Histopathologic subtypes of indolent lymphomas: caricatures of the mature B-cell system.
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Humans↗
Biomedical subjects
E S Jaffe
Publications and source records attributed to E S Jaffe.
Inflammatory pseudotumor of the spleen. A clinicopathologic and immunophenotypic study of eight cases.
We report the clinical, pathologic, and immunophenotypic findings of inflammatory pseudotumors of the spleen in eight patients. The primary importance of recognizing these uncommonly found lesions is to distinguish them from malignant lymphoma, which splenic inflammatory pseudotumors may mimic clinically and radiologically. Grossly, the splenic inflammatory pseudotumors in this study ranged from 0.5 to 11.5 cm. One case was multinodular, and seven lesions were solitary. In general, the size of the lesion correlated with the presence of symptoms. The smaller lesions were usually incidental findings, discovered as part of the workup of idiopathic thrombocytopenic purpura (three cases), during staging for Hodgkin's disease (one case), or at autopsy (one case). Microscopically, the lesions were composed of a variable mixture of inflammatory cells admixed within a spindle cell proliferation. Small, cytologically normal lymphocytes and plasma cells were constant features, in a variable mixture, with neutrophilic and eosinophilic leukocytes present in some cases. Coagulative necrosis was located centrally in six lesions; neutrophilic leukocytes were correlated with the presence of necrosis. The presence of necrosis did not correlate with the presence of symptoms. Immunohistochemical studies revealed that the small lymphocytes present were predominantly T cells. Histiocytes and polytypic plasma cells were also numerous, whereas B cells were infrequent. Inflammatory pseudotumors of the spleen are benign lesions. The clinical follow-up for the seven patients in this study who underwent splenectomy showed no evidence of recurrence or subsequent development of a hematopoietic neoplasm, with a median follow-up of 18 months (range, 3 to 135 months).
Adult↗
Malignant thymoma associated with T-cell lymphocytosis. A case report with immunophenotypic and gene rearrangement analysis.
Patients with malignant thymoma rarely may also have a peripheral T-cell lymphocytosis. "Lymphocyte spillover" from the thymus into the peripheral blood as well as a second, associated neoplasm (ie, T-cell chronic lymphocytic leukemia) are two hypotheses that have been proposed to explain this clinical phenomenon. We describe another patient with a lymphocyte-rich malignant thymoma associated with peripheral T-cell lymphocytosis. At the time of initial diagnosis, the patient's complete blood cell count was unremarkable. However, subsequent to the development of pulmonary metastases, the patient developed persistent lymphocytosis. The total leukocyte count ranged from 20 to 30 x 10(9)/L, 80% of these cells being lymphocytes. Immunophenotypic analysis of peripheral blood specimens from this patient proved that the circulating cells were mature, polyclonal T cells. The cells expressed the alpha/beta T-cell receptor and the pan-T-cell antigens CD2, CD3, CD5, and CD7, and were negative for both terminal deoxynucleotidyl transferase (TdT) and the CD1 antigen. A mixture of T-helper (CD4+) and T-suppressor (CD8+) cells were present in a ratio of 1:1.6. Gene rearrangement studies revealed that the T-cell receptor beta chain and the immunoglobulin heavy-chain genes were in the germline configuration. Serum samples from this patient were also analyzed for thymic hormones; the level of thymosin alpha 1 was markedly elevated, while that of thymosin beta 4 was decreased. These results effectively exclude the hypothesis that the lymphocytosis represents a second, associated neoplasm. The lymphocyte spillover hypothesis also seems unlikely (although not excluded), since the lymphocytes in lymphocyte-rich thymomas usually have an immature thymic cortical immunophenotype. Furthermore, one might expect nonspecific elevation of all thymic hormone levels with lymphocyte spillover. Thus, we suggest that the lymphocytosis results from a poorly defined immunoregulatory disorder, related to the presence of thymoma, and perhaps secondary thymic hormone imbalance.
Aged↗
In situ hybridization detection of human herpesvirus 6 in biopsy specimens from Chinese patients with non-Hodgkin's lymphoma.
An in situ hybridization assay was developed for the detection of human herpesvirus 6 in formaldehyde-fixed, paraffin-embedded tissue. This test was applied to specimens obtained from 45 patients with non-Hodgkin's lymphoma seen in Fujian, People's Republic of China, who had been classified by the working formulation and immunohistologically characterized. Human herpesvirus 6 sequences were detected in eight of 45 (mean incidence +/- SD, 18% +/- 6%) non-Hodgkin's lymphoma tumor samples tested. The significance of human herpesvirus 6-infected cells in lymphoma tissue remains to be determined.
