Reactive Follicular Hyperplasia Research Articles

Abnormal expression of bcl-10 protein in extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue lymphoma type

To evaluate the diagnostic role of nuclear expression of bcl-10 protein in extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type. One hundred and forty cases of MALT lymphoma were collected from Cancer Hospital of Fudan University (including 38 cases from stomach, 35 cases from ocular adnexa, 16 cases from intestine, 15 cases from skin, 15 cases from salivary gland, 14 cases from lung, 3 cases from thyroid and 4 cases from other sites). Ten cases of reactive follicular hyperplasia of tonsil, 5 cases of reactive lymphoid hyperplasia of orbit and 143 cases of non-Hodgkin's lymphoma other than MALT lymphoma (including 20 cases of NK/T cell lymphoma, 20 cases of follicular lymphomas, 20 cases of anaplastic large cell lymphomas, 20 cases of nodal diffuse large cell B-cell lymphoma (DLBCL), 10 cases of gastric diffuse large B-cell lymphoma, 13 cases of nodal marginal zone B-cell lymphoma, 12 cases of mantle cell lymphoma, 11 cases of splenic marginal zone B-cell lymphoma, 6 cases of angioimmunoblastic T-cell lymphoma, 6 cases of peripheral T-cell lymphoma, not otherwise specified, 3 cases of small lymphocytic lymphoma, 1 case of lymphoplasmacytic lymphoma and 1 case of plasmacytoma were used as controls. Immunohistochemical study for bcl-10, as well as dual staining with CD20, was performed by EnVision method in paraffin sections. In reactive follicular hyperplasia of tonsil, bcl-10 was moderately or strongly expressed in the cytoplasm of germinal center B cells, while the mantle cells were negative and the marginal zone cells and paracortical T cells showed weak staining. In the 5 cases of reactive lymphoid hyperplasia of orbit, 2 were bcl-10-negative and the remaining 3 expressed bcl-10 in the cytoplasm of germinal center B cells. As for non-MALT lymphomas, 3 gastric DLBCL showed nuclear expression. The remaining cases showed variable cytoplasmic staining. In some cases of lymphoma, bcl-10 was expressed in tumor cells but not in reactive lymphoid cells. On the other hand, 92.1% (129/140) of MALT lymphoma were bcl-10 positive. Among those cases, 54.3% (76/140) showed cytoplasmic positivity and 37.9% (53/140) showed nuclear positivity. The nuclear positivity rate of bcl-10 in different anatomic sites was different. The staining was most intense in MALT lymphoma of ocular adnexa. Dual staining with CD20 showed that the bcl-10-positive cells were also CD20-positive, though the number of bcl-10-positive cells were less than that of CD20-positive cells. Bcl-10 expression in lymphoid hyperplasia is a universal phenomenon. Cytoplasmic expression of bcl-10 is seen in many different kinds of non-Hodgkin's lymphoma and reactive lymphoid conditions. In some cases of lymphoma, bcl-10 is expressed in tumor cells but not in reactive lymphoid cells, suggesting a possible role of abnormal bcl-10 expression in tumorgenesis. Nuclear expression of bcl-10 is seen mainly in MALT lymphoma, especially when occurring in ocular adnexa and lung. This is in contrast to loss of bcl-10 expression in residual germinal center cells.

Epstein-Barr Virus Infection and Single Nucleotide Polymorphisms in the Promoter Region of Interleukin 10 Gene in Patients With Hodgkin Lymphoma

Hodgkin lymphoma is a neoplastic disease in which the immune system plays a major role in its pathogenesis. Interleukin 10 (IL-10), an immunosuppressive cytokine actively produced in patients with Hodgkin lymphomas, favors the survival of the Hodgkin/Reed-Sternberg cells. Individual variations in IL-10 levels may be due, in part, to the presence of single nucleotide polymorphisms in the IL10 gene promoter. To evaluate whether particular single nucleotide polymorphisms in the IL10 gene are found more frequently in Hodgkin lymphoma cases associated with Epstein-Barr virus infection. The identification of single nucleotide polymorphisms at positions -1082 and -819/-592 in the IL10 gene was performed by polymerase chain reaction and restriction length fragment polymorphisms analysis in 65 cases of Hodgkin lymphoma and 50 cases of reactive benign follicular lymphoid hyperplasia (non-Hodgkin lymphoma control group). The frequency of the genotype GG at position -1082 was found to be significantly higher in patients with Epstein-Barr virus-positive Hodgkin lymphoma compared with Epstein-Barr virus-negative cases. The results suggest that the presence of specific single nucleotide polymorphisms in the IL10 gene, notably those associated with high IL-10 production, may play a role in the susceptibility to Epstein-Barr virus-positive Hodgkin lymphoma development.

