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Altered immune signatures in breast cancer lymph nodes with metastases revealed by spatial proteome analyses.

BACKGROUND: Metastasis to lymph nodes is strongly associated with reduced survival in breast cancer patients. To increase the understanding on how lymph node metastasis impairs the local immune response in affected lymph nodes, we here studied spatial proteomic changes of critical lymph node immune populations in uninvolved lymph nodes (UnLN) and paired lymph nodes with metastases (LNM) from five breast cancer patients. METHODS: The proteome was analyzed for cortical lymphocyte compartments, subcapsular sinus (SCS) and medullary sinus (MS) CD169+ macrophages, using the Digital Spatial Profiling (DSP) platform from NanoString. RESULTS: Our results identified a stable proteome of SCS CD169+ macrophages in LNM, with the exception for downregulation of the anti-apoptotic protein Bcl-xL and FAPα, but a clear reduction in numbers of SCS CD169+ macrophages in LNM. In contrast, the proteome of MS CD169+ macrophages, B-cell compartments and interfollicular T-cells showed altered immune signatures in LNM, indicating that the decline in SCS CD169+ macrophages coincide with a malfunction in the local, anti-tumor immune responses. CONCLUSIONS: The findings from our study support the notion that metastasis to lymph nodes in breast cancer patients modifies local immune responses. These changes may contribute to explain unsuccessful therapeutic responses, and thereby worsened prognosis, for breast cancer patients with LNM.

Breast Neoplasms↗

Flow cytometric and immunohistochemical characterization of the gamma/delta T-lymphocyte population in normal human lymphoid tissue and peripheral blood.

We determined the quantitative and topographic distribution of gamma/delta lymphocytes in normal human lymphoid tissue and peripheral blood using a monoclonal antibody that detects a framework determinant on delta molecules and delineated the immunophenotypic characteristics of the gamma/delta lymphocyte population by one- and/or two-color immunohistochemical and two- and/or three-color flow cytometric analysis. Variable, but generally small, numbers of gamma/delta lymphocytes are present in peripheral blood and in all lymphoid tissues. The vast majority, greater than or equal to 90%, of lymphoid tissue delta lymphocytes reside in interfollicular (T-cell) zones. Approximately 90% of delta thymocytes are present in the thymic medulla. The percentage of CD3-positive T cells that express delta are: spleen 12.5 +/- 8.1%, peripheral blood 4.0 +/- 3.1%, appendix 2.9 +/- 1%, lymph node 2.2 +/- 1%, thymus 1.4 +/- 0.5%, and tonsil 0.7 +/- 0.5%. We further demonstrated that 1) gamma/delta-thymocytes and gamma/delta peripheral lymphocytes express T-cell lineage restricted antigens CD3 and CD2 but only a variable subset, 30% to 90%, express T-cell lineage associated antigens CD5 and/or CD8; (2) approximately 60% of gamma/delta thymocytes express low-density CD4 while all gamma/delta peripheral lymphocytes lack detectable CD4; 3) gamma/delta lymphocytes lack natural killer (NK), macrophage, and B-cell associated antigens CD16, CD14, and CD20, respectively, but greater than or equal to 70% of gamma/delta T lymphocytes express CD11b, Leu7, and NKH-1, antigens, which are also expressed by suppressor/cytotoxic and NK cells; and 4) a large subpopulation, approximately 25%, of gamma/delta thymocytes are in S1-G2 phase, while greater than or equal to 98% of gamma/delta peripheral lymphocytes are small lymphocytes in G0-G1 phase and lack activation/proliferation markers. Together these results indicate that gamma/delta lymphocytes are resting, mature T cells that probably play a primary role in suppressor/cytotoxic phenomena. They also indicate that gamma/delta lymphocytes variably express multiple-cell surface antigens associated with various cell lineages, suggesting that gamma/delta lymphocytes represent a considerably more heterogeneous cell population than previously appreciated and that they may actually subserve multiple functions.

Animals↗

alpha-Naphthyl acetate esterase activity--a cytochemical marker for T lymphocytees. Correlation with immunologic studies of normal tissues, lymphocytic leukemias, non-Hodgkin's lymphomas, Hodgkin's disease, and other lymphoproliferative disorders.

