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Context.—Activation-induced cytidine deaminase, necessary for immunoglobulin somatic hypermutation and class switch recombination, is usually expressed within the follicular dendritic network but is also expressed in a population of interfollicular large B cells outside the germinal center. Objective.—To report 7 cases of diffuse large B-cell lymphoma with a distinct paracortical distribution. Expression of activation-induced cytidine deaminase, previously described in interfollicular large B cells, was evaluated. Design.—A panel of immunohistochemical markers, including double staining for activation-induced cytidine deaminase and CD20, was used to illustrate the cases. Molecular studies were performed by polymerase chain reaction in the paraffin-embedded tissue for t(14;18) chromosomal translocation and immunoglobulin heavy chain and T-cell receptor rearrangements. Results.—Patients included 3 males and 4 females ranging in age from 11 to 59 years (mean, 39 years). All specimens were lymph nodes (4 from the groin, 2 from the neck, and 1 from the axilla). Malignant lymphocytes were positive for CD20 and negative for CD5 and CD10. Staining for CD30, CD43, and BCL-2 was variable. The malignant cells showed at least focal staining with activation-induced cytidine deaminase. All cases were found to be monoclonal by immunoglobulin heavy-chain gene rearrangement or showed light-chain restriction. None of the tested cases showed t(14;18). Conclusions.—Diffuse large B-cell lymphoma with a paracortical distribution is unusual and may be a distinct morphologic variant. More study is necessary to determine the stage of B-cell development and the cell of origin of these tumors. However, activation-induced cytidine deaminase expression suggests they may arise from a putative interfollicular large B cell.

Lymphoplasmacytic lymphoma (LPL) is a small B-cell lymphoma with plasmacytic differentiation that does not fulfill the criteria for any other small B-cell lymphoma. Cytogenetic characterization of nodal LPL is limited and the distinction from marginal zone lymphomas with plasmacytic differentiation can be problematic. Thus, 17 cases of lymph node-based LPL were studied with fluorescence immunophenotypic and interphase cytogenetics for the investigation of neoplasia (FICTION) using a CD79a antibody and probes to detect trisomies of chromosomes 3 (15 cases), 12 (16 cases), and 18 (17 cases); rearrangements (R) of IgH (10 cases), BCL6 (6 cases), PAX5 (7 cases), and MALT1 (16 cases); and deletion 6q21 (7 cases). Cases with IgH R were further studied with an IgH/BCL2 probe. In cases without FICTION studies, previously reported fluorescence in situ hybridization results for IgH, PAX5, and deletion 6q21 were available from prior studies. The histopathology, immunophenotype, and available clinical data were also reviewed. Three pathologic categories were recognized: 5 classic LPL, 5 vaguely nodular polymorphous (VN-P), and 7 other. Among the classic LPL, 4/4 had an IgM paraproteinemia, 5/5 had bone marrow involvement (BM+), and 1/5 had +MALT1. One of one VN-P LPL had an IgM paraprotein, 2/4 were IgM+, 2/4 IgG+, 1/3 had BM+, and 1/5 had an IgH R. Among the other cases, 2/3 had a paraprotein, 2/7 were IgM+, 5/7 IgG+, and 0/3 had BM+. Of these cases, 1 showed +12, 1 +18, and 1 IgH/BCL2 rearrangement plus +18. None of the 17 cases had a 6q21 deletion or +3. Therefore, with rare exception, lymph node-based LPL with classic or more varied histopathologic features does not have the cytogenetic abnormalities frequently associated with bone marrow-based LPL/Waldenstrom macroglobulinemia or many of the marginal zone lymphomas. The search for better objective inclusionary criteria for LPL must continue.

Context.—Reed-Sternberg cells in classic Hodgkin lymphoma are enigmatic and difficult to study because they are so sparse. Tissue microdissection allows for the isolation of single Reed-Sternberg cells. Isolated Reed-Sternberg cells show clonal immunoglobulin gene rearrangement indicating a B-cell origin. Rarely, Reed-Sternberg cells in classic Hodgkin lymphoma express T-cell antigens, suggesting a possible T-cell origin. Objective.—To determine whether there is a difference in genotype between classic Hodgkin lymphoma and classic Hodgkin lymphoma expressing T-cell antigens and to document T-cell clonality. Design.—We studied 4 cases of Hodgkin lymphoma with a characteristic phenotype and immunoreactivity for CD2 and CD3. Single CD30+ Reed-Sternberg cells from each case were isolated by laser capture microdissection for immunoglobulin heavy chain and T-cell receptor-γ genes by polymerase chain reaction studies. Comparative genomic hybridization was performed in all cases. Results.—Two of 4 cases showed clonal rearrangement of the T-cell receptor-γ; none showed immunoglobulin heavy chain rearrangement. Two control cases were negative for T cell receptor-γ but 1 showed immunoglobulin heavy chain rearrangement. Comparative genomic hybridization analysis revealed significant overlap in genomic alteration in Hodgkin lymphoma cases regardless of genotype or phenotype and several regions of imbalance specific to CD3+ Hodgkin lymphoma cases. All patients are alive with no evidence of disease from 10 to 44 months. Conclusions.—Our findings suggest that a T-cell phenotype classic Hodgkin lymphoma can be supported by genotypic studies and that there may be cytogenetic differences between classic Hodgkin lymphoma and Hodgkin lymphoma expressing T-cell antigens.

We retrospectively analyzed 45 cases of HIV-associated Hodgkin lymphoma (HIV-HL). HIV-HL generally is a disease of young white men (mean age, 40.1 years) who acquired HIV infection by homosexual or bisexual behavior (68%), intravenous drug use (24%), and/or blood transfusion (8%). The mean interval between the diagnosis of HIV and HIV-HL was 5.2 years. Morphologic classification of nodal biopsy specimens (2001 World Health Organization criteria) included 15 mixed cellularity Hodgkin lymphomas (MCHLs), 14 nodular sclerosis Hodgkin lymphomas (NSHLs), 9 lymphocyte depleted Hodgkin lymphomas (LDHLs), and 7 classic Hodgkin lymphomas, type not further categorized. The Hodgkin–Reed-Sternberg (HRS) cells expressed positive immunoreactivity with fascin (30/30 [100%]), CD30 (35/37 [95%]), CD15 (32/36 [89%]), bcl- XL (25/31 [81%]), bcl-2 (15/29 [52%]), CD20 (4/34 [12%]), bcl-6 (3/28 [11%]), and Epstein-Barr virus latent membrane protein-1 (32/33 [97%]) and were nonreactive for CD138/syndecan-1. CD4 and CD8 immunostaining showed an inverted CD4/CD8 ratio (

A t(9;14)(p13;q32) involving the PAX5 and IGH genes has been described in association with lymphoplasmacytic lymphoma. Although often described as common, the incidence of this translocation in nodal lymphoplasmacytic lymphoma has never been investigated. Recent studies of patients with Waldenstrom's macroglobulinemia (often corresponding to marrow-based lymphoplasmacytic lymphoma) have failed to identify the t(9;14). These studies have suggested that either nodal and marrow-based lymphoplasmacytic lymphomas have distinct pathogenetic mechanisms or that the t(9;14) is less frequent in lymphoplasmacytic lymphoma than was believed previously. We therefore analyzed a series of nodal or other extramedullary lymphoplasmacytic lymphomas for the presence of the t(9;14) with paraffin section interphase fluorescence in situ hybridization. We developed a BAC contig probe spanning all previously described PAX5 breakpoints and validated this assay with the KIS-1 cell line that expresses a t(9;14). Analysis with the PAX5 probe showed a lack of PAX5 rearrangements in all cases that were analyzed successfully. Similarly, analysis by an IGH fluorescence in situ hybridization probe showed no evidence of translocations involving the IGH locus. These findings indicate that the t(9;14) is at least uncommon in lymphoplasmacytic lymphoma and should no longer be considered a characteristic finding in this type of lymphoma as defined by World Health Organization criteria.