Adolescent↗
Nasal lymphomas in Peru. High incidence of T-cell immunophenotype and Epstein-Barr virus infection.
The incidence of non-Hodgkin's lymphoma of the nasal region is much higher in Peru than in the United States and is similar to the incidence of sinonasal lymphomas in Asian countries. To characterize these lymphomas, we evaluated the clinical, morphologic, and immunohistochemical features of 14 cases and also analyzed the cases for Epstein-Barr virus (EBV) RNA using a sensitive and specific in situ hybridization method. Morphologically, the cases consisted of nine large cell immunoblastic lymphomas, one diffuse mixed cell lymphoma, one diffuse small cleaved lymphoma, one small noncleaved lymphoma, and two cases unclassifiable in the Working Formulation. Eleven cases demonstrated evidence of T lineage, two were of B lineage and one of indeterminate immunophenotype. In 13 of the lymphoma cases including all of the T-cell lymphomas, EBV RNA was detected in a high percentage of cells. Double-labeling immunohistochemical and in situ hybridization studies identified CD43 positivity in the cells labeling for EBV RNA. Much smaller amounts of EBV RNA were detectable in six of eight control benign nasopharyngeal biopsy specimens, and two were completely negative. These findings are similar to the prevalence of EBV-positive T-cell lymphomas in Asian countries and differ from the findings of the more common EBV-negative B-cell nasal lymphomas in the United States. These findings suggest that EBV plays a role in the development of nasal T-cell lymphomas and that the incidence of EBV infection may explain the reported "East-West" difference in the incidence of nasal T-cell lymphomas.
Adolescent↗
Clustered mutations in the second exon of the MYC gene in sporadic Burkitt's lymphoma.
The primary tumors from 15 untreated patients with Burkitt's lymphoma were analysed for abnormalities in the coding region of the MYC gene by single stranded conformational polymorphism (SSCP) analysis followed by DNA sequencing. Fourteen of the 15 tumors had one or more clonal mutations. Forty one mutations were found in the second exon; only one occurred in the third exon. Seven tumors had mutations that clustered in a region spanning amino acids 38-63. Four of these possessed mutations that altered prolines at positions 57 (3), 60 (1), and 63 (1). Seven tumors were mutated in the central portions of the second exon. These occurred at position 95 (2), position 115 (2), position 137 (1), and position 138 (3). Analysis of the published sequences from five lymphoma cell lines and one primary tumor showed a similar clustering of mutations, with all six having mutations in codons between positions 38-63. The regions where mutations occurred have been associated with a variety of properties, including transcriptional activation and cellular transformation. The number and location of mutations showed no correlation with either chromosome 8 or chromosome 14 breakpoints or with the Epstein-Barr virus positivity of the tumors. This unexpected, frequent occurrence of clustered mutations in the second exon of the MYC gene suggests a role for the mutated MYC proteins in the pathogenesis of Burkitt's lymphoma, possibly through altered interactions of this domain with other cellular factors.
Amino Acid Sequence↗
Hodgkin's disease following non-Hodgkin's lymphoma. A clinicopathologic and immunophenotypic study of nine cases.
We describe nine patients who initially developed non-Hodgkin's lymphoma and subsequently developed Hodgkin's disease. The median interval from the diagnosis of non-Hodgkin's lymphoma (NHL) to the diagnosis of Hodgkin's disease (HD) was 5 years (range, 2-12 years). The median age of the patients at time of diagnosis of NHL was 54 years (range, 27-81 years). Seven of nine cases (78%) of NHL were primarily nodal. According to the Working Formulation, seven NHL were follicular (two small cleaved cell, three mixed small and large cell, two large cell), one was diffuse large cell, and one was large cell immunoblastic. All NHL had histologic or immunophenotypic findings indicative of B-cell lineage. Seven of the nine patients were treated in a nonuniform manner: four with chemotherapy and three with chemotherapy and radiation therapy. At the time of HD, the median age of the patients was 59 years (range, 35-85 years). Lymph nodes were involved in all patients. Six HD biopsies were subclassified as nodular sclerosis, one as mixed cellularity, and two cases were not further subclassified. Immunophenotypic studies revealed that the Reed-Sternberg and Hodgkin cells were LeuM1 or BerH2 positive and LCA negative in eight of nine biopsies, supporting the histologic diagnosis. These results further demonstrate that patients with NHL may subsequently develop HD. The NHLs are usually of B-cell lineage. The results also emphasize the need for rebiopsy in patients with NHL who experience an apparent clinical relapse.
Adult↗
An overview of the classification of non-Hodgkin's lymphomas: an integration of morphological and phenotypical concepts.