Cytochemical identification of T lymphocytes on the basis of alpha-naphthyl acetate esterase (NAE) activity was compared with immunologic markers for cell suspensions and/or cryostat sections of 113 specimens. Nonneoplastic tissues (peripheral blood, lymph nodes, spleens, tonsils, thymus, and pleural fluid) and specimens from various lymphoproliferative disorders, including acute and chronic lymphocytic leukemia, lymphosarcoma cell leukemia, hairy cell leukemia, non-Hodgkin's lymphomas of B-and T-cell types, and Hodgkin's disease, were evaluated. T (E-rosetting) cells demonstrated several patterns of NAE reactivity: 1) a strong globular reaction product, the most specific pattern for T-cell identification, 2) granular cytoplasmic staining, or 3) no reactivity. B lymphocytes revealed a granular pattern of NAE staining, were devoid of enzyme, or, in rare instances, exhibited strong NAE activity. Percentages of lymphoid cells with strong (globular) NAE activity closely paralleled T-cell (E-rosette) values in the majority of cases, with the best correlations observed for peripheral blood studies. However, discordant results were noted for some neoplastic and nonneoplastic tissues, including cases of T-cell lymphoma or leukemia. Markedly discrepant results were noted for thymic lymphocytes, most of which revealed E-rosette formation and weak or absent NAE activity. Lymph nodes involved by Hodgkin's disease demonstrated a heterogeneous pattern of staining in E-rosetting cells and in Reed-Sternberg variants. Cryostat section studies of reactive lymph nodes and nodular lymphomas demonstrated strong NAE staining in lymphoid cells of T-cell (interfollicular, internodular) areas, with little or no positivity in follicles or nodules (B-cell areas). NAE staining patterns further suggested that T cells comprise part of the follicular cuff and possibly represent a minor population of some neoplastic nodules. Although NAE determinations do not represent a consistently reliable alternative to immunologic methods for T-cell identification, this easily applicable cytochemical marker is complementary to other techniques in assessing neoplastic or nonneoplastic tissues, particularly cryostat sections. (Am J Pathol 97:17--42, 1979).

Adult↗

[Double immunoenzymatic and two-color flow cytometric analyses of tonsillar T-cell subsets].

Distribution of various T-cell subsets in the palatine tonsil was investigated by two-color flow cytometry and double immunoenzymatic stain. Tonsillar lymphocytes contained many (about 20%) helper T (CD4+ Leu8-) cells and few (only 1%) suppressor T (CD8+ CD11b+) cells. In interfollicular area, each T-cell subset, i.e., helper, helper-inducer (CD4+ CD29+), suppressor-inducer (CD4+ CD45RA+), cytotoxic (CD8+ CD11b-), and suppressor, was identified by double immunoenzymatic labeling technique using alkaline phosphatase and peroxidase. On the other hand, only two T-cell subsets, helper, and cytotoxic T-cell subpopulations, were recognized in germial center. These results indicate that double immunoenzymatic stain as well as two-color flow cytometry gives us useful informations in terms of tonsillar T-cell subsets.

Flow Cytometry↗

Mucosal immune activation and maturation of the small intestine at weaning in the hypothymic (nude) rat.

Activation of the mucosal immune system peaks at weaning on days 21 and 22 of life in the rat. We have investigated activation in the gut associated lymphoid tissue and maturation of intestinal mucosa in hypothymic (nude) and in phenotypically normal heterozygous CBH rats at 22 days of life. Intestinal maturation, as assessed by villus area, crypt length, crypt cell production rate and disaccharidase activity, was similar in hypothymic and normal rats, and indices of mucosal immune function were elevated in both groups at this time. The proportion of mononuclear cells from the mesenteric lymph node expressing IL-2R was 11% in heterozygous and 14% in hypothymic rats as determined by flow cytometry. Immunoperoxidase staining of MLN sections confirmed the presence of IL-2R+ cells in the T-dependent interfollicular areas. However, the number of T-cells was considerably depleted in hypothymic rats. Intraepithelial lymphocyte counts and serum rat mucosal mast cell protease II concentrations were similar in the two groups, while counts of jejunal mucosal mast cells and eosinophils were paradoxically increased in hypothymic animals. As T lymphocyte function is thought to be impaired in hypothymic rats, the intact mucosal immune activity in hypothymic rats could be due to activation of intrinsic "thymic independent" T lymphocytes in hypothymic rats, or to engraftment with extrinsic maternal milk-derived lymphocytes and their activation in the infant rat gut.