Cutaneous follicle center lymphoma (FCL) is reported to have a unique immunophenotype and clinical course as compared with nodal FCL. We studied 19 cases of FCL of the skin using paraffin embedded tissue. An immunohistochemistry panel included CD45, CD3, CD20, CD43, CD21, bcl-2, bcl-6, CD5, and CD10. Molecular studies were performed by polymerase chain reaction for immunoglobulin heavy chain (IgH) and t(14;18). Trisomy 3 was performed by fluorescent in situ hybridization (FISH) in 13 cases. Follow up was obtained in 17 cases (range 3 to 137 months). Patients included 10 females and 9 males ranging in age from 33 to 88 years at first presentation (mean, 64). Twelve of 19 presented in the head and neck and 6 in the trunk and 1 on the arm. All had no known lymph node disease at presentation. Seventeen patients had no nodal disease with a minimum 3 month follow-up; 2/19 had unknown lymph node status with no follow-up. All cases were immunoreactive with CD20 and negative with CD3. Bcl-2 was immunoreactive in 11/18 cases, bcl-6 in 15/15, CD10 in 14/17, CD43 in 2/16 (both were CD10 immunoreactive) and CD5 in 1/15 (it was also bcl-6 immunoreactive). Eight of 18 cases were monoclonal for IgH. Three of 17 showed the presence of t(14;18). FISH was positive in 4 cases for trisomy 3 ranging from 16 to 22% (12% threshold). Follow-up showed no evidence of disease in 14/17 patients (4 to 137 mos). 3/17 patients are alive with disease (17 to 100 mo), and no patients died of disease.

Primary non-Hodgkin's lymphoma of the salivary gland is an uncommon tumor that most often occurs in the parotid gland. The most common subtype is marginal-zone B-cell lymphoma, extranodal, mucosa-associated lymphoid tissue type. This subtype has recently been included in the Revised European-American Classification of Lymphoid Neoplasms, as well as in the upcoming World Health Organization classification of hematopoietic and lymphoid neoplasms. This low-grade lymphoma usually arises in a background of benign lymphoepithelial lesion or myoepithelial sialadenitis that is associated with the autoimmune disease Sjögren's syndrome. It occasionally develops in patients who do not have a history of autoimmune disease. When mucosa-associated lymphoid tissue lymphoma occurs in the salivary gland, as in other extranodal sites such as the stomach, it is usually an indolent neoplasm that tends to remain localized for long periods of time, even without treatment. Eventually, however, the tumor may disseminate or transform to a higher grade. The histologic distinction of myoepithelial sialadenitis from low-grade B-cell mucosa-associated lymphoid tissue lymphoma can be a difficult diagnostic challenge and many of these lesions continue to be ambiguously diagnosed as "pseudolymphoma." Immunophenotypic or flow cytometric analysis may be useful in showing an aberrant phenotype or immunoglobulin light-chain restriction, which helps to support a diagnosis of malignant lymphoma in most cases. Molecular genetic analysis for immunoglobulin gene rearrangements also may be useful in showing monoclonality, although the exact significance of this finding in some cases remains controversial.

The authors investigated the relations between outcome and apoptosis, immunohistochemical demonstration of bcl-2 protein, and immunohistochemical staining for p53 protein in patients with gastrointestinal stromal/smooth muscle tumors (GIST). Patients whose tumors demonstrated cellular apoptosis using the terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL) assay had an improved survival over those whose tumors did not improve. In contrast, patients whose tumors demonstrated staining for bcl-2 protein had a decreased survival compared with those whose tumors did not demonstrate bcl-2. There was no relation between p53 immunoreactivity and survival. These results suggest that inhibition of apoptosis may be associated with malignant behavior in patients with gastrointestinal stromal/smooth muscle tumors.

Context.—Inflammatory pseudotumor is an uncommon and enigmatic lesion. The spindle cells found in this tumor have features of myofibroblasts. Because of the indefinite relationship of these lesions with inflammatory fibrosarcoma and their indefinite biologic behavior, inflammatory pseudotumor is currently classified as inflammatory myofibroblastic tumor (IMT). To date, only case reports or small series have been published on these tumors, which are primary in the spleen. Design.—In this study, we describe the clinical, morphologic, and immunophenotypic findings of 12 cases of splenic IMT and examine their relationship to Epstein-Barr virus (EBV). Results.—The patients included 8 women and 3 men, ranging from 19 to 77 years of age (mean, 53 years; median, 60 years). Demographic data were unavailable for 1 patient. Patients generally presented with abdominal pain (n = 5) and fever (n = 4). Associated lesions included renal cell carcinoma (n = 2), colonic adenocarcinoma (n = 1), and cholecystitis (n = 1). All tumors were composed of a bland spindle cell proliferation in association with a variable mixed inflammatory component. There were 2 growth patterns, namely, a cellular spindle cell pattern and a hypocellular fibrous pattern. An immunohistochemical panel confirmed the myofibroblastic nature of the spindle cells. The spindle cells of 2 cases were immunoreactive for EBV latent membrane protein 1, whereas 6 of 10 cases were positive for EBV-encoded RNA using in situ hybridization. Follow-up was available for 8 patients; 6 were alive with no evidence of recurrence and 2 were dead of other causes. Conclusion.—Splenic IMTs are uncommon lesions that can be distinguished from other conditions using a combination of clinical, histologic, and immunophenotypic findings. Epstein-Barr virus may play a role in the pathogenesis of splenic IMT, and there may be an association of splenic IMT with concomitant disease or malignancy. Most splenic IMTs have an excellent long-term prognosis.

Interfollicular small lymphocytic lymphoma (I-SLL) has not been well characterized and its relationship to small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL) is uncertain. Moreover, two different proliferation center growth patterns have been described with respect to reactive germinal centers. In this study, we evaluate the histological and immunophenotypic features of 13 cases of I-SLL and immunoglobulin heavy chain variable (VH) gene sequences from 10 cases. Immunophenotypic analyses indicate that cases showing either growth pattern have the same CD5-positive B cell phenotype typical of SLL or CLL. Sequence analysis revealed the use of VH, D, and J gene segments often found in CLL, although there may be more frequent use of J6. Similar to recent studies of CLL, there were approximately equal numbers of cases with either mutated or unmutated VH genes without evidence of ongoing mutation, consistent with I-SLL having either a naïve or memory B cell origin. Interestingly, the mutational status of the I-SLL VH genes seemed to correlate with the two different histological growth patterns. These studies support the proposal that I-SLL represents SLL/CLL and suggest the recently proposed two types of CLL originating from either memory or naïve B cells may have different histological patterns of growth in lymph nodes that show architectural preservation.

Primary female reproductive system lymphomas are distinctly uncommon, and are defined as lymphomas that present primarily as gynecologic tumors. We describe 3 cases which presented in this location, 1 primary ovarian disease and 2 others presenting the initial manifestations of disseminated lymphoma. Clinical history, follow-up information, and paraffin embedded archival tissue were available for all 3 cases. A panel of immunoperoxidase studies and molecular genetic studies were performed for each case. The primary ovarian follicle center lymphoma was a grade III/III (large cell) while the cases representing secondary involvement were grade I/III (small cell). Immunohistochemistry demonstrated reactivity of the malignant cells in each case with CD20 and bcl-2. In the grade I/III cases the cells were immunoreactive for CD45RA and CD10. Molecular genetic analysis demonstrated the t(14;18) translocation in the case of primary ovarian follicle center lymphoma. Follicle center lymphoma uncommonly presents in the female genital system, and may rarely be primary to this site. Immunoperoxidase and molecular studies in concert with the morphology are invaluable in rendering a correct diagnosis and ensuring correct treatment of the patient. Ann Diagn Pathol 4:293-299, 2000.

Primary angiosarcoma of the spleen is a rare neoplasm that has not been well characterized. We describe the clinical, morphologic, and immunophenotypic findings of 28 cases of primary splenic angiosarcoma, including one case that shares features of lymphangioma/lymphangiosarcoma. The patients included 16 men and 12 women, aged 29 to 85 years, with a mean of 59 years and median of 63 years. The majority of patients (75%) complained of abdominal pain, and 25% presented with splenic rupture. The most common physical finding was splenomegaly (71%). Seventeen of 21 patients were reported to have anemia. Macroscopic examination showed splenomegaly in 85% cases. Sectioning revealed discrete lesions in 88% of cases, ranging from well-circumscribed firm nodules to poorly delineated foci of necrosis and hemorrhage associated with cystic spaces. Microscopically, the tumors were heterogenous; however, all cases demonstrated at least a focal vasoformative component lined by atypical endothelial cells. Solid sarcomatous, papillary, and epithelioid growth patterns were observed. The solid sarcomatous component resembled fibrosarcoma in two cases and malignant fibroushistiocytoma in one case. Hemorrhage, necrosis, hemosiderin, extramedullary hematopoiesis, and intracytoplasmic hyaline globules were frequently identified. A panel of immunohistochemical studies revealed that the majority of tumors were immunoreactive for at least two markers of vascular differentiation (CD34, FVIIIRAg, VEGFR3, and CD31) and at least one marker of histiocytic differentiation (CD68 and/or lysozyme). Metastases developed in 100% of patients during the course of their disease. Twenty-six patients died of disease despite aggressive therapy, whereas only two patients are alive at last follow-up, one with disease at 8 years and the other without disease at 10 years. In conclusion, primary splenic angiosarcoma is an extremely aggressive neoplasm that is almost universally fatal. The majority of splenic angiosarcomas coexpress histiocytic and endothelial markers by immunohistochemical analysis, which suggest that some tumors may originate from splenic lining cells.