An analysis of trends in the incidence of non-Hodgkin's lymphoma requires an understanding of individual disease entities within this broad group. The non-Hodgkin's lymphomas represent a diverse group of malignancies that have in common an origin from lymphoid cells. Nevertheless, these disorders are heterogeneous in their clinical behavior, morphological appearance, cellular origin, etiology, and pathogenesis. A modern classification of non-Hodgkin's lymphomas must include an integration of morphological, immunophenotypical, and molecular concepts in order to delineate individual diseases within this broad group. Existing classification schemes such as the working formulation, while they may be useful in providing a guide to clinical management, cannot provide this information in the absence of other data. This point is most readily made with the low-grade B-cell lymphomas which include follicular lymphomas, mantle cell lymphomas, small lymphocytic lymphomas, immunosecretory disorders, and lymphomas of mucosa-associated lymphoid tissues. Each of these malignancies has a distinct phenotype and genotype, and indubitably each has a different etiology. The postthymic T-cell tumors are equally diverse. Analysis of epidemiological data from cancer registries must include a recognition that our ability to recognize individual diseases from historical data is limited. Studies of trends in the non-Hodgkin's lymphomas should attempt to delineate biological markers that may be of relevance to pathogenesis in both historical and prospectively accrued cases.
Humans↗
MYC rearrangements in histologically progressed follicular lymphomas.
Histologic transformation of low-grade follicular lymphoma to an aggressive-grade lymphoma occurs in 60% to 80% of patients during their clinical course. The events that drive the transformation process are poorly understood. Deregulation of the MYC gene has been implicated in a small number of cases. This observation led us to examine the molecular organization of the MYC oncogene in 38 cases of histologically transformed lymphomas that arose from follicular lymphomas, and in 18 of the initial pretransformation follicular lymphomas. In addition, we examined 58 "control" low-grade follicular lymphomas that had not yet shown evidence of histologic progression. Immunoglobulin heavy chain and light chain gene rearrangements were detected in all biopsies and rearrangements of the BCL-2 locus were seen in 36 of 38 of the transformed lymphomas (consistent with their origin from follicular lymphomas), in 18 of 18 of the pretransformation follicular lymphomas, and in 51 of 58 of the control follicular lymphomas. All 18 pretransformation follicular lymphoma specimens displayed at least one immunoglobulin gene and BCL-2 rearrangement in common with the corresponding histologically progressed lymphoma, indicating a clonal relationship between the original follicular lymphoma and the histologically transformed lymphoma. MYC rearrangements were detected in 3 of 38 (8%) transformed lymphomas and in 1 of 58 (2%) control follicular lymphomas. The latter MYC rearranged follicular lymphoma was clinically aggressive and transformed to a high-grade lymphoma that led to the death of the patient within 20 months. None of the 18 pretransformation follicular lymphomas showed MYC rearrangement, including two from patients who later demonstrated MYC rearrangement in the progressed aggressive lymphoma. PvuII mutational analysis failed to identify additional MYC gene abnormalities in the progressed lymphomas. Because the Epstein-Barr virus (EBV) is associated with a fraction of high-grade lymphomas and is known to upregulate BCL-2, we looked for a potential role for this agent in our progressed lymphomas. We did not detect viral sequences in any case indicating that EBV does not play a major role in progression. The presence of MYC rearrangements in a small fraction of progressed aggressive lymphomas, and not in the corresponding antecedent follicular lymphomas, suggests that acquisition of a MYC rearrangement is in some cases associated with the transformation event.
Chromosome Aberrations↗
Hodgkin's disease following non-Hodgkin's lymphoma.
The risk of Hodgkin's disease following non-Hodgkin's lymphoma (NHL) was estimated using information collected by the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Histopathologic material representing both diagnoses was reviewed for 11 patients in whom Hodgkin's disease was reported after NHL. Diagnoses of both diseases were confirmed in nine patients. Comparisons with population rates indicated that patients with NHL are at an almost threefold risk of subsequently having Hodgkin's disease. Survival in this series was poor; seven of the nine patients died within 16 months after the diagnosis of Hodgkin's disease.
Adult↗
Delta-positive T-cell lymphoma that produces interferon gamma.
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Histiocytosis, Non-Langerhans-Cell↗
Detection and localization of Epstein-Barr viral genomes in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy-like lymphoma.