Animals↗

Distribution of T-lymphocytes in follicular lymphomas as revealed by acid alpha-naphthol acetate esterase.

Twelve cases of follicular centroblastic/centrocytic malignant lymphoma were studied for acid non-specific esterase. The majority of the lymphocytes in interfollicular areas showed a pattern of enzymatic activity consistent with a T-cell nature. Variable numbers of lymphocytes with a similar enzymatic pattern were also seen among the negative centroblasts and centrocytes in neoplastic follicles.

Carboxylic Ester Hydrolases↗

Distribution of lymphoid cells in tonsillar compartments in relation to infection and age. A quantitative study using image analysis.

The distribution of lymphoid cells in the mantle zone, germinal center, interfollicular area, and subepithelial area of the tonsil was evaluated quantitatively by image analysis in 66 subjects aged 3 to 66 years. The number of Ig-positive cells in the tonsil decreased with advancing years in all compartments. This inverse correlation to age was statistically significant for IgD-, IgM-, and IgG-positive cells. For T-cells, overall change of each T-cell subset with age was smaller than those of Ig-positive cells. An age-related marked decline was seen for CD4-positive cells only in the subepithelial area and for CD8-positive cells only in the interfollicular area. Ki-67-positive cells, cells undergoing active division, were mainly found in the germinal centers and also diminished with advancing years. Patients with frequent episodes of tonsillitis demonstrated a significant increase of IgD-positive cells and IgG-positive cells in interfollicular and subepithelial compartments and a decrease of CD4-positive T-cells in the germinal centers and subepithelial areas. These results suggest that the tonsillar involution with age is immunologically associated in all compartments with the decrease of Ig-positive cells and Ki-67-positive activated cells resulting in a relative increase of T-cell subsets. The method of image analysis provides a novel and unique approach for quantitative immunohistological study of the tonsil.

Adolescent↗

Tissue localization of T-lymphocytes by the histochemical demonstration of acid alpha-naphthyl acetate esterase.

Nonspecific acid alpha-naphthyl acetate esterase (ANAE) activity has previously been evaluated with the sheep erythrocyte (E) rosette assay and found to be a useful T-cell marker in cell suspension studies. T-lymphocytes display a solitary red brown nodule of reaction product (T-pattern) which can be readily distinguished from the diffuse, cytoplasmic staining of monocytes (M-pattern). Freshly obtained human tissue blocks were fixed with buffered formal sucrose and maintained in Holt's syrup; cryostat sections were cut and incubated under conditions appropriate for the histochemical demonstration of lymphocyte acid alpha-naphthyl acetate esterase activity. The results clearly demonstrate that T-pattern ANAE+ lymphocytes populate the paracortical and interfollicular regions of normal lymph nodes and tonsils and the periarteriolar sheaths of normal spleen, T-cell zones, while nearly every germinal center (B-cell area) lymphocyte is ANAE-. Macrophages and dendritic reticulum cells display diffuse cytoplasmic ANAE activity (M-pattern). Nodular malignant lymphomas (B-cell origin) are ANAE-; an E+ diffuse, cutaneous lymphoma was ANAE+. The histochemical demonstration of ANAE activity may represent the first reproducible, routine technique to localize T-lymphocytes in tissue sections.

Carboxylic Ester Hydrolases↗

Immunohistochemical distribution of adult T-cell leukemia-derived factor/thioredoxin in epithelial components of normal and pathologic human skin conditions.

Tissues from normal human skin and various skin diseases were studied with the immunoperoxidase technique using an antibody to adult T-cell leukemia-derived factor (ADF), a homologue of human thioredoxin. Normal human skin showed positive immunostaining for ADF/thioredoxin in the outer root sheath of hair follicle, sebaceous glands, and secreting components of apocrine and eccrine sweat units, but not in the unexposed interfollicular epidermis and other parts of both hair follicles and the sweat units. Immunoreactivity of benign skin tumors gave similar distribution to their normal counterparts; trichilemmal cyst, nevus sebaceus, senile sebaceous hyperplasia, and mixed cell tumor were positive for immunostaining, whereas epidermal cyst and pilomatricoma were not. No immunoreactivity was detected in malignant skin tumors such as basal cell carcinoma and poorly differentiated squamous cell carcinoma. Solar keratosis, well-differentiated squamous cell carcinoma, some of metastatic lesions of squamous cell carcinoma, and extramammary Paget's disease reacted with the antibody. These immunoreactivities reflected numerous functions of thioredoxin in higher organisms. Our findings suggest that the expression of ADF/thioredoxin in both normal and abnormal human skin is related to epithelial cell differentiation.