Context.—CD10 was originally reported in non–T-cell lymphoblastic lymphomas/leukemias. It has since been identified, however, in a minority of cases of T-lympho-blastic lymphoma/leukemia and other hematopoietic and nonhematopoietic entities. The usual method for the detection of CD10 previously required fresh tissue. A new antibody for CD10 (56C6) in paraffin embedded tissue sections, however, has recently become available. Objective.—To study the expression of CD10 in paraffin sections of T-lymphoblastic lymphoma/leukemia using monoclonal antibody 56C6. Design.—Twenty-four cases of T-lymphoblastic lymphoma/leukemia in various anatomic sites were studied. Immunohistochemical analysis with CD10 and a panel of other hematolymphoid antibodies was performed in all 24 cases. Gene rearrangement studies for the T-cell receptor by the polymerase chain reaction were performed in 18 of 24 cases. Results.—All cases were positive with at least 2 T-cell markers. In 15 (63%) of 24 cases CD10 was positive. T-cell receptor gene rearrangement was detected in 10 of 18 cases. Conclusions.—Immunodetection of CD10 in T-lympho-blastic lymphoma/leukemia using monoclonal antibody 56C6 is common. This finding is useful in the evaluation of T-cell neoplasms.

We describe 2 cases of a unique type of extramedullary manifestation of multiple myeloma (systemic plasmacytoma) that presented as subcutaneous nodules and mediastinal mass, respectively. Both lesions had a similar morphologic appearance, with dilated vascular-like lumina that was separated by thin fibrovascular septa, filled with erythrocytes, and lined by mature and immature plasma cells and plasmacytoid cells. The plasma and plasmacytoid lining cells showed κ light chain restriction in both cases, consistent with a B-cell monoclonal process. The lining cells were also focally positive for epithelial membrane antigen but were negative for endothelial cell markers. Abundant delicate capillaries were seen in the septa that separated the vascular lumina, mimicking a vascular tumor. Furthermore, we believe that our cases are different from the previously described blood lakes in a plasmacytoma by the presence of well-formed fibrovascular septa that separated the vascular-like spaces. Neoangiogenesis propagated by myeloma cells may contribute to this unusual morphologic manifestation of extramedullary manifestation of multiple myeloma.

Inhibitors of apoptosis may regulate tissue differentiation and promote cell survival in neoplasia. A new apoptosis inhibitor of the bcl-2 gene family, bcl-X(L), was recently found in some types human neoplasia but not in normal tissue. We investigated bcl-X(L) expression in 419 cases of normal and neoplastic lymphoid lesions using immunohistochemistry with the monoclonal antibody bcl-X(L) (YTH-2H12). Ninety-four percent (141/150) of classic Hodgkin's disease (HD) were positive for bcl-X(L) with strong intensity in most Reed-Sternberg (RS) cells. Forty-eight percent (38/80) of nodular lymphocyte predominance (LPHD) were positive. In the non-Hodgkin's lymphomas (NHL), bcl-X(L) was expressed in a low percentage of cases (< 20%), with the exception of follicle center lymphoma, grade III/III (78%). All reactive hyperplastic lesions were negative for bcl-X(L). RS cells, which expressed bcl-X(L), were not labeled by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). We found RS cells expressing bcl-X(L) were absent of DNA fragmentation (apoptosis). Our data provide evidence that bcl-X(L) is abnormally expressed in the RS cells of HD and some types of NHL raising speculation that inhibition of apoptosis may be important in the pathogenesis of lymphoma, specifically HD. In addition, the previously reported correlation between bcl-X(L) and Epstein-Barr virus expression in HD was not supported by this study.

Objective. Recent epidemiologic studies have identified a trend of increasing cancer incidence in younger patients. The purpose of this study was to determine whether this might be reflected by different molecular mechanisms for tumor development. Study Design. Dysplastic and malignant oral lesions from age-distinct patient populations were immunohistochemically analyzed for expression of p53 and cyclin D1. Chi-square analysis was used to determine statistical significance. Results. Eighty-two percent of “older” and 75% of “younger” carcinomas stained positively with p53; 63% of carcinomas in the older population and 55% of carcinomas in the younger population showed cyclin D1 positivity. Dysplasias showed similar cyclin D1 staining in both groups. Interestingly, 100% of “younger” dysplasias stained positively for p53, whereas 35.3% of “older” dysplastic lesions showed immunoreactivity. Staining of carcinomas was not statistically significant, whereas p53 staining of dysplasias proved highly significant (P < .025). Conclusions. p53 immunoreactivity is detectable at an earlier stage of carcinogenesis in younger patients than in the traditional risk population for oral cancer. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88:326-32)

The metastasis suppressor gene KAI1 was identified by its ability to inhibit the formation of pulmonary metastases in experimental models for prostatic carcinoma. Down-regulation of this gene may be correlated with the invasive phenotype in melanomas and colon and bladder carcinomas and with the metastatic phenotype in carcinomas of the lung, breast, prostate, and pancreas. The goal of our study was to establish an immunohistochemical method to detect KAI1 expression in archival tissues. Using cell lines with known KAI1 levels and paraffin-embedded KAI1 positive tissues as controls, we observed strong membrane staining in lymphoid follicular centers and squamous epithelia. We then demonstrated the utility of our assay by studying KAI1 expression in 34 lymphoid and 57 squamous lesions. All eight reactive lymph nodes were KAI1 positive. In contrast, three of 13 follicular small cleaved and five of 13 diffuse large cell lymphomas were KAI1 negative. Seventy-nine percent (37 of 47) of invasive squamous cell carcinomas from the lung (n = 15), head and neck (n = 18), and cervix (n = 14) showed extensive KAI1 down-regulation. Loss of KAI1 expression was also found in a subset of 10 high-grade cervical dysplasias. Our data show that (i) immunohistochemistry is a suitable technique for evaluating KAI1 expression in archival tissues; (ii) KAI1 was not expressed in a subset of both low-grade and high-grade lymphomas; and (iii) there was extensive down-regulation of KAI1 in squamous cell carcinomas, suggestive of an important role of the gene in the suppression of invasion in these malignancies.

Background : Clonal rearrangement of genes encoding the immunoglobulins (Ig) and T-cell antigen receptors (TCR) are considered to be useful markers for the diagnosis of lymphoma and for determining the clonal origins of B- and T-cell populations in lymphoid neoplasms. Methods and Results : Polymerase chain reaction-based clonality assays for TCR γ , TCRβ, and immunoglobulin (Ig) heavy chain (IgH) gene rearrangements were evaluated for diagnostic sensitivity and specificity in 569 formalin-fixed, paraffin-embedded (FFPE) tissues. Combined TCRβ and TCRγ assays enhanced the routine detection of TCR clonality to 90% of all peripheral T-cell lymphoma (PTCL) cases. IgH clonality was detected in 59% of 241 peripheral T-cell lymphoma (BCL) cases and 6% of 169 PTCL cases. Of 452 lymphomas, 5% could not be classified phenotypically as B or T lineage after immunohistochemical and clonality studies. Of all BCL cases analyzed, 24% had detectable TCRβ and/or TCR γ clonality. Of these BCL with biclonal results, 47% were extranodal lymphomas from skin and various tissues. Conclusions : Clonality assays were useful for distinguishing reactive or benign lymph nodes from neoplastic lymphoid infiltrates in most cases. The inclusion of TCRβ and TCR γ assays in the assessment of lymphomas results in a significant increase in the sensitivity of clonality detection, but is of limited utility in assessing the T- or B-cell phenotype of the tumor.

