Incidental cases of localized fibrin-associated Epstein-Barr virus (EBV)+ large B-cell proliferations have been described at unusual anatomic sites and have been included in the category of diffuse ...large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) in the WHO Classification. We describe 12 cases and review the literature to define their clinicopathologic spectrum and compare features with typical cases of DLBCL-CI. Median age was 55.5 years with a M:F ratio of 3. In all 12 cases, the lymphoma was an incidental microscopic finding involving atrial myxomas (n=3), thrombi associated with endovascular grafts (n=3), chronic hematomas (n=2), and pseudocysts (n=4). All cases tested were nongerminal center B-cell origin, type III EBV latency, and were negative for MYC rearrangements and alternative lengthening of telomeres by FISH. Most showed high CD30, Ki67, and PD-L1, and low to moderate MYC and p53 expression. Among 11 patients with detailed follow-up, 6 were treated surgically, 3 with cardiac or vascular lesions had persistent/recurrent disease at intravascular sites, and 4 died of causes not directly attributable to lymphoma. Reports of previously published fibrin-associated cases showed similar features, whereas traditional DLBCL-CI cases with a mass lesion had significantly higher lymphoma-associated mortality. Fibrin-associated EBV+ large B-cell lymphoma is clinicopathologically distinct from DLBCL-CI, warranting separate classification. Most cases, particularly those associated with pseudocysts, behave indolently with the potential for cure by surgery alone and may represent a form of EBV+ lymphoproliferative disease rather than lymphoma. However, primary cardiac or vascular disease may have a higher risk of recurrence despite systemic chemotherapy.
The presence of
occult bone marrow metastases (OM) has been reported to represent an
important prognostic indicator for patients with operable breast cancer
and other malignancies. Assaying for OM ...most commonly involves
labor-intensive manual microscopic analysis. The present report
examines the performance of a recently developed automated
cellular image analysis system (ACIS; ChromaVision Medical Systems,
Inc.) for identifying and enumerating OM in human breast cancer
specimens. OM analysis was performed after immunocytochemical staining.
Specimens used in this study consisted of normal bone marrow
( n = 10), bone marrow spiked with carcinoma cells
( n = 20), and bone marrow obtained from breast
cancer patients ( n = 39). The reproducibility of
ACIS-assisted analysis for tumor cell detection was examined by having
a pathologist evaluate montage images generated from multiple ACIS runs
of five specimens. Independent ACIS-assisted analysis resulted in the
detection of an identical number of tumor cells for each specimen in
all instrument runs. Additional studies were performed to analyze OM
from 39 breast cancer patients with two pathologists performing
parallel analysis using either manual microscopy or ACIS-assisted
analysis. In 17 of the 39 cases (44%), specimens were classified by
the pathologist as positive for tumor cells after ACIS-assisted
analysis, whereas the same pathologist failed to identify tumor cells
on the same slides after analysis by manual microscopy. These studies
indicate that the ACIS-assisted analysis provides excellent sensitivity
and reproducibility for OM detection, relative to manual microscopy.
Such performance may enable an improved approach for disease staging
and stratifying patients for therapeutic intervention.
Recent polymerase chain reaction (PCR)-based studies focused on the detection of immunoglobulin heavy chain gene (IgH) rearrangements have suggested that clonal populations may be amplified more ...easily from certain categories of B-cell neoplasia than others and that primer makeup can be a critical factor in successful amplification. However, these particular reports contained relatively few low grade B-cell lymphoproliferative disorders of nonfollicular center cell type (LG-BLPD) and used only a limited panel of available primer sets for PCR amplification of monoclonal B-cell populations. To address this issue more extensively we evaluated 156 samples of LG-BLPD by the PCR to determine optimal primer selection in this setting. All cases were classified according to standard morphological and immunophenotypic criteria, with monoclonality documented by Ig light chain restriction analysis. The LG-BLPD included 33 cases of chronic lymphocytic leukemia (CLL), 57 cases of small lymphocytic lymphoma (SLL), 10 cases of atypical CLL, 32 cases of mantle cell lymphoma (MCL), 17 plasma cell neoplasms (PCNs), and seven cases of hairy cell leukemia (HCL). All primer sets included a 3' IgH joining region consensus primer, whereas the 5' IgH variable region (VH) primer was different in each set. The first-line panel included the following: Set 1, VH-framework III consensus primer, and Set 2, seven separate VH-framework I family-specific primers. A reserve panel of alternate VH consensus primers directed at framework II or III regions was used only when Set 1 showed no evidence of B-cell monoclonality.
