Etiology

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.

Clinical Features

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.

Histopathology

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.

Differential Diagnosis

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.

Treatment

Excision is the treatment of choice. Intralesional steroid injections have been used with variable results. Recurrences are occasionally noted. The presence of blood or peripheral eosinophilia has generally been reported with numerous or recurrent lesions.

Classification

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.

Etiology

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.

Staging

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.

Clinical Features

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.

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 />