Case of Chronic Hepatitis C Presenting with Right Axillary Lymphadenopathy

Purpose: Chronic hepatitis C is the most common cause of chronic liver disease. Most patients with chronic infection are usually asymptomatic or have mild nonspecific symptoms such as fatigue, myalgias, arthralgias, weakness, and weight loss. Extrahepatic manifestations have been associated with chronic hepatitis C infection. We present an unusual case of a patient with hepatitis C presenting with right axillary lymphadenopathy. Case Presentation: This is a 52 year old African-American male with history of hepatic C who noticed an enlarging mass under his right armpit for 2 1/2 months. He reports no night sweats, fevers, fatigue or weight loss. He denied any abdominal pain and review of system was otherwise negative. Physical exam was notable for 6 cm area of adenopathy in his right axilla. All other areas including supraclavicular, cervical, groin and left axillary were negative for adenopathy. Abdominal exam was nontender without hepatosplenomegaly. Liver enzymes including AST, ALT, Alk Phos were normal. The right axillary lymph node was excised. Pathology revealed florid follicular hyperplasia (Fig. 1). There was no evidence of Reed-Sternberg cells or variants. Immunostain for hepatitis C virus showed multiple foci of scattered positive intranuclear staining of macrophages and lymphocytes. The final diagnosis was florid reactive follicular hyperplasia associated with hepatitis C viral infection. Conclusion: To our knowledge, this is the first case of a patient with chronic hepatitis C presenting with right axillary adenopathy associated with the disease.

Detection of t (14; 18) chromosomal translocation in paraffin-embedded tissues of follicular lymphoma and its clinical significance

To study the genetic aberrations and their pathologic significance in follicular lymphoma (FL). Paraffin-embedded tissue samples of 55 cases of FL, 28 cases of other small B-cell lymphomas and 10 cases of reactive follicular hyperplasia were retrieved. Nested polymerase chain reaction (PCR) was used to detect clonal rearrangement of immunoglobulin heavy chain gene (IgH) in FL and other small B-cell lymphomas. The translocation t (14; 18) was studied by PCR and dual-color fluorescence in-situ hybridization (FISH) in FL. Cases of reactive follicular hyperplasia were used as controls. Amongst the 55 cases studied, 49 cases were nodal and 6 cases were extranodal. There were 33 males and 22 females. The male-to-female ratio was 1.5:1. The median age of the patients was 57 years. Twenty-five cases belonged to histologic grade 1, while 19 cases were grade 2 and 11 cases were grade 3. Beta-actin DNA was detected in 50 cases of FL. Amongst those 50 cases, clonal IgH rearrangement was present in 34 (68%). Twenty-four cases (48%) and 25 cases (50%) were positive for FR3A and FR2 respectively. Fifteen cases (30%) showed dual positivity for both FR3A and FR2. Thirty-four cases (68%) demonstrated clonal IgH rearrangement. As for other small B-cell lymphomas, 25 cases were positive for beta-actin. FR3A and FR2 were detected in 18 and 17 cases respectively. Clonal IgH rearrangement was demonstrated in 24 cases. In contrast, none of the 4 cases of reactive follicular hyperplasia showed the clonal rearrangement pattern. Amongst the 44 cases of nodal FL analyzed, t (14; 18) was detected in 15 cases (with 14 cases in MBR and 1 case in mcr). In general, FISH was superior to PCR in detecting t (14; 18) using paraffin-embedded tissue samples. The detection rate of clonal IgH rearrangement in FL is lower than that in other small B-cell lymphomas. Demonstration of t (14; 18) in paraffin-embedded tissue samples by FISH helps in diagnosis of FL. FISH is superior to PCR, as the technique is more sensitive and less labor intensive.