Small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL) are small B-cell lymphomas that share many morphological and immunophenotypic features, both expressing the T-cell antigen CD5. Because of this, there is speculation that these two lymphomas may have a common origin, both arising from the mantle zone of the lymph node. CD44 (HCAM), a glycoprotein "homing receptor," has been reported as a marker of small B-cell lymphomas for determining behavior as well as the nodal cell of origin. Intensity of CD44 expression also has been correlated with dissemination of lymphoma. We studied 50 cases with classic features of SLL (30 cases) or MCL (20 cases). Immunophenotypic analysis was performed on paraffin sections. All cases of MCL and SLL were CD20 positive; CD5 was expressed in 19 of 25 (76%) SLL and 11 of 15 (73%) MCL. Cyclin D1 was expressed in 11 of 17 (76%) MCL and no cases of SLL. CD43 coexpression was seen in 27 of 29 (93%) SLL and 17 of 19 (89%) MCL. CD23 was positive in 25 of 28 (89%) SLL and 2 of 20 (10%) MCL. Bcl-2 was positive in 18 of 22 (82%) SLL and 15 of 16 (94%) MCL. CD44 was positive with moderate to strong intensity in 11 of 30 SLL and 15 of 20 MCL. Peripheral blood involvement did not correlate with CD44 immunoreactivity. MCL tended to have intense CD44 immunoreactivity, whereas SLL tended to show weaker CD44 intensity. This trend in the intensity of CD44 in MCL suggests that CD44 may be helpful in distinguishing SLL from MCL and possibly elucidating the origin of these CD5-positive B-cell neoplasms.

We present three cases of blastic mantle cell lymphoma with an unusual initial manifestation in Waldeyer's ring with methods for differentiating it from other blastic neoplasms of the head and neck. All cases presented with a feeling of fullness inthe area of the mass. Morphologically, the tumours were blastic with a high mitotic rate (three to nine per high power field). All were B-cell phenotype with coexpression of CD43. In all cases cyclin Dl and bcl-2 were positive and CD23 negative. Blastic mantle cell lymphoma occurring in Waldeyer's tonsillar ring may be mistaken for other high grade haematopoietic neoplasms. Immunohistochemistry and awareness of this type of lymphoma arehelpful in differentiating it from other neoplasms.

The products of the MTSI/CDKN2 and retinoblastoma (RB) tumor suppressor genes, p16 and pRB, act as agonists in controlling the late G 1 cell cycle checkpoint. Inactivation of either gene occurs in a wide range of human malignant neoplasms. Data on the expression of both genes in the same set of malignant lymphoid neoplasms are scarce. We studied the p16/pRB pathway in low-grade and high-grade non-Hodgkin's lymphomas, using immunohistochemical techniques. Paraffin sections of 9 reactive lymph nodes and 43 low-grade and 60 high-grade malignant lymphomas were reacted with antibodies against pRB and p16. All benign lymph nodes showed a normal pattern of RB and MTS1/CDKN2 expression. Of 101 evaluable lymphomas, only a single high-grade tumor displayed loss of RB reactivity. Loss of p16 was identified in 14 of 55 evaluable high-grade lymphomas but not in any of the low-grade lesions. All but 3 of the RB- and p16-negative cases were diffuse large cell lymphomas, for an abnormality rate of 55% in this category. While loss of RB function was a rare event in human lymphomagenesis, p16 was absent in some 25% of high-grade non-Hodgkin's lymphomas; diffuse large cell lymphomas were the primary target of tumor suppressor gene inactivation.

The bcl -2 gene is implicated in oncogenesis by its ability to prolong cell survival through the inhibition of apoptosis, without increasing cell proliferation. An association between immunohistochemical staining for bcl-2 protein and the histological type and prognosis of non-small cell carcinoma was hypothesized by Pezzella et al. ( N Engl J Med 329:690–694, 1993). In a case series, we stained formalin-fixed, paraffin-embedded tumor tissue from 106 surgical non-small cell lung cancer patients with an antibody to bcl-2 protein (DAKO clone 124, Carpinteria, CA). The resulting bcl-2 staining data were evaluated for associations with demographic, histological, immunohistochemical, and genetic features, including p53 mutations. Bcl-2 staining was observed in tumors from 29 of 106 (27%) of subjects, but was significantly less frequent in subjects' adenocarcinoma histology (8 of 55, 14.6%) ( P = .007). This finding persisted after adjustment for age, gender, stage, grade, smoking history, and disease-free survival. In univariate analyses, no association was seen with age, weight, body mass index, gender, or pack-years smoking; tumor grade, stage, or patient performance status; p53 or c-erbB2 immunohistochemical staining, or p53 mutations. These data agree with earlier reports that bcl-2 staining is less common in adenocarcinomas; however, our data do not support the hypothesis that bcl-2 staining confers a better prognosis overall, in squamous cell carcinoma, or in an older patient population.

We describe the clinical, histologic, immunophenotypic, and genotypic features of five cases of histologically discordant lymphomas with B-cell and T-cell components. Three patients presented with B-cell lymphoma; T-cell lymphoma subsequently developed. One patient presented with T-cell lymphoma; B-cell lymphoma subsequently developed. One patient presented with synchronous B-cell and T-cell lymphomas. There were three men and two women. The median age at the initial diagnosis of lymphoma was 66 years. The mean interval between the development of the two lymphomas was 83 months. All patients died of disease. The mean survival was 96 months after the initial diagnosis of lymphoma and 14 months after the diagnosis of the histologically discordant lymphoma. Epstein-Barr virus was found in two cases--the B-cell lymphoma in the patient who presented with synchronous lymphomas, and the subsequent T-cell lymphoma in one of the patients who presented with B-cell lymphoma. Based on the results of immunophenotypic and genotypic analyses, these cases likely represent the occurrence of two distinct lymphoid neoplasms rather than histologic progression of the same neoplastic clone. Furthermore, a subset of these cases are Epstein-Barr virus-associated.

BACKGROUND. The term pseudolymphoma has been used to describe lymphoid lesions that show: 1) borderline features between hyperplasia and neoplasia or 2) benign tumor-like enlargement of lymphoid tissue. The term pseudolymphoma has been applied to lesions in many anatomic locations, with the stomach being one of the more common sites. In spite of the frequent use of this term, neither the histologic criteria nor the clinical significance of this lesion have ever been clearly defined. Since the description of mucosa-associated lymphoid tissue (MALT) and its corresponding MALT-type lymphomas, the value of the term gastric pseudolymphoma has come into question. METHODS. The authors reviewed all cases diagnosed as gastric pseudolymphomas at the Armed Forces Institute of Pathology from 1970 to 1985. This period predated the description of low grade B-cell lymphoma of MALT-type. The cases were reclassified in light of current criteria and correlated with immunohistochemical findings and follow-up information. No patients were treated with chemotherapy or radiation therapy. RESULTS. Seventy-seven of 97 cases formerly diagnosed as pseudolymphoma were determined to be malignant lymphomas; the majority (51 cases) were extranodal marginal zone B-cell lymphomas (MALT-type). The remaining cases included reactive lymphoid hyperplasia associated with chronic follicular gastritis (15 cases) and atypical lymphoid infiltrates (5 cases). CONCLUSIONS. Most cases previously considered to be gastric pseudolymphomas are, by current criteria, malignant lymphomas. A small proportion are benign reactive lymphoid hyperplasias. Those cases of borderline or inconclusive nature are best diagnosed as atypical lymphoid infiltrates. The term gastric pseudolymphoma should be abandoned.

The clinicopathological and immunohistochemical findings in 25 cases of inflammatory pseudotumor of lymph nodes (IPT) are presented. The patients were 13 women and 12 men between 8 and 81 years of age. Clinically, symptoms of prior infection, fatigue, abdominal pain, weight loss, fever of unknown origin, pelvic inflammatory disease, or nausea and night sweats were obtained in 15 patients, whereas six patients presented with asymptomatic lymphadenopathy. In four additional patients, no clinical information was obtained. The involved nodes included cervical, supraclavicular, inguinal, mesenteric, and mediastinal lymph nodes. In two cases, there was synchronous involvement of separate lymph node groups (inguinal and cervical in one case and cervical and mediastinal in another case), whereas in a third patient there was synchronous involvement of the spleen and a paraaortic lymph node. Histologically, the lesions were characterized by a fibrosing/inflammatory process that showed marked heterogeneity and striking variation from case to case. Based on their histological features, the lesions could be classified into three different groups: Stage I was characterized by the appearance of single or multiple small foci containing a spindle cell proliferation admixed with a prominent inflammatory background, with complete preservation of the remainder of the nodal architecture; stage II was characterized by more diffuse involvement of the lymph node with a marked inflammatory response admixed with a prominent myofibroblastic proliferation leading to subtotal effacement of the nodal architecture, often with extension of the process beyond the capsule into perinodal fat; and stage III was characterized by almost complete replacement of the lymph node by diffuse sclerosis with scant residual inflammatory elements and total loss of the normal nodal architecture. Immunohistochemical studies in 20 cases showed a striking number of vimentin- and actin-positive myofibroblastic cells with moderate increase in CD20/CD45+ small lymphocytes and polyclonal plasma cells in the stage I lesions, the emergence of numerous CD68+ histiocytes admixed with lymphocytes, plasma cells, and abundant fibromyofibroblastic cells in the stage II lesions, and only few remaining scattered CD68+ histiocytes and fibroblasts in the stage III lesions. Our findings suggest that inflammatory pseudotumor of lymph node represents an evolving, dynamic process that may adopt different morphological appearances depending on its stage of evolution. Recognition of the various stages of this process may be of importance for differential diagnosis with other fibrosing/inflammatory conditions of lymph nodes.

