Nasal T-cell lymphoma

Annals of Oncology 5 (Suppl. 1): S39-S42, 1994. © 1994 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Nasal T-cell lymphoma L. M. Weiss,1 D. A. Arber 1 & J. G. Strickler2 1 Division of Pathology, City of Hope National Medical Center, Duarte, California; 2 Department of Pathology, Mayo Clinic, Rochester, Minnesota, USA

Summary

Nasal T-cell lymphomas represent a controversial subset of malignant lymphomas and include lesions previously termed midline malignant reticulosis, lymphomatoid granulomatosis, and polymorphic reticulosis. Nasal T-cell lymphomas are rare in Western populations and much more prevalent in Asian countries. Clinically, adult males are most often affected. Histologically, an angiocentric infiltrate composed of a spectrum of atypical cells is usually present. Phenotypically, the neoplastic cells lack expression of B-lineage markers, and usually express the T-lineage-associated markers CD2, CD45RO, and CD43; however, they often lack other pan-T-

Key words: Epstein-Barr virus, lymphomatoid granulomatosis, malignant lymphoma, nasal lymphoma, natural killer cells, polymorphic reticulosis, T-cell lymphoma

Nasal lymphomas represent a controversial subset of malignant lymphomas, owing in part to the difficulty of recognizing them, both clinically and pathologically. Clinically, nasal lymphomas are part of the clinical spectrum of lethal midline granuloma or midfacial necrotizing lesions caused by various pathologic processes which also include Wegener's granulomatosis, infections, sarcoidosis, and idiopathic midline destructive disease. Pathologically, a mixed infiltrate is often found, difficult to distinguish from reactive processes. This has led to the use of an array of confusing pathologic terms, such as malignant granuloma, midline malignant reticulosis, lymphomatoid granulomatosis, and polymorphic reticulosis. The incidence of nasal lymphomas is difficult to assess, given the difficulty of recognition, the tendency in the literature to group these uncommon lymphomas with lymphomas arising in adjacent structures such as the sinuses and nasopharynx (which may or may not be similar to nasal lymphomas), and the differences among different populations studied. In 'Western' populations, nasal lymphomas are rare. In a series from the University of Virginia, 1.5% of all non-Hodgkin's lymphomas occurred in the nasal cavity and paranasal sinuses, although cases of 'midline malignant reticulosis' were excluded from the analysis [1]. Of 33 402 cases of malignant lymphomas registered in the Kiel Lymph Node Registry from 1972 to 1987, the incidence of malignant lymphomas in the nasal cavity and paranasal sinuses was found to be 0.17% of all malignant lymphomas and 0.44% of all extranodal malignant

lymphomas [2]. Eighty-five percent of these cases were considered to be primary in the nose, while only 15% were primary in the sinuses. In this latter study, cases with extranasal or extrasinusal tumor at the time of biopsy were excluded. Among Western populations, the incidence of a B-cell vs. T-cell phenotype varies widely among different series. In a combined series from the University of Virginia and the University of Minnesota, 85% of cases of nasal lymphoma were of B-cell phenotype, although the series may have been skewed by inclusion of cases from the nasal sinuses and exclusion of cases of 'midline malignant reticulosis' [3]. However, in the Kiel series B-cell lymphomas also predominated, accounting for 74% of cases of primary lymphomas of the nose [2]. Other, although smaller series, have shown a preponderance of cases of T-cell phenotype [4-8], particularly when selected for clinical features of lethal midline granuloma [4] or for histologic features of 'polymorphic reticulosis' [8]. Nasal lymphomas are much more prevalent in Asian countries and represent the second most frequent group of extranodal lymphomas after gastrointestinal tract lymphomas [9, 10]. In a series of 294 cases of malignant lymphoma occurring in Hong Kong Chinese patients, nasal lymphomas represented 2.6% of all nonHodgkin's lymphomas [9], while in a second series of 75 cases, nasal lymphomas represented 6.7% of nonHodgkin's lymphomas [10]. The overwhelming majority, perhaps representing greater than 90% of these Asian cases, possess at least some T-lineage markers

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lineage markers. They often express the natural killer marker CD56, but usually lack the natural killer markers CD16 and CD57. Gene rearrangement studies have shown a germline configuration for the antigen receptor genes in the majority of cases. To date, evidence of Epstein-Barr virus has been consistently demonstrated, regardless of the geographic region studied. In situ hybridization studies have localized the Epstein-Barr virus to the atypical cells.