Adult↗

Immunohistochemical identification of T-and B-lymphocytes delineated by the unlabeled antibody enzyme method. II. Anatomical distribution of T- and B-cells in lymphoid organs of nude mice.

Tissue sections of the spleen, lymph nodes, and Peyer's patches were examined using an immunohistochemical demonstration of T- and B-lymphocytes in athymic homozygous nude mice possessing a known 1-5% of T-lymphocytes. Some of the few lymphocytes in the tyhmus-dependent periarteriolar zone of the spleen white pulp, the paracortex of lymph nodes and interfollicular area of Peyer's patches, were identified as T-lymphocytes. Also, singular T-lymphocytes occur in the thymus-independent marginal zone of the spleen white pulp, cortex and medulla of lymph nodes, as well as the follicular and subepithelial zones of Peyer's patches. These results indicate that the decreased numbers of T-cells in nude mice are found preferably in thymus-dependent regions, and to a smaller degree may recirculate in a similar way as in normal mice.

Animals↗

Comparative histological studies of regional lymph nodes of 201 melanoma patients. (Microscopic features in relation to individual age, site, and metastatic spread).

Since May 1968 a total of 2.108 regional lymph nodes (l.n.) dissected from 201 melanoma patients (86 axillary, 107 groin, and 8 neck) have become available for study. The purpose was to detect histological differences between the l.n. of 134 patients lacking and those of 67 patients exhibiting l.n. metastases, histologically verified in 104 of 706 nodes. The main finding is a more than six-fold increase in number and an eleven-fold increase in total area (evaluated by a microscope micrometer) of germinal centers in the lymph follicles of patients with, as compared to those without, l.n. metastases (P less than or equal to 0.05). Paracortical areas were found to be diminished in 56.7% of cases with metastatic spread. Accumulations of plasma cells were mainly seen in the nodes of elderly patients (48.4%) and of those exhibiting regional metastases (47.8%). The observation of numerous and dilated blood vessels in the interfollicular regions noticeably corresponded to the occurrence of lymphatic metastases (P less than or equal to 0.01), suggesting a "tumor angiogenic factor". A negative correlation with metastatic involvement was found as to histiocytosis of marginal sinuses and with respect to the observed fibrinoid hyalinosis of pulp vessels (P less than or equal to 0.01). The marked hyperplasia of lymph node B-lymphocyte regions as opposed to diminished T-lymphocyte areas prevailing in cases with metastatic melanoma is in accord with findings of humoral immunologic blocking activity and impaired T-cell response in advanced malignant melanoma.

Adolescent↗

Immunoblastic lymphoma with abundant clear cytoplasm. A comparative study of B- and T-cell types.

The morphologic, phenotypic, molecular genetic, and clinical features of 34 cases of clear-cell immunoblastic lymphoma (IBLC) are described. Sixteen cases were of B-cell type (IBLC-B) and 18 cases were of T-cell type (IBLC-T). There were no significant differences in the morphologic characteristics of the neoplastic cells in the two types, although IBLC-B was less likely to be polymorphic than IBLC-T. Interfollicular proliferation, a higher mitotic rate, infiltration by eosinophils, and an increase in capillary-sized blood vessels were also features of IBLC-T, whereas necrosis and fibrosis were more extensive in IBLC-B. Patients with IBLC-B were predominantly female, whereas those with IBLC-T were predominantly male. The mean age was 62 years for those with IBLC-B and 46 years for those with IBLC-T. Patients with IBLC-B usually had lower-stage disease, but there was no significant difference in survival rate between those with IBLC-B and those with IBLC-T. Although most cases of IBLC have been considered to be of peripheral T-cell origin, the authors conclude that IBLC-B is more common than previously considered and that clear-cell morphologic characteristics are not a reliable indicator of T-cell type.