Hodgkin's disease typically presents as peripheral lymphadenopathy, with or without constitutional symptoms. Although skeletal involvement may occur during the course of the disease, bony or adjacent soft tissue masses are extremely unusual, especially as a primary presentation. With this in mind, the authors searched the files of the Armed Forces Institute of Pathology Tumor Registry for all cases that had been diagnosed as Hodgkin's disease in open bone biopsies between the years 1970 to 1992. From a total of 29, we selected 18 that represented all cases with documented clinical records and paraffin-embedded tissue blocks for immunophenotypic analysis. The majority of these predated the use of immunohistochemical markers, and the diagnosis had been made primarily on examination of hematoxylin and eosin stained slides alone. The authors reviewed the hematoxylin and eosin stained slides and performed immunophenotypic analysis for CD45RB, CD20, CD3, CD45RO, kappa and lambda light chains, CD15, CD30, vimentin, cytokeratin, epithelial membrane antigen, factor VIII, and CD57. Seven of 18 cases showed unequivocal morphologic and immunophenotypic findings consistent with Hodgkin's disease of the nonlymphocyte predominance type. There was a male:female ratio of 6:1 and an age range of 21-39 years (median, 30 years; mean 30.4 years). Of these, only two of seven patients had a prior documented history of Hodgkin's disease (stages IB and IIB). After careful morphologic examination and immunophenotypic analysis, the authors found that the remaining 11 cases represented Hodgkin's-like lesions, including atypical lymphoid infiltrates (three cases), large B-cell lymphoma (five cases), anaplastic large-cell lymphoma (one case), large T-cell lymphoma (one case), and metastatic carcinoma with a prominent desmoplastic response (one case). These cases were excluded from this study. This report describes the clinicopathologic features of Hodgkin's disease presenting as bony and adjacent soft tissue masses and confirms the potential difficulty of making this diagnosis, especially in the absence of immunohistochemical markers. Int J Surg Pathol 3(3):147-154, 1996

Twenty-eight lipid cell (steroid cell) tumors of the ovary were studied by immunohistochemistry using an avidin-biotin complex detection system; 75% of tumors were vimentin positive, 46% were positive for cytokeratin (CAM5.2 antibody), 37% were positive with the cytokeratin cocktail AE1/AE3 and CK1, and 29% were positive for smooth muscle alpha-actin. Three tumors were positive for CD68 (KP-1), a histiocyte marker, and each of the following markers was positive in two cases: desmin, epithelial membrane antigen, neuron-specific enolase, and S-100 protein. All tumors tested were negative for chromogranin A, CD15 (Leu-M1), myoglobin, neurofilament protein, alpha-fetoprotein, carcinoembryonic antigen, and melanoma-associated antigen (HMB-45 antibody). Immunoreactivity for cytokeratins was usually focal, paranuclear, and globoid, while reactivity for actin and vimentin was diffuse and cytoplasmic. Based on these findings, melanomas and some carcinomas should be distinguishable from lipid cell tumors. However, the immunohistochemical profiles of smooth-muscle tumors, other gonadal stromal tumors (granulosa cell tumors, thecomas), and hepatocellular, renal cell, and adrenocortical carcinomas overlap with that of lipid cell tumors, and therefore these tumors may not be distinguishable from lipid cell tumors using this technique. In 10 cases (36%), negative controls exhibited weak to moderate nonspecific cytoplasmic staining. Evidence obtained using a biotin blocking kit, and a monoclonal antibody against biotin, suggests endogenous biotin-like reactivity as the source of the nonspecific staining.

The association of Dilantin (hydantoin) therapy and lymphadenopathy in the form of "pseudolymphoma" or malignant lymphoma has been reported primarily in the clinical literature in single case reports or small series, most of which contain very few pathologic details. We studied a series of 25 lymph node lesions collected at the Armed Forces Institute of Pathology from 1965 to 1991 that were suspected to be related to intake of the antiseizure medication Dilantin. Each case had been coded by the Environmental and Toxicology Department according to the so-called "operational degrees of certainty," which gives the possibility that a pathologic change is the result of a drug. Of the 25 cases, six were coded as probable, 17 as possible, and two as coincidental. The male:female ratio was 11:14, and patient ages ranged from 24 to 81 years (median, 53 years). Documented lymphadenopathy developed 1 week to 30 years (median, 5 years) after the start of Dilantin. The histologic features were reviewed in 25 of 25 cases, and the immunophenotypic data was available in 18 of 25. Fifteen of 25 cases showed a benign histology, which we primarily classified according to the presence or absence of immunoblastic hyperplasia. Seven cases were non-Hodgkin's lymphoma, and three were Hodgkin's disease. In two of five cases for which sequential biopsies were available for review, there was progression from paracortical hyperplasia to malignant lymphoma. Our report describes the clinicopathologic features of 25 cases of Dilantin-associated lymphadenopathy and confirms the heterogeneity and nonspecificity of these histologic patterns.

Sixty small cell tumors of bone and adjacent soft tissue were studied in an attempt to define the incidence of immunohistochemically detectable p53 protein and cor relate these findings with the results of proliferating cell nuclear antigen (PCNA) immunohistochemical staining and mitotic counts. All of the lesions had been for malin-fixed and paraffin-embedded; half were subjected to decalcification prior to processing. The study population included 12 Ewing's sarcomas of bone, 3 atypical Ewing's sarcomas of bone, 3 primitive neuroectodermal tumors of bone, 11 Askin tumors of the thoracopulmonary region, 11 small cell osteosarcomas of bone, 10 mesenchymal chondrosarcomas of bone, and 10 malignant lymphomas involving bone. The patients ranged in age at the time of presentation from 17 to 67 years. Overall, the incidence of p53 positivity was extremely low in these lesions, irre spective of tumor type. Positive nuclear staining with an antibody to p53 was found in none of the 12 Ewing's sarcomas, none of the 3 atypical Ewing's sarcomas, none of the 3 primitive neuroectodermal tumors of bone, 1 of the 11 Askin tumors of the thoracopulmonary region (1.5% of tumor cells positive), 1 of the 11 small cell osteosarcomas (2% of tumor cells positive), 1 of the 10 mesenchymal chondrosar comas of bone (7% of tumor cells positive), and 2 of the 10 malignant lymphomas involving bone (0.5% and 1% of tumor cells positive, respectively). The majority of tumors showed PCNA positivity within the tumor cells, although the incidence of PCNA positivity within the histologic types varied greatly; in general, the higher PCNA counts corresponded to higher mitotic counts within the individual lesions. The present study did not demonstrate any correlation between mutant p53 accu mulation detected by immunohistochemistry and tumor type, and so it is unlikely that p53 positivity will prove to be of great use in the differential diagnosis of these lesions. A correlation between p53 positivity and PCNA staining or mitotic activity was not apparent. Int J Surg Pathol 2(4):259-268, 1995