In situ follicular lymphoma with a 14;18 translocation diagnosed by a multimodal approach

The main differential diagnosis for follicular lymphoma (FL, or in situ localization of follicular lymphoma) is follicular hyperplasia. However, this differentiation is quite challenging when the initial presentation of FL is in one lymph node and such a lymph node is only partially involved. In other words, only a few lymphomatous follicles are present in an otherwise nodal reactive follicular hyperplasia. The use of FISH on formalin-fixed, paraffin-embedded tissue as an adjunct to routine histomorphological and immunohistochemical evaluation is valuable for reaching an initial diagnosis of in situ follicular lymphoma in a lymph node which shows predominantly reactive follicular hyperplasia. In this report, we describe our experience in rendering such an initial diagnosis of in situ FL in an apparently healthy individual who has a single persistently enlarged lymph node. The recognition of in situ FL is of utmost importance because it is associated with localized early stage disease (stage I), which according to standard regimens is amenable to local radiation therapy with a good chance for inducing remission. To the best of our knowledge, this is the first such case reported in the English literature using innovative FISH technology on formalin-fixed, paraffin-embedded tissue in conjunction with other routine histological modalities to produce an initial diagnosis of in situ follicular lymphoma.

Activation of Mammalian Target of Rapamycin Signaling Promotes Cell Cycle Progression and Protects Cells from Apoptosis in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is characterized by the t(11;14) and cyclin D1 overexpression. However, additional molecular events are most likely required for oncogenesis, possibly through cell cycle and apoptosis deregulation. We hypothesized that mammalian target of rapamycin (mTOR) is activated in MCL and contributes to tumor proliferation and survival. In MCL cell lines, pharmacological inhibition of the phosphoinositide 3-kinase/AKT pathway was associated with decreased phosphorylation (activation) of mTOR and its downstream targets phosphorylated (p)-4E-BP1, p-p70S6 kinase, and p-ribosomal protein S6, resulting in apoptosis and cell cycle arrest. These changes were associated with down-regulation of cyclin D1 and the anti-apoptotic proteins cFLIP, BCL-XL, and MCL-1. Furthermore, silencing of mTOR expression using mTOR-specific short interfering RNA decreased phosphorylation of mTOR signaling proteins and induced cell cycle arrest and apoptosis. Silencing of eukaryotic initiation factor (eIF4E), a downstream effector of mTOR, recapitulated these results. We also assessed mTOR signaling in MCL tumors using immunohistochemical methods and a tissue microarray: 10 of 30 (33%) expressed Ser473p-AKT, 13 of 21 (62%) Ser2448p-mTOR, 22 of 22 (100%) p-p70S6K, and 5 of 20 (25%) p-ribosomal protein S6. Total eIF4E binding protein 1 and eukaryotic initiation factor 4E were expressed in 13 of 14 (93%) and 16 of 29 (55%) MCL tumors, respectively. These findings suggest that the mTOR signaling pathway is activated and may contribute to cell cycle progression and tumor cell survival in MCL.

Benign, atypical and malignant lymphoproliferative disorders in rheumatoid arthritis patients

Lymphadenopathy, which may be associated with systemic symptoms, is frequently associated with rheumatoid arthritis (RA). Reactive non-neoplastic tissue comprises the majority of the lymph node lesions. However, several cohort studies have demonstrated that RA has an increased risk of non-Hodgkin's lymphomas (NHLs). Since the early 1990s, an atypical or malignant lymphoproliferative disorders (LPD) in patients immunosupressed with methtorexate (MTX) therapy for RA has been emphasized, namely MTX-associated LPDs. Epstein–Barr virus (EBV) has received attention in connection with the etiology of RA. The present review describes the clinicopathologic and immunohistochemical findings of reactive, atypical and malignant LPDs associated with RA along with the presence or absence of EBV in LPDs using the in situ hybridization (ISH) method. The majority of reactive lymph node lesions exhibit reactive follicular hyperplasia with interfollicular polyclonal plasmacytosis. Atypical LPDs rarely appears in RA patients. However, these cases occasionally pose difficult problems in the differential diagnosis from malignant lymphomas associated with RA or atypical and malignant LPDs showing RA-like clinicopathological findings. Clinicopathologically, three types of atypical LPDs have delineated, i.e. (i) resembling multicentric Castleman’s disease (MCD); (ii) atypical paracortical hyperplasia with lymphoid follicles (APHLF) and; (iii) atypical lymphoplasmacytic immunoblastic proliferation. Malignant lymphoma associated with RA is characterized by; (i) predominance of elderly cases; (ii) usually female predominance, reflecting the sex ratio of RA; (iii) longstanding history of RA; (iv) relatively frequent advanced stage of disease; (v) majority of the patients had the B-cell phenotype; and (vi) an increased frequency of diffuse large B-cell lymphoma (DLBCL) in RA. It is unlikely that EBV is the causative agent of either reactive or atypical LPD. Among malignant lymphomas, EBV-associated lymphoma comprised only a small fraction of all NHLs in the general RA patient population.