We studied 23 cases of angioimmunoblastic lymphadenopathy (AILD) and AILD-like lymphoma for evidence of Epstein-Barr virus (EBV) using the polymerase chain reaction (PCR) and in situ hybridization studies. EBV nucleic acid sequences were found by either PCR or in situ hybridization in 96% of the cases. There was a wide range in the number of EBV-positive cells among the different cases as detected by in situ hybridization. The EBV-positive cells most often possessed nuclei of intermediate to large size. Double-labeling immunohistochemistry/in situ hybridization studies demonstrated that most of the EBV-positive cells expressed the B-lineage antigen CD20 (as detected by L26), with a minority of the EBV-positive cells stained for the T-lineage associated antigen, CD43 (as detected by Leu 22). The abnormally high amounts of EBV found in AILD and AILD-like lymphoma may be a reflection of decreased immunocompetence in these patients. The presence of EBV-positive B cells may explain the presence of B-cell clones found by others as well as the paradoxical occurrence of B-cell lymphoma in a primary T-cell lymphoproliferative disorder.
Adult↗
Histogenetic correlations between subcategories of small noncleaved cell lymphomas.
To assess the biologic relevance of the morphologic distinctions between subtypes of small noncleaved cell lymphomas (SNCL), ie, the sporadic Burkitt's type (sBT) and the non-Burkitt's type (nBT), we have examined the molecular organization of several lymphomagenic oncogenes (c-myc, bcl-1, bcl-2) and the potential pathogenetic contribution of the Epstein-Barr virus (EBV). Twenty-nine cases of SNCL, not associated with immunodeficiency syndromes, were reviewed and classified as sBT (18 cases) or nBT (11 cases) without knowledge of the clinical or molecular data. Southern blot analysis of 18 sBTs found 17 to contain c-myc rearrangements. Fifteen of these comigrated with an Ig heavy-chain gene segment, indicating t(8;14) translocation. Chromosome 8 breakpoints were clustered in the first exon and the first intron of the c-myc gene. Chromosome 14 breakpoints mapped to the JH locus in three tumors, the S mu locus in nine tumors, and the S alpha locus in the remaining three tumors. Cases involving the S alpha locus appeared to have a more rapid clinical course. All sBTs possessed germline bcl-2 and bcl-1 gene fragments. In contrast, Southern blot analysis of 11 nBTs found none with c-myc rearrangements. Rather, three of 10 evaluable nBTs had bcl-2 rearrangements. The remaining seven showed no evidence of involvement by any of the lymphoma-associated oncogene/breakpoint regions studied. EBV genome was detected in two sBTs and in one nBT, and thus was not a distinguishing feature. These results indicate that the subtle histologic differences that distinguish subcategories of SNCL are significant biologically and reflect distinct molecular mechanisms of lymphomagenesis. Furthermore, the data suggest that the nBTs comprise a heterogeneous group with respect to their molecular genetic composition and confirm the remarkable molecular genetic homogeneity of the sBT group.
Adolescent↗
Detection of human herpesvirus 6 in tissues involved by sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease).
After preliminary serologic data demonstrated elevated antibody titers to human herpesvirus (HHV) 6 in patients with sinus histiocytosis with massive lymphadenopathy (SHML) or Rosai-Dorfman disease, tissues were examined from 9 patients with classical SHML to search for evidence of HHV-6 infection. Involved tissues from 7 of the 9 patients had detectable HHV-6 by in situ hybridization: Tissue from 1 had detectable Epstein-Barr virus genome but no HHV-6 and tissue from another had no detectable HHV-6 or Epstein-Barr virus. These studies suggest that HHV-6 and, to a lesser extent, Epstein-Barr virus may be involved in the etiology of SHML.
Antibodies, Viral↗
CD5 expression in B-cell small lymphocytic malignancies. Correlations with clinical presentation and sites of disease.
The authors examined the relationship between CD5 antigen expression and a nodal or extranodal presentation for three subtypes of low-grade non-Hodgkin's lymphoma: small lymphocytic (23 cases), small lymphocytic with plasmacytoid differentiation (10 cases), and lymphocytic lymphoma of intermediate differentiation (IDL) (29 cases). Antigen expression was studied by the avidin-biotin complex immunoperoxidase technique in frozen sections and correlated with expression of other B- and T-cell markers. Lack of CD5 expression was significantly associated with extranodal presentation among the over-all study group (p less than 0.001), as well as for those with small lymphocytic lymphoma and IDL, but not for those presenting with small lymphocytic lymphomas with plasmacytoid differentiation (p less than 0.21). Eleven patients presented exclusively with extranodal disease involving lung and respiratory tract, skin and subcutaneous tissue, salivary gland, stomach, conjunctiva, and uterus. All such lesions were CD5 negative and had been classified as small lymphocytic (four cases), small lymphocytic-plasmacytoid (four cases), and IDL (three cases). Retrospective review of these 11 cases demonstrated common histologic features described as characteristic of lymphomas of mucosa-associated lymphoid tissue (MALT). Two additional patients presented with disseminated nodal disease and involvement of gastrointestinal tract and oropharynx; both were CD5 positive. These findings support the concept that at least two antigenically distinct B-cell subpopulations may be involved in pathogenesis of low-grade small lymphocytic malignancies.
