomas occur in the head and neck. Although most are diffuse large B-cell lymphomas, other types are seen in specific sites and populations of patients. These include Burkitt’s lymphoma occurring in the facial bones of young patients and T-cell and natural killer cell lymphomas in the nasofacial region, producing the clinical condition termed midline granuloma. A large proportion of lymphomas arise within lymph nodes embedded in the salivary tissues. Lymphomas may also arise within salivary gland parenchyma; they resemble those arising in mucosa-associated lymphoid tissue (MALT). This group of tumors, now known as extranodal marginal zone lymphomas, is genotypically and phenotypically unique and is characterized by a relatively long and indolent natural history.
The microscopic classification of NHL continues to evolve. At least eight classifications have been proposed over the past 30 years, but none have gained universal acceptance. The current and most widely adopted system is that from the World Health Organization (WHO) (Table 9-1), which is based on a prior system known as the Revised European American Lymphoma (REAL) scheme. This scheme divides lymphomas into T- and B-cell groups and includes a number of entities that arise at extranodal sites. This system focuses on distinct biological entities defined by a combination of clinical, morphologic, immunophenotypic, and genotypic features. It has been shown to be highly reproducible and clinically relevant. Moreover, because it is a list of entities, new lymphomas can be added when they are identified and characterized. Both the WHO and REAL classification systems have been criticized for their heavy reliance on immunohistochemical phenotyping and their problematic application when clinical information is missing or limited. Moreover, because both systems provide a list of entities without biological groupings, learning the systems can be difficult.
|B-Cell Neoplasms||T-Cell and Postulated NK-Cell Neoplasms|
|Precursor cell neoplasms||Precursor B-lymphoblastic lymphoma/leukemia||Precursor T-lymphoblastic lymphoma/leukemia|
|Peripheral (mature) cell neoplasms||B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL)||T-cell chronic lymphocytic leukemia|
|Lymphoplasmacytoid lymphoma||Large granular lymphocytic leukemia (T-cell or NK-cell type)|
|Mantle cell lymphoma||Mycosis fungoides|
|Marginal zone B-cell lymphoma (extranodal or nodal)||Peripheral T-cell lymphoma, unspecified|
|Splenic marginal zone B-cell lymphoma||Angioimmunoblastic lymphoma|
|Hairy cell leukemia||Intestinal T-cell lymphoma|
|Plasmacytoma||Adult T-cell lymphoma/leukemia|
|Diffuse large B-cell lymphoma||Anaplastic large cell lymphoma|
Little is known about the origin of NHL. Variations in incidence in different ethnic groups suggest a strong genetic predisposition. Immunodeficiency, whether acquired or congenital, is an important risk factor for the development of some lymphomas and may be related to a defective immune response to the Epstein-Barr virus (EBV), permitting clonal expansion of infected cells. Some lymphomas are clearly associated with specific chromosome translocations such as t(8;14), t(8;22), and t(2;8) in Burkitt’s lymphoma and t(11;14) in mantle cell lymphoma (Table 9-2). These specific chromosome translocations result in the dysregulation of oncogenes or tumor suppressor genes, producing unregulated cell proliferation. Why specific translocations occur is not known.