Clinical investigations of lymphadenopathy, including lymph node biopsies, in 24 homosexual men with antibodies to the human T-cell lymphotropic virus type III (HTLV-III).

The findings of 27 lymph node biopsies performed on 24 homosexual patients with lymphadenopathy are presented. Six had acquired immune deficiency syndrome (AIDS) and 18 lymphadenopathy only, of whom one subsequently developed AIDS. All these patients had antibodies to the human T-cell lymphotropic virus type III (HTLV-III) suggesting that HTLV-III is currently the commonest cause of lymphadenopathy in homosexual men. The histopathological findings of six of seven nodes from AIDS patients showed either follicular depletion alone or follicular and paracortical lymphocyte depletion. Nodes from four patients showed Kaposi's sarcoma, three of which also showed follicular hyperplasia. In two of these patients there were no cutaneous manifestations of this condition. One lymph node from a patient with persistent generalized lymphadenopathy (PGL) showed Mycobacterium tuberculosis. Six nodes from six other patients have had features of toxoplasmosis although there was no serological or clinical evidence of recent toxoplasma infection. The remaining 11 lymph nodes from patients with PGL and one node from a patient with transient lymphadenopathy, showed reactive follicular hyperplasia only. We conclude that homosexuals with lymphadenopathy who are HTLV-III antibody positive do not need a routine node biopsy unless an alternative diagnosis is strongly suspected.

Proteomic Profiling of Mature CD10+ B-Cell Lymphomas

Proteomic profiling with protein-chip technology has been used successfully to discover biomarkers with potential clinical usefulness in several cancer types. Little proteomic study has been done in B-cell lymphomas. We determined whether the expression of a set of proteins by protein-chip technology coupled with new informatics tools could be used to build a model to molecularly classify B-cell lymphoma subgroups. We used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to analyze 18 CD10+ B-cell lymphomas, including 6 grade 1 (G1) follicular lymphomas (FLs), 7 grade 3 (G3) FLs, and 5 Burkitt lymphomas. We used 7 reactive follicular hyperplasia cases as a control group. By using SAX2 ProteinChip arrays (Ciphergen Biosystems, Fremont, CA), we found a unique protein expression profile for each type of lesion. Two-way hierarchical clustering analysis of these protein expression profiles differentiated reactive follicular hyperplasia, FL, and Burkitt lymphoma, with 5 major clusters of differentially expressed protein peaks. In addition, we identified histone H4 as a potential differentially expressed protein marker that seems to distinguish G1 from G3 FL. To our knowledge, this is the first proteomic study using protein-chip technology for molecular classification of B-cell lymphoma subtypes with clinical samples.

Proteomic Profiling of Mature CD10+ B-Cell Lymphomas

Proteomic profiling with protein-chip technology has been used successfully to discover biomarkers with potential clinical usefulness in several cancer types. Little proteomic study has been done in B-cell lymphomas. We determined whether the expression of a set of proteins by protein-chip technology coupled with new informatics tools could be used to build a model to molecularly classify B-cell lymphoma subgroups. We used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to analyze 18 CD10+ B-cell lymphomas, including 6 grade 1 (G1) follicular lymphomas (FLs), 7 grade 3 (G3) FLs, and 5 Burkitt lymphomas. We used 7 reactive follicular hyperplasia cases as a control group. By using SAX2 ProteinChip arrays (Ciphergen Biosystems, Fremont, CA), we found a unique protein expression profile for each type of lesion. Two-way hierarchical clustering analysis of these protein expression profiles differentiated reactive follicular hyperplasia, FL, and Burkitt lymphoma, with 5 major clusters of differentially expressed protein peaks. In addition, we identified histone H4 as a potential differentially expressed protein marker that seems to distinguish G1 from G3 FL. To our knowledge, this is the first proteomic study using protein-chip technology for molecular classification of B-cell lymphoma subtypes with clinical samples.