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lesion (AIL) to describe these lymphomas [18]; most of the lesions occurring in the nose have had features of AIL grade 2 (polymorphous lymphoid infiltrate with atypia in the small lymphoid cells) or grade 3 (monomorphous population of large atypical lymphoid cells, associated with prominent necrosis) [8]. In contrast, nasal lymphomas of B-cell phenotype generally show a monomorphous population of large atypical lymphoid cells, without a prominent admixture of reactive cells. In addition, nasal B-cell lymphomas usually do not demonstrate angiocentricity or angioinvasion. Nasal T-cell lymphomas characteristically demonstrate a highly unusual phenotype. By definition, they lack expression of reliable B-lineage markers, such as CD20, CD19, or immunoglobulin expression. They usually express CD2, CD45RO, and CD43, consistent with a T-lineage neoplasm [4, 6-8, 13, 15, 17, 19]. However, they often completely lack other pan-, or subset-T-lineage markers such as CD3, CD5, alpha/ beta protein, gamma/delta protein, CD4, and CD8 [7, 13, 15, 19], although some studies have found the majority of the cases to be positive for CD3 [6, 8, 13]. The expression of the majority T-cell marker CD7 is also controversial, and has been reported to be usually positive [4, 7] and usually negative [15]. Analysis of recurrences has sometimes demonstrated a progressive loss of antigens, including CD3 [13]. Interestingly, these cases usually show expression of the natural killer marker CD56, although expression of other markers of natural killer cells, such as CD16 and CD57, is not generally found [7, 15, 19, 20]. In addition, a proportion of the tumor cells usually also express the activation markers CD25, CD30, and HLA-DR [4, 7, 12]. A variable rate of positivity has been found using the proliferation marker Ki-67; high proliferation rates are generally found in cases with a high component of large cells [4]. Antigen receptor gene rearrangement studies have yielded surprising results in these lymphomas. Although large numbers of these cases have not been studied, the majority have shown a germline configuration for the beta, gamma, and delta T-cell receptor genes [6, 15, 19, 21, 22], even when the monoclonality of the tumor cells can be demonstrated by other studies [22]. Occasional cases have been found to possess isolated beta, gamma, or delta T-cell receptor gene rearrangements [7,19,21,22]. To date, evidence of Epstein-Barr virus (EBV) has been consistently demonstrated in virtually all nasal T-cell lymphomas, including those from Asia, Peru, and Western populations, using polymerase chain reaction, Southern blot, in situ hybridization, and immunohistochemical studies [8, 14, 17, 21-24]. Southern blot studies employing a probe that hybridizes to a region adjacent to the terminal repeat region have demonstrated that EBV genomes are present in a monoclonal population of cells [21, 22]. In situ hybridization studies have localized EBV DNA (internal repeat region) [7, 14, 23] and RNA (EBER) to the atypical lymphoid

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and lack B-lineage markers [10-15]. A high incidence of nasal lymphoma is also found in Peru, where nasal lymphoma represents approximately 8% of all hematolymphoid neoplasms [16]. Similar to the Asian cases, a high incidence of a T-cell phenotype is seen [17]. Clinically, series of patients with nasal T-cell lymphoma generally show a male predominance [8, 17], particularly in Asian populations [12, 13]. The median age affected is about fifty years. Nasal obstruction, with or without a discharge, is the presenting symptom in the majority of patients [12,17]. In one series, recurrent maxillary sinusitis was the presenting symptom in the majority of cases [7], and epistaxis and swelling of the face also occur in some patients. The lymphomas may involve the right or left nasal cavity (or both) or the septum. Grossly, they appear as a destructive mass, with frequent ulceration. The lymphomas are usually localized to the nose or show invasion of adjacent structures such as the nasopharynx, the paranasal sinuses, or the oropharynx, including the palate. Dissemination at the time of presentation occurs in a minority of patients and usually involves extranodal sites such as skin and lung, rather than lymph nodes [4, V]. Treatment has been inconsistent in the literature, with some groups using localized radiotherapy alone (for 'polymorphic reticulosis') [6, 8, 13], while other groups prefer multiagent chemotherapy with or without additional radiation therapy [7]. Use of chemotherapy alone has often not been sufficient to completely eradicate local disease [7]. Although some groups report a long median survival, death from disease occurs in approximately 50% of patients [8]. Relapse may occur either locally or may be systemic, often involving extranodal sites such as skin and lung. Histologically, a mixed infiltrate is characteristically present, including lymphoid cells, plasma cells, eosinophils, and histiocytes. The infiltrate often is angiocentric or frankly angioinvasive, and may also show invasion of cartilage or bone. Necrosis may be focal or widespread, and is often due to vascular compromise. The lesions vary from cases in which a mixed infiltrate of small atypical and large cells is found to cases in which atypical large cells predominate. Biopsies of recurrences may show a greater proportion of large cells than the initial biopsy [4]. Giemsa-stained touch preparations of the lesions may reveal azurophilic granules in the atypical cells [15]. The surface epithelium usually is ulcerated or undergoes squamous metaplasia, but occasionally may show pseudoepitheliomatous hyperplasia [6]. Nonulcerated epithelium may often contain small infiltrates of epitheliotropic atypical lymphocytes [12]. In the Working Formulation, most of the cases would fit into the categories of intermediate-grade lymphoma, diffuse mixed small- and large-cell and diffuse large-cell lymphoma, and high-grade lymphoma, largecell immunoblastic [6, 8, 12, 17]. Some investigators have used the term angiocentric immunoproliferative

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Correspondence to: Lawrence M. Weiss, M.D. Division of Pathology City of Hope National Medical Center 1500 E. Duarte Road Duarte, California 91010 USA

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