Cytoplasm↗

The athymic nude rat. Immunobiological characteristics with special reference to establishment of non-antigen-specific T-cell reactivity and induction of antigen-specific immunity.

The aim of the present review has been to describe some immunobiological characteristics of the athymic nude rat and on the basis of these to describe the possibilities of establishing non-antigen-specific T-cell reactivity and inducing antigen-specific immunity. After a brief introduction, some general characteristics of the autosomal recessive rnu/rnu rat are outlined. This athymic mutant normally has a longer lifespan than athymic nude mice and is easier to breed. Inbred nude rats are now available with several rat strain backgrounds. Since the rnu/rnu rat is athymic, the morphology and function of the thymus are briefly described. The thymus has two main functions: production of T lymphocytes and production of thymic hormones. The intrathymic T-cell ontogeny is described along with the two thymocyte selection mechanisms, positive and negative selection. Different thymic hormones are mentioned and their possible function outlined. However, thymic hormones still do not play an important role in immunotherapy. There are some striking differences in the morphology of lymphatic tissues of athymic and euthymic rats. The thymic area in nude rats consists only of fat and clusters of epithelial cells. Little research has been performed on bone marrow of athymic nude rats but morphologically there seems to be no difference from findings in normal animals. The thymus-dependent areas of peripheral lymphoid organs, i.e. the paracortical area of lymph nodes, the periarteriolar sheet of the splenic white pulp, and the interfollicular areas of Peyer's patches, are severely cell-depleted in the athymic nude rat. The lower lymphocyte content of these organs is not reflected in the lymphocyte counts of peripheral blood, but the lymphocyte counts of thoracic duct lymph are much lower than those found in euthymic animals. Few T-lymphocyte marker-positive cells are found in the athymic nude rat, and in the epithelium of the intestine there are also lymphocytes bearing neither T nor B markers. These cells probably represent the tau delta receptor-bearing cells. Immunologically the athymic nude rat reflects the thymic aplasia. Normal B-lymphocyte function has been found in both in vitro and in vivo tests, whereas the T-cell function is virtually absent both in vitro and in vivo. Non-MHC-restricted cells with killer activity like NK cells are present in the nude rat, and these cells function normally both in vitro and in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

The neuroimmune connection in human tonsils.

The present light microscopic immunohistochemical study evaluates the distribution of peptidergic nerve fibers in human tonsil and describes their spatial relationship with specific cells of the immune system. Further, using a panneural marker protein gene product (PGP) 9.5, a qualitative evaluation of the density of specific peptidergic innervation of the human tonsil was performed. Nerve fibers staining for tachykinins, calcitonin gene-related peptide, neuropeptide Y, or vasoactive intestinal polypeptide/peptide histidine isoleucine showed characteristic distribution patterns, but constituted only a minor subfraction of the PGP 9.5-stained fiber population. Both peptide- and PGP 9.5-immunopositive fibers predominantly supplied the vasculature; nonvascular areas were less densely innervated. Double staining for surface antigens thought to be associated with subsets of lymphoid cells, i.e., T-cells, B-cells, granulocytes, and macrophages, and for peptides or PGP 9.5 revealed close proximity of characteristic subpopulations of neurochemically defined nerve fibers and the various immune cells. The presence of peptidergic nerve fibers among T-cells was more prevalent than peptidergic nerve fibers adjacent to macrophages. Few positively stained nerve fibers resided in B-cell compartments. Neuro-B-cell interrelations were extremely infrequent. Neuroimmune connections were restricted to paravascular, subepithelial, and interfollicular regions, while germinal centers were devoid of nerve supply. The results are compatible with the view that peptides, being present in small-diameter nerve fibers, could exert an indirect immunoregulatory role by influencing vascular tone and/or permeability. In quantitative terms, a direct neuroimmunomodulatory action of endogenous neurally derived peptides appears to be of minor importance, because nonvascular neuroimmune circuits were found infrequently and were regionally restricted. However, we cannot be sure that all fibers were stained. The functional state of the peptidergic and nonpeptidergic innervation of the human palatine tonsil may be of physiological and pathophysiological significance within the psycho-neuro-immuno-endocrine network. The peptide-coded neuroimmune link may play a role in tonsillar pain.

Biomarkers↗

Interleukin-2 and interferon-gamma production in follicular lymphomas.