Multilocular thymic cyst associated with follicular hyperplasia: clinicopathologic study of 4 resected cases

We report here 4 cases of multilocular thymic cysts (MTCs) with reactive lymphoid follicular hyperplasia. They were admitted to our hospital to examine anterior mediastinal masses demonstrated on chest computed tomographic scans. Three patients presented high-grade intermittent fever, and 2 patients were associated with Sjogren syndrome with elevated serum antinuclear antibody levels. All patients were subjected to extended thymectomy. Interestingly, their fever disappeared immediately after surgery. Histologically, the lesions were characterized by several cystic spaces separated by various thick walls with dense lymphoid tissue containing large reactive germinal centers. The inner cyst walls were lined by flattened cuboidal epithelia in some portions. Columnar epithelia with focal cilia were partially observed in 2 cases. These pathological findings led to a diagnosis of MTCs that were thought to result from cystic transformation of medullary duct derivatives by acquired inflammatory processes. The pathological findings, together with clinical courses of our cases, suggest that inflammation accompanied by autoimmune diseases may play, in part, an important role in the development of MTCs.

Differential expression of cytokines, chemokines and their receptors in follicular lymphoma and reactive follicular hyperplasia: Assessment by complementary DNA microarray

Follicular lymphoma (FL) is pathologically categorised as a low-grade B-cell lymphoma and histopathologically shows follicular proliferation of neoplastic B cells. In the neoplastic follicles of FL, the presence of T cells, macrophages and follicular dendritic cells (FDCs) suggests that these cells may promote a favourable environment for the growth of FL cells. Because FL cells are generally associated with FDCs, FDCs may be considered an important source of cytokines and chemokines. FDCs form the framework for germinal centres and also provide networks for nodules of FL. To evaluate the gene expression in neoplastic follicles of FL and reactive follicles of reactive follicular hyperplasia (RFH), we performed gene expression profiling of FL (n=5) and RFH (n=5) using complementary DNA (cDNA) microarray of cytokines/chemokines and their receptors. FL and RFH exhibited a diffuse down-regulated profile compared with normal peripheral blood cells, which were used as controls, although some genes displayed up-regulated profiles. Hierarchical clustering analysis separated FL and RFH into two distinct groups based on their gene expression profiles. FL cases exhibited significantly higher expression of interleukin 3 receptor alpha (IL-3Ralpha) than RFH. Immunohistochemically, neoplastic follicles of FL frequently expressed IL-3Ralpha, especially in FDCs, but not in FL cells. However, IL-3Ralpha expression was rare or weak in the reactive follicles of RFH. These findings suggest the importance of the micro-environment for FL cell growth. Further studies of cDNA microarray should provide new insight into the molecular pathology of FL and may allow the design of improved therapies.

Clinical Implication of Florid Reactive Follicular Hyperplasia in Japanese Patients 60 Years or Older: A Study of 46 Cases

Florid reactive follicular hyperplasia (FRFH) of the enlarged lymph node in middle-aged or elderly patients requiring biopsy is a relatively uncommon phenomenon as compared with that in younger age groups. Between 1984 and January 2004, we encountered 46 patients, aged 60 years or older, in whom histology of biopsied lymph node specimens showed inappropriate FRFH for the patient's age. An apparent cause of lymphadenopathy was initially identified in 17 cases (37%): 11 with autoimmune disease and related disorders, 3 with cancer-reactive lymphadenopathy, 2 with Epstein-Barr virus-associated lymph node lesion exhibiting transient autoimmune-disease-like clinical findings, and 1 with atypical mycobacterial infection. Among 29 patients without specific etiology, 16 patients (55%) exhibited histologic findings of progressive transformed germinal center (PTGC). Only 1 of our patients developed malignant lymphoma during the follow-up period. The present study indicates that PTGC is included in the etiology of FRFH in elderly Japanese patients as well as imbalance of the immune system such as autoimmune-disease-associated lymphadenopathy and idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia. By in situ hybridization, Epstein-Barr virus genomes were demonstrated in only 6 (15%) of 39 cases examined.