Background. Non-Hodgkin's lymphomas (NHLs) of the sinonasal tract are uncommon neoplasms that can be morphologically difficult to distinguish from destructive nonneoplastic processes or other malignant neoplasms in this site. Methods. From the files of the Otolaryngic Tumor Registry - Armed Forces Institute of Pathology from 1965 to 1992, 120 cases of NHL involving the sinonasal tract were selected for which clinical records and paraffin-embedded tissue blocks were available. The histologic features and immunophenotypic findings of each patient were examined, and follow-up data were obtained for 66 (55%). Results. The ratio of males to females was 1.35 :1, and the ages ranged from 3 to 94 years (median, 59 years). Sixty percent of the cases of NHL occurred in the patients' sixth to eighth decades of life. Clinical presentations varied according to histologic type. The low grade lymphomas presented with a nasal cavity or paranasal sinus mass associated with obstructive symptoms. The high grade lymphomas were more likely to present with aggressive signs and symptoms including nonhealing ulcer, cranial nerve manifestations, facial swelling, epistaxis, or pain. Of note, the high grade B-cell lymphomas tended to present with soft tissue or osseous destruction, particularly of the orbit with associated proptosis, whereas the T-cell lymphomas were associated with nasal septal perforation and/or destruction. Sites of disease included the nasal cavity, one or more paranasal sinuses, or multiple regions within the sinonasal tract. Of patients who received adequate follow-up, nodal and extranodal dissemination were identified in a limited number (n = 11). Nodal dissemination occurred in cervical and axillary lymph nodes. Extranodal sites of involvement included the larynx, skin, liver, uvula, kidney, breast, lacrimal gland, testis, and prostate gland. There was a wide spectrum of morphologic types of lymphoma, classified according to the Working Formulation. Immunophenotypic analysis on paraffin embedded tissue sections of all patients demonstrated a B-cell to T-cell ratio of 1.18 :1. Treatment primarily included radiotherapy and chemotherapy. Follow-up information was available for 66 (55%) patients ranging from 1 to 16 years (median, 3 years). Of these 66 patients, 24 (36.4%) died of disease, 17 (25.7%) are alive without disease, 13 (19.7%) are alive with disease, and 12 (18.2%) are dead of unrelated or unknown causes. Conclusions. Non-Hodgkin's lymphomas of the sinonasal tract are heterogeneous diseases that can be clinically aggressive. The frequency of these lymphomas in the United States cannot be estimated accurately because all of our cases were of histologic slides submitted for consultations. There appears, however, to be a slight B-cell predominance in this population that previously has been observed, unlike in South America and Asia where the majority of cases have a T-cell phenotype. Cancer

An altered anti–Epstein-Barr virus (EBV) serologic profile preceding diagnosis is associated with an increased risk of Hodgkin lymphoma. It is unknown whether this atypical pattern predicts Hodgkin lymphoma risk further subdivided by determination of EBV in tumor cells. A nested case-control study of 128 incident Hodgkin lymphoma cases and 368 matched controls from active-duty military personnel with archived serum in the US Department of Defense Serum Repository was conducted to determine whether a panel of anti-EBV antibody titers differed in EBV+ and EBV− Hodgkin lymphoma. Among 40 EBV+ Hodgkin lymphoma cases and matched controls, statistically significant increased risks were associated with elevated anti-EBV VCA IgG antibody titers (relative risk = 3.1; 95% confidence interval [CI], 1.1-8.7), and an anti–EBNA-1/anti–EBNA-2 antibody ratio ≤ 1.0 versus > 1.0 (relative risk = 4.7; 95% CI, 1.6-13.8). In contrast, no significant associations were found among 88 EBV− Hodgkin lymphoma cases relative to their matched controls. In case-case analysis, EBV+ disease was significantly associated with a low anti–EBNA-1/anti–EBNA-2 antibody ratio. This distinc-tive serologic response to EBV latent antigens, indicative of immune dysfunction in other clinical settings, is associated with an increased risk of developing EBV+ but not EBV− Hodgkin lymphoma.

Adrenal epithelioid angiosarcomas (AEA) are rare neoplasms. We report the clinicopathologic features of nine cases of AEA. AEA occurred most frequently in the sixth and seventh decades of life (age range, 45-85 years; median, 60); five cases occurred in men and four in women. Presenting symptoms included abdominal mass with or without pain, weight loss, fever, and weakness. Two cases were asymptomatic; one was discovered during evaluation for other disease(s) and the other at autopsy. All neoplasms were nonfunctioning. Radiographic evaluation demonstrated suprarenal or retroperitoneal neoplasms ranging in size from 6 to 10 cm in greatest dimension. Histologically, the neoplasms were invasive, predominantly arranged in solid sheets or nests, and composed of epithelioid cells. Endothelial cell differentiation was suggested by the transition areas between dilated anastomotic vascular spaces and the sheet-like growth, the cytomorphologic similarity between the endothelial cells lining the discernible vascular spaces and those seen in the solid foci, and the presence of intracytoplasmic vacuolization occasionally containing red blood cells. Endothelial derivation was confirmed by immunohistochemistry including Factor VIII-related antigen (FVIII), CD-34 (hematopoetic progenitor cell antigen), and/or Ulex europaeus agglutinin-1 lectin immunoreactivity (UEA-1) and by ultrastructural findings, including rod-shaped microtubulated bodies and intracytoplasmic lumen formation. In addition, cytokeratin reactivity was seen in seven cases, and B72.3 (tumor-associated glycoprotein-72) reactivity was seen in six. Surgical resection was the treatment of choice, occasionally supplemented by chemotherapy. Three patients are presently alive, free of disease, at 13, 11, and 6 years following diagnosis. Three died with metastatic AEA of the lung, and three died of unrelated causes.

The coexpression of CD5 and CD10 has previously been reported in cases of intermediate- and high-grade lymphomas and in precursor B cells in normal or regenerating bone marrow. We report 3 cases of low-grade B-cell lymphoma that were found to coexpress CD5 and CD10 at the time of initial diagnosis. The first case was classified as small lymphocytic lymphoma; the second as follicle center lymphoma, follicular grade 1; and the third as small B-cell lymphoma otherwise not specified. Currently, the clinical implication of the coexpression of CD5 and CD10 is not known. We describe this finding to highlight the difficulty that may be encountered in classifying lymphomas in cases where this coexpression is present.

Lymph nodes from patients with acute infectious mononucleosis (AIM) typically show marked paracortical expansion and a prominent immunoblastic proliferation that can occur in nodules and sheets, as well as within sinuses. The marked immunoblastic proliferation, coupled with Reed-Sternberg-like cells and a polymorphous inflammatory cell background, may simulate either non-Hodgkin's lymphoma or Hodgkin's disease. A recently described entity, Ki-1-positive lymphoma, or large cell anaplastic lymphoma, shares some clinicopathologic and phenotypic features with AIM and must be considered in the differential diagnosis. The present case describes a 20-year-old male who had signs and symptoms consistent with AIM, which he was later proven serologically to have, but whose cervical lymph node showed features suspicious for large cell anaplastic lymphoma. In addition, the Ki-1 (CD30) antigen was expressed by some of the atypical immunoblasts, further raising this possibility.

Lymphoplasmacytic lymphoma (LPL) is a small B-cell neoplasm with plasmacytic differentiation that does not fulfill the criteria for any other type of B-cell leukemia or lymphoma. In many cases, LPL is associated with Waldenstrom macroglobulinemia (WM), although WM may also be associated with other types of lymphoma. Recent studies have demonstrated that del(6q) is the most common structural abnormality in patients with bone marrow-based LPL. It is unknown whether del(6q) might also be associated with nodal LPL. We, therefore, examined 10 well-characterized LPL involving lymph nodes or other extramedullary tissues for del(6q) using paraffin section interphase fluorescence in situ hybridization (FISH). Dual-color FISH was performed using a chromosome 6 centromere probe (CEP6) and a probe for 6q21 (RP11-91C23). The latter probe has previously been reported as deleted in up to 63% of cases of bone marrow-based LPL. In contrast, no nuclei containing a del(6q) pattern were identified in any case of extramedullary LPL examined in this study, and 89-98.5% of nuclei contained a normal signal pattern. These results indicate that del(6q) is at least uncommon in nodal LPL, and cannot be employed as a diagnostic marker to identify this type of lymphoma. Furthermore, these findings suggest that nodal LPL and bone marrow-based cases of LPL may be associated with different cytogenetic findings.

Histiocytic sarcoma (HS) is a rare but controversial hematopoietic neoplasm. In the past, malignancies have been misclassified as histiocytic tumors due to overlapping histologic features and inadequate phenotypic data. CD163, a recently characterized hemoglobin scavenger receptor, appears to be a 'specific' marker of histiocytic lineage and a promising diagnostic tool for evaluating histiocytic neoplasms. Five cases of HS were studied to further elucidate the clinicopathologic features of these rare tumors and to demonstrate the diagnostic utility of CD163. Criteria for diagnosis included histologic and immunohistochemical evidence of histiocytic differentiation, CD45 positivity, and exclusion of lymphoid, epithelial, melanocytic and dendritic cell phenotype. Sites of disease included the colon (two cases), palate, inguinal lymph node, and testis. The clinical course was aggressive in 4/5 patients (survival=2-15 months). One patient with localized disease of the palate, survived 17 years after diagnosis. All patients with poor survival had tumorsor =3.5 cm. Histologically, all cases showed diffuse architecture with large, discohesive polygonal cells. Spindling of cells was focally noted. Hemophagocytosis was identified in 3/5 cases. A prominent inflammatory background was present in 4/5 tumors. All cases were immunoreactive for CD45, CD163, CD68, and lysozyme. S-100 was focally positive in 4/5 cases. Antibodies for melanocytic, epithelial, lymphoid, and dendritic cell markers were negative. Molecular studies showed monoclonal IgH gene rearrangements in three cases. Our findings suggest that HS is an uncommon neoplasm frequently extranodal in presentation and aggressive in behavior, with rare exceptions. Stage of disease and possibly tumor size are significant prognostic indicators. Molecular studies remain controversial in the diagnosis. The morphologic and phenotypic features are relatively uniform; however, the diagnosis requires exclusion of more common neoplasms by extensive immunophenotypic studies. CD163 appears to be a specific histiocytic marker and is important in establishing the diagnosis of HS.