|Lymphoma Type||Translocation||Oncogene or Tumor Suppressor Genes||Mechanism|
|Follicular lymphoma||t(14;18)||Bcl-2||Juxtaposition of Bcl-2 with IgH promoter results in overexpressed antiapoptotic protein Bcl-2|
|Extranodal marginal zone||t(11;18)||AP12, MLT||Chimeric protein that inhibits apoptosis Juxtaposition of lymphoma Bcl-10 with IgH promoter results in overexpressed Bcl-10 protein|
|Mantle cell lymphoma||t(11;14)||Bcl-1 (cyclin D1)||Juxtaposition of Bcl-1 with IgH promoter results in overexpressed cyclin D1 protein|
|c-Myc||Overexpression of Myc is due to juxtaposition of the c-Myc gene with IgH, Igκ, or Igλ|
|Anaplastic large cell lymphoma||t(2;5)||NPM, ALK||Production of chimeric NPM, ALK protein, which has lymphoma tyrosine kinase activity|
The importance of proper staging (determining the clinical extent of disease) for patients with lymphoma in the oral region cannot be overemphasized. Staging serves a number of important purposes, including determination of the type and intensity of therapy, the overall prognosis for the patient, and potential complications associated with the disease. The Ann Arbor method, although initially designed to stage Hodgkin’s lymphoma, is now widely used for NHL (Box 9-1). Generally, patients are assigned a stage between I and IV depending on the site and extent of their tumor. In addition, patients are classified as “A” (no symptoms) or “B” (constitutional symptoms).
The staging procedure often differs according to the type and site of lymphoma. Gastrointestinal assessment is performed for lymphomas of Waldeyer’s ring because these tumors are often accompanied by gastrointestinal involvement. Extranodal marginal zone lymphoma tends to remain localized for prolonged periods and has a relatively indolent clinical course, hence less extensive investigation is often required. Assessment of the central nervous system (CNS) is performed for lymphomas of the nose and paranasal sinuses, and for lymphoblastic lymphoma and undifferentiated types. Bone marrow biopsy is generally performed for all extranodal lymphomas of the head and neck, but staging laparotomy is rarely done because visceral organ involvement is unlikely.
Clinically, three broad groups of NHLs can be discerned on the basis of biological behavior (Table 9-3). These lymphomas may be indolent, aggressive, or highly aggressive. Indolent lymphomas are characterized by slow growth, wide dissemination at presentation, a long natural history, and relative incurability. By contrast, aggressive and highly aggressive groups are characterized by rapid growth, frequent localized presentation, a short natural history, and frequent responsiveness to chemotherapeutic agents. Paradoxically, the most aggressive lymphomas are the ones most likely to be cured. Most lymphomas in adults are diffuse B-cell lymphoma or follicular lymphomas, which together make up more than 50% of all types. Follicular lymphoma is predominantly a tumor of lymph nodes and rarely occurs in the oral cavity. By contrast, T-cell lymphomas are considerably less common at all sites, including the oral cavity. In children, aggressive and highly aggressive lymphomas are the most common, with Burkitt’s lymphoma accounting for more than 40% of types.
|Examples of types||Follicular lymphoma B-CLL/SLL
Mantle cell lymphoma
|Diffuse B-cell lymphoma
Peripheral T-cell lymphoma
|Age||Adults||Any||Children, young adults|
|Stage at presentation||High (>80% stages III and IV)||Any||High|
|Tumor growth rate||Slow; proliferative fraction is low||Fast||Very fast; proliferative fraction >95%|
|Bone marrow involvement||Yes||Uncommon||Common|
|Natural history if untreated||Indolent, usually takes years to kill patient||Patient death in 1 to 2 years||Patient death in weeks to months|
|Response to treatment||Poor||Responsive||Very responsive|
Modified from Chan JKC: Chapter 21. In Fletcher CDM: Diagnostic histopathology of tumors, ed 2, London, 2000, Churchill Livingstone.
The clinical presentation of lymphomas of the oral region varies with their site of origin and tumor type, but most present as a mass or an ulcerated mass and resemble squamous cell carcinoma or salivary neoplasm. Other lymphoid malignancies, such as plasmacytoma and Burkitt’s lymphoma, show a striking predilection for primary involvement of bone. The microscopic characterization of specific lymphoma types is important because staging procedures and therapy may differ for each type. The only reliable method of distinguishing and characterizing these lesions is by immunophenotyping with the use of tissue-based immunologic studies or by flow cytometry of material obtained by fine-needle aspiration. Lymphomas arising within the oral cavity account for less than 5% of oral malignancies. In the head and neck, lymphomas may be />