Progressive transformation of germinal center presenting with histological features of hyaline‐vascular type of Castleman's disease

We report three cases showing progressive transformation of the germinal center (PTGC) with histological features reminiscent of the hyaline-vascular (HV) variant of Castleman's disease (CD). Each case contained a few small HV germinal centers as well as PTGC and hyperplastic germinal centers with or without follicular lysis. Moreover, some of the PTGC were penetrated by hyalinized small vessels. Our three cases also showed some of the characteristic histological findings of HV type of CD: (i) reactive lymphoid follicles with small hyaline-vascular germinal centers surrounded by small lymphocytes in a concentrated fashion; (ii) a few small foci of plasmacytoid monocytes; (iii) perivascular fibrosis; (iv) interfollicular vascularity; (v) tight/concentric pattern of the follicular dendritic cell network; and (vi) absence of CD57+ T-cells in the HV follicles. The PTGC with coexistent HV type of CD may represent a certain form of reactive follicular hyperplasia. The possibility of PTGC should be considered and excluded before diagnosing CD.

Cytologic differential diagnosis of follicular lymphoma grades 1 and 2 from reactive follicular hyperplasia: Cytologic features of fine-needle aspiration smears with Pap stain and fluorescence in situ hybridization analysis to detect t(14;18)(q32;q21) chromosomal translocation

Fine-needle aspiration cytology (FNAC) is a well-established technique for diagnosis of malignant lymphoma (ML). Generally, Giemsa but not Pap stain is used in FNAC. However, cytologic features obtained from Pap stain are also valuable. Very few studies on the cytologic characteristics of ML, as determined by Pap stain, are available. It is easier to observe nuclear irregularity and to identify nucleoli in ML cells by Pap stain than by Giemsa stain. Here, we applied Pap stain for cytomorphologic differential diagnosis of follicular lymphoma (FL) from reactive follicular hyperplasia (RFH). Eighteen biopsy-confirmed cases of FL grades 1 and 2, with available FNAC smears, and six cases of RFH were selected for this study. Low-power magnification showed well-known features, and tingible body macrophages and lymphoid cell aggregates were observed frequently in RFH and FL, respectively. In addition, the so-called two-nuclei-like cleaved cells were observed frequently in FL. These cells showed notably cleaved nuclei, and therefore, appeared to possess two nuclei. Under high-power magnification, the occurrence of cells with nucleoli >1 microm and of cleaved cells was high in FL compared to RFH. It is believed that FL derives from centrocytes and that FL cells are slightly larger than non-neoplastic small lymphocytes. However, analysis of cell diameter in this study indicated that small lymphoma cells were predominant in half the cases of FL grades 1 and 2, and the percentage of these cells was similar to that in RFH, showing why false-negative diagnosis of FL grades 1 and 2 occasionally occurs. There are limitations of FNAC in the diagnosis of FL. However, we believe that the appearance of two-nuclei-like cleaved cells and the high percentage of nucleoli-possessing cells, which we describe here, provide significant and valuable clues for the differential diagnosis of FL from RFH. Of 18 cases of FL grades 1 and 2, t(14;18)(q32;q21) was found in 13 cases with the use of destained FNAC smears. Our study suggests that, together with the cytomorphologic findings described earlier, FISH analysis for the chromosomal translocation, t(14;18)(q32;q21), is crucial for final cytologic diagnosis of FL grades 1 and 2.

Küttner's tumor: Unusual presentation with bilateral involvement of the lacrimal and submandibular glands

Chronic sclerosing sialadenitis, known as Küttner's tumor (KT), is a chronic inflammatory disease of the salivary gland characterized by progressive periductal fibrosis, dilated ducts with a dense lymphocyte infiltration and lymphoid follicle formation, and acinar atropy. We report a unique case of KT in a 30-year-old female who presented with time-serial involvement of the bilateral lacrimal and submandibular glands with reactive follicular hyperplasia of bilateral upper cervical lymph nodes. All tissue samples of the submandibular and lacrimal glands were typical of KT on pathologic examination. There was no evidence of lymphoepithelial lesions or intraepithelial lymphocytes. This is the first case of KT involving both lacrimal and submandibular glands, suggesting that KT is closely related to an active local immune process.