Human immunodeficiency virus-type 1 (HIV-1) replicates actively in infected individuals, yet cells with intracellular depots of viral protein are observed only infrequently. Many cells expressing the HIV-1 Gag protein were detected at the surface of the nasopharyngeal tonsil or adenoid. This infected mucosal surface contained T cells and dendritic cells, two cell types that together support HIV-1 replication in culture. The infected cells were multinucleated syncytia and expressed the S100 and p55 dendritic cell markers. Eleven of the 13 specimens analyzed were from donors who did not have symptoms of acquired immunodeficiency syndrome (AIDS). The interaction of dendritic cells and T cells in mucosa may support HIV-1 replication, even in subclinical stages of infection.

Formalin fixation and paraffin embedding are conventional tissue preservation and processing methods used for histologic diagnosis in over 90% of cases. However, formalin fixation has three disadvantages: (1) slow fixation (16-24 h) hinders intraoperative decision making, (2) slow quenching of enzymatic activity causes RNA degradation, and (3) extensive molecule modification affects protein antigenicity. Applying high-frequency, high-intensity ultrasound to the formalin fixative cuts fixation time to 5-15 min. Fixation of various tissues such as lymph node, brain, breast, and prostate suggests that, compared to the conventional method, implementation of ultrasound retains superior and more uniform tissue morphology preservation. Less protein antigenicity is altered so that rapid immunohistochemical reactions occur with higher sensitivity and intensity, reducing the need for antigen retrieval pretreatment. Better RNA preservation results in stronger signals in in situ hybridization and longer RNA fragments extracted from fixed tissues, probably due to rapid inhibition of endogenous RNase activity. Molecules extracted from ultrasound-fixed tissues are of greater integrity and quantity compared to conventionally fixed tissues, and thus better support downstream molecular analyses. Overall, ultrasound-facilitated tissue preservation can provide rapid and improved morphological and molecular preservation to better accommodate both traditional and molecular diagnoses.

We retrospectively analyzed 45 cases of HIV-associated Hodgkin lymphoma (HIV-HL). HIV-HL generally is a disease of young white men (mean age, 40.1 years) who acquired HIV infection by homosexual or bisexual behavior (68%), intravenous drug use (24%), and/or blood transfusion (8%). The mean interval between the diagnosis of HIV and HIV-HL was 5.2 years. Morphologic classification of nodal biopsy specimens (2001 World Health Organization criteria) included 15 mixed cellularity Hodgkin lymphomas (MCHLs), 14 nodular sclerosis Hodgkin lymphomas (NSHLs), 9 lymphocyte depleted Hodgkin lymphomas (LDHLs), and 7 classic Hodgkin lymphomas, type not further categorized. The Hodgkin-Reed-Sternberg (HRS) cells expressed positive immunoreactivity with fascin (30/30 [100%]), CD30 (35/37 [95%]), CD15 (32/36 [89%]), bcl-X(L) (25/31 [81%]), bcl-2 (15/29 [52%]), CD20 (4/34 [12%]), bcl-6 (3/28 [11%]), and Epstein-Barr virus latent membrane protein-1 (32/33 [97%]) and were nonreactive for CD138/syndecan-1. CD4 and CD8 immunostaining showed an inverted CD4/CD8 ratio (1/20) in all cases. At diagnosis, most patients (n = 27) had high-stage disease (IV(E)) associated with an aggressive course (16% 5-year survival). LDHL behaved more aggressively than MCHL and NSHL (15% vs 40%, 5-year survival, respectively), as did disease with a sarcomatoid pattern (11% 5-year survival). Chemotherapy and radiotherapy proved efficacious in a minority of these patients.

A t(9;14)(p13;q32) involving the PAX5 and IGH genes has been described in association with lymphoplasmacytic lymphoma. Although often described as common, the incidence of this translocation in nodal lymphoplasmacytic lymphoma has never been investigated. Recent studies of patients with Waldenström's macroglobulinemia (often corresponding to marrow-based lymphoplasmacytic lymphoma) have failed to identify the t(9;14). These studies have suggested that either nodal and marrow-based lymphoplasmacytic lymphomas have distinct pathogenetic mechanisms or that the t(9;14) is less frequent in lymphoplasmacytic lymphoma than was believed previously. We therefore analyzed a series of nodal or other extramedullary lymphoplasmacytic lymphomas for the presence of the t(9;14) with paraffin section interphase fluorescence in situ hybridization. We developed a BAC contig probe spanning all previously described PAX5 breakpoints and validated this assay with the KIS-1 cell line that expresses a t(9;14). Analysis with the PAX5 probe showed a lack of PAX5 rearrangements in all cases that were analyzed successfully. Similarly, analysis by an IGH fluorescence in situ hybridization probe showed no evidence of translocations involving the IGH locus. These findings indicate that the t(9;14) is at least uncommon in lymphoplasmacytic lymphoma and should no longer be considered a characteristic finding in this type of lymphoma as defined by World Health Organization criteria.

To evaluate the clinical, pathologic, and computed tomographic (CT) features of littoral cell angioma of the spleen in eight patients.Two abdominal radiologists retrospectively reviewed the contrast material-enhanced CT images obtained in six, the contrast-enhanced and nonenhanced CT images obtained in two, and the photographs of gross pathologic specimens resected from seven patients. They also retrospectively reviewed clinical data (ie, demographic data, presenting signs and symptoms, physical findings, and medical histories). Histopathologic specimens from the eight patients were reviewed by a hematopathologist. The CT images were reviewed for the presence of splenomegaly. The number, size, and enhancement characteristics of the splenic masses at CT were compared with the histopathologic and gross pathologic specimen findings.All patients had laboratory evidence of hypersplenism. Seven patients (88%) had splenomegaly and innumerable splenic masses ranging from 0.2 to 6.0 cm in diameter at CT. The single patient with a normal spleen size had four splenic masses. The splenic masses were hypoattenuating relative to the normal spleen at CT in all patients and correlated with blood-filled nodules at gross pathologic examination and with blood-filled vascular channels of littoral cell angioma at histopathologic examination. The early and late portal venous phase CT images that were available in one case demonstrated progressive homogeneous contrast enhancement of the masses such that they were indistinguishable from the normal splenic parenchyma.Littoral cell angioma is a primary splenic neoplasm that most commonly manifests at CT as multiple hypoattenuating masses in an enlarged spleen. Histopathologically, these masses represent blood-filled vascular channels.

Rb protein in its hypophosphorylated form acts as a cell cycle regulator for G1 arrest. Both cyclin D1 overexpression and P16(INK4) loss of protein produce persistent hyperphosphorylation of Rb with resultant evasion of cell cycle arrest. To better establish the mechanisms of loss of Rb function in neuroendocrine lung tumors, we performed an immunohistochemical analysis of the P16(INK4)/cyclin D1/Rb pathway in the spectrum of neuroendocrine tumors, including 34 typical carcinoids (TCs), 25 atypical carcinoids (ACs), 42 large cell neuroendocrine carcinomas (LCNECs), and 79 small cell lung carcinomas (SCLCs). Absence of Rb expression was not observed in TCs but was seen in 21% of ACs, 68% of LCNECs, and 87% of SCLCs. P16 was expressed in 91% of TCs, 77% of ACs, 78% of LCNECs, and 93% of SCLCs. Cyclin D1 was overexpressed in 6% of TCs, 20% of ACs, 9.5% of LCNECs, and 1.3% of SCLCs. There was an inverse relationship between Rb and P16 in high-grade tumors (P < 0.001) and a direct relationship between cyclin D1 and Rb (P < 0.001) in all tumors, demonstrating that P16 and cyclin D1 act exclusively on the Rb pathway for cell cycle regulation. Overall, the Rb pathway (Rb/P16(INK4)/cyclin D1) was altered more frequently in ACs than in TCs (P = 0.001) and more frequently in LCNECs than in ACs (P = 0.001). Although Rb-negative tumors had shorter survival in the overall group (P < 0.001) as a result of lack of Rb in most SCLCs, cyclin D1 overexpression and P16 loss did not influence survival in any individual category. We conclude that Rb pathway of G1 arrest is consistently compromised in high-grade neuroendocrine lung tumors (92%), primarily through loss of Rb protein, and is intact in low-grade TCs. In ACs an intermediate level of alterations (59%) is seen, consistent with their less-aggressive behavior compared with high-grade tumors. The specific profile of the Rb pathway parameters might provide specific therapeutic targets in neuroendocrine lung tumors.