Mantle cell lymphomas (MCLs) are typically CD5-expressing B-cell non-Hodgkin's lymphomas (NHLs) that frequently harbor the chromosomal translocation t(11;14) or bcl-1 gene rearrangements. ...Insufficient data are available on the biologic features and clinical behavior of rigorously characterized MCL. As these NHLs have been reported to exhibit various histologic and cytologic expressions, and in order to avoid using somewhat arbitrary and subjective morphologic definitions, we chose to study cases of MCL selected on more objective grounds. Specifically, 15 samples (from 14 patients) of CD5-expressing B-cell NHLs with detectable bcl-1 gene rearrangement were included. Overall, these patients had relatively uniform clinical manifestations. Most were older men (mean age, 67 years) who presented with lymph-adenopathy, high-stage disease, and bone marrow involvement. All but two patients relapsed, demonstrated residual tumor, or had disease progression after an initial response to various therapies. Nine patients have died; these patients had a median survival of only 19 months. All cases could be classified within the broad morphologic spectrum previously described for MCL, and no predominant histologic subtype was observed. However, cases could be segregated into two major groups according to tissue architecture: one with a purely diffuse pattern and the other with at least a focal nodular component. Patients with purely diffuse tumors had a lower survival rate (0%) than those with tumors having a nodular component (62% survival rate). In contrast to the morphologic variability, these NHL exhibited a rather homogeneous immunophenotypic pattern. All cases demonstrated intense CD20 expression, with typically intense IgM and light chain expression, and relatively weak IgD expression. In no case was CD10 detected on the neoplastic cells. DNA content analysis showed aneuploidy only in three instances, and two groups of cases could be arbitrarily defined on the basis of their S-phase fraction. A relationship between a purely diffuse growth pattern and a high S-phase fraction (greater than 5%) was observed. As expected from this association, patients with tumors having high S-phase fractions fared worse (14% survival rate) than those patients with tumors showing lower S-phase fractions (57% survival rate). Thirteen NHLs from 12 patients had amplifiable bcl-1 gene rearrangements at the major translocation cluster (MTC). The bcl-1 breakpoints aggregated within a 63-bp region of the MTC, and the amplified tumor DNA from each patient had unique N-nucleotide junctional sequences and Ig joining region breakpoint sites. Two additional NHLs had bcl-1 gene rearrangements detected only with Southern blot hybridization using a genomic probe directed at a breakpoint site distant from the MTC. We conclude that CD5-expressing B-cell NHLs with bcl-1 gene rearrangement can be morphologically classified as MCL, have relatively uniform immunophenotypic characteristics, and are associated with an overall poor prognosis. Architectural growth pattern and kinetic information, such as S-phase fraction, may help separate a more aggressive group of these NHL from a relatively less aggressive subset.
Lymphomatoid papulosis (LyP) is a chronic dermatosis that histologically resembles malignant lymphoma. Thus far, only a few cases of LyP have been characterized in detail with regard to ...immunophenotype, genotype, and karyotype.
Our purpose was to study seven patients with LyP and compare the results to those reported in the literature.
Skin biopsy specimens were analyzed by frozen section immunohistochemical and molecular biologic techniques. Cytogenetic analysis was also performed in three cases.
The atypical lymphoid cells consisted of activated helper T cells; four of the seven patients had lesions with a detectable clonal T-cell population. A peripheral T-cell lymphoma developed in one patient before the emergence of a genotypically different LyP T-cell clone. Cytogenetic studies were abnormal in one case of LyP and normal in another, whereas the karyotype of the lymphoma was abnormal.
LyP is a preneoplastic proliferation of activated helper T cells, which is often clonal and may regress and expand with the development of new LyP clones or lymphoma.
Although T-cell-rich B-cell lymphoma (TCRBCL) is a recently recognized form of non-Hodgkin's lymphoma (NHL), limited information regarding its incidence, cellular origin, morphologic spectrum, and ...biologic behavior is currently available. In this study, the clinicopathologic features of eight patients with TCRBCL are presented. This neoplasm comprised about 1% of all NHLs seen at Emory University Hospital over 2 years. The male-to-female ratio was 1.6, and the mean age at diagnosis was 60 years. At presentation, TCRBCL was nodal in 88% of the patients and widely disseminated in 50% of the patients. A complete remission was seen in three of the five patients treated with combination chemotherapy that was directed at intermediate grade NHL. Three patients received inadequate or incomplete chemotherapy. One of these patients later achieved a complete remission with more intensive therapy. Two of the patients were not evaluable for response to therapy. The actuarial and disease-free survival rates of the group at 5 years were 72% and 21%, respectively. Morphologically, the lymph nodes in seven of eight cases were diffusely obliterated, whereas one had markedly expanded interfollicular zones that lead to an initial diagnosis of T-zone lymphoma. All tumors were characterized by no more than 25% large lymphoid cells, which were scattered in a background of small lymphocytes with round or irregular nuclei. The presence of numerous histiocytes imparted a lymphoepithelioid appearance in two cases. Although immunoperoxidase stains of frozen tissue were initially suggestive of a peripheral T-cell lymphoma in some cases, paraffin immunoperoxidase stains clearly established the B-cell nature of the large cells, whereas most of the small cells were T lymphocytes. The clonal nature of the large cells was confirmed in seven cases by monotypic immunoglobulin (Ig) light chain restriction or Ig gene rearrangements. Epstein-Barr virus genomic DNA was detected in two of the six cases tested by polymerase chain reaction or Southern blot analysis, but no evidence of a bcl-2 rearrangement was found in any of the five cases examined. These findings indicate that TCRBCL is an uncommon form of NHL with a therapeutic response and overall survival consistent with intermediate grade lymphoma. Paraffin immunoperoxidase stains and occasionally genotypic analysis are required to exclude the diagnosis of PTCL or diffuse lymphocyte predominant Hodgkin's disease. The authors found no morphologic or molecular evidence to support a follicular center cell origin in these cases of TCRBCL.