In situ hybridization with specific RNA radiolabeled probes was used to analyze the production of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) by 21 low-grade follicular lymphomas (FLs). All of the 21 FLs tested contained lymphokine-synthesizing cells in the interfollicular and follicular areas. Enumeration of lymphokine synthesizing cells indicated heterogeneous IL-2 production among lymph nodes tested; 2 of the 21 had much higher densities of IL-2-producing cells (855 and 570/cm2) than did the remaining 19 (mean, 92 +/- 15/cm2). IFN-gamma-producing cells displayed no such variation (mean, 77 +/- 8 IFN-gamma-producing cells/cm2). The mean IL-2/IFN-gamma-producing cell ratio was 2.69 +/- 0.84, indicating preferential induction of IL-2. The detailed distribution of lymphokine-producing cells showed that IL-2 and IFN-gamma-producing cells were located mainly in the follicular areas. The mean follicular/interfollicular ratio was 1.82 +/- 0.16 for IL-2 and 1.92 +/- 0.19 for IFN-gamma-producing cells. The results show that T-cell activation, defined by lymphokine production, occurs in FL lymph nodes in direct contact with malignant B cells. Thus, lymphokine production may play an important role in the control of tumor growth, which is the result of interaction between tumor cells and host-derived immune reaction.

Humans↗

[Induction and functional analysis of gamma delta TCR-bearing T cells from human tonsil by Streptococcus pyogenes stimulation].

The killer cell characteristics of gamma delta TCR-bearing T cells induced from human tonsil by streptococcus pyogenes stimulation were examined. Immunohistologic staining of tonsil showed that gamma delta TCR-bearing T cells were mainly located in the interfollicular area connected with stratified squamous epithelium. Streptococcus pyogenes could induce the proliferation of gamma delta TCR-bearing T cells from tonsil in the presence of low-dose of IL-2. This streptococcus pyogenes-induced gamma delta TCR-bearing T cell proliferation was likely to be independent on the IL-2/IL-2R system since an obvious inhibition was not observed with anti-IL-2 and anti-IL-2R mAbs. More importantly, these gamma delta TCR-bearing T cells exhibited cell-mediated cytotoxic activity in a 4 hr 51 Cr-release assay. In addition, immunocytochemical staining revealed that these cells contained a killer protein perforin. These results demonstrate that gamma delta TCR-bearing T cells from tonsil exhibit typical killer cell characteristics. These data also suggest that gamma delta TCR-bearing T cells in human tonsil may play a cytotoxic role in protecting the integrity of tonsil from infection.

Cytotoxicity, Immunologic↗

T-zone lymphoma in association with systemic lupus erythematosus.

Two patients with systemic lupus erythematosus (SLE) and T-zone lymphoma are described. On admission, both showed arthralgia, generalized lymphadenopathy, hypergammaglobulinemia and positive antinuclear antibody. Lymph node biopsies revealed diffuse infiltration of atypical T-lymphocytes in the expanded interfollicular area (T-zone), a finding characteristic for the T-zone lymphoma. Renal biopsy showed lupus nephritis and neoplastic lymphoid cell infiltration in the glomeruli of one patient, but only diffuse infiltration of neoplastic lymphoid cells and mature plasma cells were observed in the interstitium of the other patient. Both patients responded remarkably well to prednisolone (1 mg/kg/day).

Humans↗

Warthin's tumor as a hamartomatous dysplastic lesion: a histochemical and immunohistochemical study.

The etiology of Warthin's tumor was sought by histochemical and immunohistochemical methods using 7 surgically extirpated samples and normal salivary glands as a control for the epithelial component. All the samples exhibited a variety of amyloid deposition in the interfollicular area of the lymphoid component. The interfollicular lymphoid cells were both T-cells and cells of B-cell lineage with an almost 1 to 2 population ratio. Most antigen-positive B-cells were plasma cells that exhibited polyclonality of immunoglobulin. B-cells were also present in the lymphoid mantles and a few were found in the germinal centres. The epithelial component exhibited mucinous and proteinaceous fluid in the lumen and varied immunohistological reactions; being particularly positive to carcinoembryonic antigen, S-100 protein, and B-cell antigen; quite similar to that of normal salivary duct cells. The results suggest that Warthin's tumor may not be a hamartomatous neoplasm at all but a hamartomatous dysplastic lesion.

Adenolymphoma↗