Antigens, CD↗
T-cell lymphoblastic lymphoma with eosinophilia associated with subsequent myeloid malignancy.
Three patients with T-cell lymphoblastic lymphoma and peripheral blood eosinophilia are reported. At the time of diagnosis, all patients had lymphadenopathy, and one had a mediastinal mass. Lymph node biopsies revealed lymphoblastic lymphoma admixed with a variable number of mature eosinophils. Immunophenotypic studies demonstrated that each lymphoma had an immature T-cell immunophenotype. Bone marrow biopsies were hypercellular with myeloid hyperplasia and eosinophilia but were negative for lymphoma. All patients received multiagent chemotherapy; one patient achieved a complete remission, and two patients had partial remissions. All patients subsequently developed a myeloid malignancy. Two died of acute myeloid leukemia within 18 months of the diagnosis of lymphoblastic lymphoma. The third patient relapsed with a lymphoma that had histologic and immunophenotypic features of both T-cell lymphoblastic lymphoma and granulocytic sarcoma and also developed a poorly defined myeloproliferative disorder. These findings suggest that T-cell lymphoblastic lymphoma associated with eosinophilia may represent a distinct clinico-pathologic entity with a high risk of subsequent myeloid neoplasia.
Acute Disease↗
Mediastinal lymphoblastic lymphoma with an immature B-cell immunophenotype.
A 19-year-old woman presented with a large mediastinal mass, histologically shown to be malignant lymphoma of lymphoblastic type (LBL). Immunophenotypic and gene rearrangement analysis unequivocally demonstrated that the neoplasm was of B-cell lineage. The neoplastic cells expressed terminal deoxynucleotidyl transferase, the pan-B cell antigens CD19, CD20, and CD22, and were negative for immunoglobulins and numerous T-cell antigens tested. Southern blot analysis showed rearrangement of one allele of the immunoglobulin heavy chain gene while the immunoglobulin kappa and T-cell receptor beta chain genes were in the germline configuration. Thus, the immunophenotypic and molecular findings in this case correspond to an early stage of B-cell differentiation, the pre-pre B-cell stage as has been named by others. In contrast with LBL of immature T-cell lineage, precursor B-cell LBLs involving the mediastinum are truly rare. Occasional cases have been reported that have arisen elsewhere and subsequently involved the mediastinum at time of relapse or tumor progression. Well-documented examples of immature B-cell LBL arising in the mediastinum are virtually unreported. The site and cell population giving rise to this neoplasm is unknown. However, origin from precursors of normal thymic medullary B cells is proposed as one possibility.
Adult↗
Localization of Epstein-Barr viral genomes in angiocentric immunoproliferative lesions.
Epstein-Barr virus has been demonstrated in angiocentric immunoproliferative lesions. However, these studies, which have used the polymerase chain reaction technique or Southern blot analysis, have not revealed the identity of the cell population harboring the virus. To address this issue, we analyzed 12 angiocentric immunoproliferative lesions (14 biopsy specimens) for Epstein-Barr virus RNA using a sensitive and specific in situ hybridization method. Epstein-Barr virus RNA was detected in five of 12 cases. Each positive lesion was a high-grade angiocentric immunoproliferative lesion (i.e., angiocentric lymphoma) in which Epstein-Barr virus was identified in numerous cells. Furthermore, the Epstein-Barr virus-positive cells were often larger than normal lymphocytes and thus were most likely the malignant cells. Double-labeling immunohistochemistry/in situ hybridization studies revealed that the majority of Epstein-Barr virus-positive cells were CD43-positive and CD20-negative, consistent with T-cell lineage. The remaining seven cases, all grade I or II angiocentric immunoproliferative lesions, were either completely negative (four cases) or had only rare to occasional Epstein-Barr virus-positive cells (three cases). The results obtained with the polymerase chain reaction and Southern blot hybridization studies generally confirmed those obtained with in situ hybridization. We conclude that Epstein-Barr virus is frequently associated with angiocentric immunoproliferative lesions, particularly within high-grade lesions, in which the virus is probably present within the neoplastic cells. These findings also suggest that Epstein-Barr virus may be involved in the transformation of low-grade angiocentric immunoproliferative lesions to histologically unequivocal angiocentric lymphomas.
Adult↗