Pediatric Follicular Lymphomas, Marginal Zone Lymphomas, and Marginal Zone Hyperplasia

Whereas most B-cell lymphomas in children are of diffuse large B-cell or Burkitt type, other B-cell lymphomas, including follicular and marginal zone B-cell lymphomas, rarely occur Pediatric follicular lymphomas (FLs) have many features indistinguishable from those seen in adults but demonstrate an increased proportion that are localized, lack bcl-2 protein expression, lack bcl-2 translocations, and are grade 3 but still indolent. They also tend to have large expansile follicles. Although usually at nodal or tonsillar sites, other extranodal involvement also occurs, with FL of the testis well described. Distinction from potentially clonal but reactive follicular hyperplasia is important. Marginal zone B-cell lymphomas of nodal and extranodal types are other indolent B-cell neoplasms that usually are seen in adults but also occur in children. The differential diagnosis must include the very recently reported lambda light chain class-restricted marginal zone hyperplasias of the tonsil or appendix that might closely mimic a lymphoma. Understanding the full spectrum of B-cell neoplasia in children and its unique features is important for diagnostic, therapeutic, and academic purposes.

Intravesical mass consisting of mucosa‐associated lymphoid tissue

We report on a patient with an intravesical mass consisting of hyperplastic follicles in mucosa-associated lymphoid tissue. Computed tomography and ultrasonography revealed two intravesical masses measuring 3.5 cm and 1.5 cm along the long axis. Imaging diagnosis was invasive tumors of the bladder. However, the pathological diagnosis on transurethral bladder tumor biopsy was a lesion in lamina propria consisting of hyperplastic follicles and lymphatic infiltrate between them with no cell atypia. Light microscopically, the lesion was considered to be reactive follicular hyperplasia. Antibiotic therapy resulted in an almost complete disappearance of the tumors. Such large follicular hyperplasia in the lamina propria of the bladder is rare.

Prominent clonal B-cell populations identified by flow cytometry in histologically reactive lymphoid proliferations.

We describe 6 cases from the University of Washington Hematopathology Laboratory (Seattle) in which prominent, clonal, follicle center B-cell populations were identified by flow cytometry and confirmed by molecular methods, but in which the histologic features showed reactive follicular hyperplasia without evidence of bcl-2 overexpression or the t(14;18). The 6 cases included 5 lymph node biopsy specimens and 1 tonsillectomy specimen. Of the 6 cases, 5 occurred in young males (8-28 years) with no known immunologic abnormality; the other case was a 32-year-old, HIV-positive woman. In all 6 cases, clonal CD10+ B cells representing at least 20% of the total B cells were identified. Available clinical follow-up ranging from 13 to 56 months revealed no evidence of lymphoma in any of the 6 patients. Our findings add rare cases of follicular hyperplasia to the list of histologically reactive settings in which clonal B-cell populations might be present.

Similarities of prosurvival signals in Bcl-2-positive and Bcl-2-negative follicular lymphomas identified by reverse phase protein microarray

Overexpression of Bcl-2 protein has been known to play a role in the pathogenesis of follicular lymphoma (FL). However, 10–15% of FLs are negative for Bcl-2 by immunohistochemistry, raising the possibility that another gene product(s) may provide prosurvival signal(s). We used reverse phase protein microarray to analyze lysates of follicle center cells isolated by laser capture microdissection from: Bcl-2+ FL, Bcl-2− FL and reactive follicular hyperplasia (FH) (nine cases each group). TUNEL assay confirmed similar and reduced levels of apoptosis in Bcl-2+ FL and Bcl-2− FL, indicating the likelihood of Bcl-2-independent inhibition of apoptosis. Arrays were quantitatively analyzed with antibodies to proteins involved in the apoptotic pathway. As expected, Bcl-2 levels were up to eight-fold higher in Bcl-2+ FL than in FH and Bcl-2− FL. However, there was no difference in levels of Mcl-1 and survivin among these three groups. Bcl-XL showed a trend for increased expression in Bcl-2− FL as compared with Bcl-2+ FL, although the differences did not reach statistical significance (P>0.1). The increase in Bcl-XL may provide an alternative antiapoptotic signal in FL negative for Bcl-2 protein. Interestingly, Bax expression was higher in FL (Bcl-2+ or −) than in FH (P=0.001). Notably, phospho-Akt (Ser-473) was increased in FL (Bcl-2+ or −) (P<0.03) with increased phospho-Bad (Ser-136), as compared with levels in FH. The activation of the Akt/Bad pathway provides further evidence of prosurvival signals in FL, independent of Bcl-2 alone. These data suggest that nodal FL represents a single disease with a final common biochemical pathway.