A possible etiologic role for Epstein-Barr virus (EBV) in Hodgkin's disease (HD) was investigated by probing for EBV genome in 52 biopsy specimens involved with HD and 43 hyperplastic lymph node ...specimens. Using dot-blot hybridization (Bam HIW probe), Southern blot hybridization (Xho I probe), and polymerase chain reaction analyses, 27%, 27%, and 58% of the nodes with HD were positive for EBV genome, respectively, as compared to 16%, 14%, and 43% in the hyperplastic lymph nodes. Clonal and nonclonal episomal EBV and linear replicating EBV genome were present in both conditions. Immunoglobulin heavy chain gene rearrangements were found in two clonal and two nonclonal EBV-positive HD cases, but not in the lymphoid hyperplasia cases. These findings and other recent reports showing EBV genome in benign lymphoid cells by in situ hybridization in Hodgkin's disease suggest that the characteristics of EBV infection in HD could be explained by the reactive cellular milieu, especially in the setting of defective immunity. The identification of EBV genome in Reed-Sternberg cells may, therefore, be a nonspecific phenomenon.
Many nonrandom chromosome abnormalities have been associated with non-Hodgkin's lymphomas (NHL). Some of these are nonspecific changes seen in many different histologic subtypes. We describe a series ...of abnormalities of chromosome bands 10q23-25 seen in 159 consecutive NHL patients with abnormal cytogenetic findings. The proportion of karyotypes with abnormalities of 10q varied from 3% among the immunoblastic lymphomas to 67% in the diffuse large cleaved cell lymphomas. Seventeen (10.7%) had abnormalities of 10q23-25. All but one of these were B-cell tumors. The abnormalities consisted of six deletions and 11 translocations. Sixteen of the 17 patients had the 10q abnormality when cells were first karyotyped. The remaining patient acquired the 10q abnormality in the third of a series of biopsies. In the follicular histologic subtypes follicular small cleaved cell (FSC), follicular mixed small cleaved and large cell (FM), and follicular large cell noncleaved (FL-NC), abnormalities of 10q were found in nine patients, all in association with abnormalities of 14q32. Seven of these were associated with the t(14;18)(q32;q21). Overall, 10q23-25 abnormalities were observed in 11.9% (8/67) of low-grade small lymphocytic (SL), FSC, and FM lymphoma cases. DNA was available from five patients with abnormalities of 10q and was probed for rearrangements with the HOXII (TCL3) oncogene probe. As expected, we did not find such rearrangements in these five patients with B-cell tumors. Abnormalities of 10q23-25 have been reported previously in NHL but not at this frequency.
We report a case of solitary unifocal Langerhans' cell histiocytosis presenting as a large lower extremity soft tissue mass in a 48-year-old white man. Radiologically, this was an infiltrating mass ...involving all compartments of the right thigh; the mass had a maximum diameter of 18 cm. Extensive evaluation revealed no evidence of involvement of any other organ. An incisional biopsy was performed under the presumptive clinical impression of sarcoma. A definitive diagnosis of Langerhans' cell histiocytosis was established on the basis of characteristic morphologic features, cell surface marker findings by immunohistochemistry and flow cytometry, and electron microscopic studies. The patient was treated with four courses of chemotherapy, (etoposide and prednisone) and had no evidence of disease 3 years after the initial presentation. A review of the literature revealed that soft tissue Langerhans' cell histiocytosis usually presents in the head and neck area of children and usually has associated bone, lung, or reticuloendothelial system involvement. To our knowledge, this is the first reported case of solitary Langerhans' cell histiocytosis in an adult in which the presentation mimicked sarcoma.
The identification of minimal residual disease (MRD) in non-Hodgkin's malignant lymphoma is of immediate clinical relevance. Although several polymerase chain reaction (PCR)-based strategies are ...currently available, they all share serious technical or theoretic limitations with respect to their ability to detect the broad spectrum of mature B-cell neoplasia. We report a new strategy based on anchored PCR that does not rely on a particular chromosomal translocation or VH consensus sequence. It can yield the complete DNA sequence of the immunoglobulin heavy chain variable region (VHDJH). The assay is capable of detecting one neoplastic cell among 10(3)-10(4) normal cells with high specificity and has the potential to greatly expand the variety of B-cell malignant neoplasms that can be studied.
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