OBJECTIVE. The purpose of this report is to describe the clinical, CT, and pathologic features of non-Hodgkin's lymphoma of the vermiform appendix.CONCLUSION. Non-Hodgkin's lymphoma of the appendix typically manifests with acute symptoms in patients who have no prior history of lymphoma. Most patients with the disease present clinically with signs and symptoms suggestive of acute appendicitis. On CT, lymphomatous infiltration of the appendix produces markedly diffuse mural soft-tissue thickening (range of diameters, 2.5-4.0 cm; mean diameter, 3.2 cm). The vermiform morphology of the appendix is usually maintained, and aneurysmal dilatation of the lumen is sometimes seen. Stranding of the periappendiceal fat seen on CT may represent superimposed inflammation or even direct lymphomatous extension. Coexisting abdominal lymphadenopathy is not seen in all patients. Although appendiceal lymphoma is rare, the characteristic CT appearance could lead to a preoperative diagnosis.

Sickle cell anemia (SCA) is a disease caused by production of abnormal hemoglobin, which binds with other abnormal hemoglobin molecules within the red blood cell to cause rigid deformation of the cell. This deformation impairs the ability of the cell to pass through small vascular channels; sludging and congestion of vascular beds may result, followed by tissue ischemia and infarction. Infarction is common throughout the body in the patient with SCA, and it is responsible for the earliest clinical manifestation, the acute pain crisis, which is thought to result from marrow infarction. Over time, such insults result in medullary bone infarcts and epiphyseal osteonecrosis. In the brain, white matter and gray matter infarcts are seen, causing cognitive impairment and functional neurologic deficits. The lungs are also commonly affected, with infarcts, emboli (from marrow infarcts and fat necrosis), and a markedly increased propensity for pneumonia. The liver, spleen, and kidney may experience infarction as well. An unusual but life-threatening complication of SCA is sequestration syndrome, wherein a considerable amount of the intravascular volume is sequestered in an organ (usually the spleen), causing vascular collapse; its pathogenesis is unknown. Finally, because the red blood cells are abnormal, they are removed from the circulation, resulting in a hemolytic anemia. For the patient with SCA, however, the ischemic complications of the disease far outweigh the anemia in clinical importance.

Lymphoplasmacytic lymphoma/immunocytoma (LLI) was defined initially as a small B-cell lymphoma with plasmacytoid or plasmacytic features. Because other types of small B-cell lymphoma, particularly marginal zone B-cell lymphoma may exhibit plasmacytic differentiation, the revised European-American lymphoma classification and World Health Organization has defined LLI more narrowly to exclude other small B-cell lymphomas. The goal of this study was to reevaluate LLI as a clinicopathologic entity. Twenty cases were selected from 43 previously diagnosed as "small lymphocytic lymphoma, plasmacytoid" or "immunocytoma" from 1985 to 1998. Cases fulfilling the criteria for B-cell small lymphocytic lymphoma, follicular lymphoma, marginal zone B-cell lymphoma, or other types of B-cell lymphoma were excluded. The histopathology and immunoreactivity for CD20, CD79a, CD3, CD43, CD23, CD5, kappa, lambda, and immunoglobulins (Ig's) M, G, and A were reviewed, in addition to available clinical findings. There were 13 men and seven women, with a mean age of 69 years. Five patients had documented Waldenstrom's macroglobulinemia (WM). Three architectural patterns were observed. Pattern A (seven of 20) showed open sinuses, small follicles, and hemosiderosis; pattern B (four of 20) showed hyperplastic follicles; and pattern C (nine of 20) showed diffuse effacement. Epithelioid histiocytes were prominent in patterns B and C but absent in A. Cytologically, six of 20 were polymorphous with 10% to 40% transformed cells; 14 of 20 were lymphoplasmacytic. Five cases showed minor foci of monocytoid B cells. One case showed a composite histology of LLI and small lymphocytic lymphoma. Amyloid was present in two cases. All cases were CD20 and/or CD79a immunoreactive, with two of 20 positive for CD43. Twelve cases were kappa monoclonal and eight cases were lambda monoclonal. Twelve of 17 cases that could be evaluated were positive for IgM and five were positive for IgG. All cases were negative for CD5 and CD23 with the exception of the one case with a composite histology. Eleven of 20 patients with available follow-up died of disease (median, 48 months), and eight of 20 are alive with disease at a follow-up of 6 months to 2 years. LLI does appear to represent a distinct clinicopathologic entity even though it shows morphologic heterogeneity and overlapping features with marginal zone B-cell lymphoma and small lymphocytic lymphoma. Recognition of LLI is important because the overall prognosis may be worse than for other types of small B-cell lymphomas.

Three cases of primary cutaneous B-cell lymphoma with prominent signet ring-cell features are presented. The patients were three men between the ages of 37 years and 74 years (average, 55.5 years). Clinically, the three patients presented with multiple skin nodules. In one patient, the nodules had been present for approximately 5 weeks, although in the two other patients, the nodules were of unknown duration. The lesions were located in the upper extremities (forearm) and measured from 2 cm to 3 cm in diameter. No evidence of lymphadenopathy was observed in any of the patients. Surgical excision of the nodules was performed. Histologically, in two cases, the superficial and deep dermis was replaced by a diffuse cellular proliferation, and in one patient, the tumor cell population adopted a nodular pattern of growth involving adnexal structures and infiltrating the subcutaneous fat. In all cases, the tumors were composed of cells showing signet ring-cell features, with striking indentation of the nuclei toward the periphery of the cell. Immunohistochemical studies using antibodies for B-cell and T-cell markers (L-26 and UCHL) as well as antibodies for leukocyte common antigen, keratin, and kappa and lambda light chains were performed in all cases. The tumor cells showed a positive reaction for leukocyte common antigen, L-26, and lambda light chain restriction. Follow-up information was only available in one patient, who has remained alive and well 2 years after diagnosis without evidence of progression of the disease. The present cases highlight the importance of recognizing this unusual morphologic type of lymphoma so as to arrive at a correct diagnosis.

Primary anaplastic large-cell lymphoma is a rare malignancy in the lung. Anaplastic large-cell lymphoma characteristically involves the lymph nodes or skin, with few reports from other sites. We studied the clinical and pathologic features of five cases of anaplastic large-cell lymphoma limited to the lungs. The patients were three women and two men aged 27 to 66 years (mean, 44.6 y) The tumors ranged in size from 1.1 to 5 cm. All patients were CD 30 (Ki-1) positive and CD 15 (LeuM-1) negative. Epithelial membrane antigen immunoreactivity was seen in two patients. Epstein-Barr virus was not detected by immunohistochemistry (four patients tested) or by polymerase chain reaction studies (three patients tested). The immunophenotypes were T cell (n = 3) and null (n = 2). Gene rearrangement studies supported the immunophenotypic findings. One patient who had underlying HIV infection died of infectious complications. One patient died at 6 months. Two patients developed recurrent disease and are alive after 42 and 51 months of follow-up. The remaining patient is alive at 8 years of follow-up without evidence of disease. ALCL can mimic metastatic or primary carcinoma and should be considered in the differential diagnosis of large cell neoplasms of the lung.

Primary non-Hodgkin's lymphoma of the breast is uncommon. Most primary breast lymphomas are of B-cell phenotype, with only rare cases showing a T-cell phenotype. In this study, we report the clinicopathologic features of four cases of T-cell lymphoma in the breast. The patients all were female with a mean age of 48 years (range, 13 to 77 years). All cases showed immunoreactivity in paraffin-embedded tissue for T-cell markers CD3, CD45RO, and CD43. beta F1 was positive in three of four cases. The four cases were further subclassified as anaplastic large cell lymphoma (CD30 positive) of T-immunophenotype; natural killer/T-cell lymphoma; peripheral T-cell (CD4 positive), large cell type; and peripheral T-cell (CD8 positive, T-cell intracellular antigen positive), medium cell type. Three of the four cases were monoclonal for T-cell receptor beta and/or T-cell receptor gamma. The one case of natural killer/T-cell lymphoma was negative for monoclonality with both T-cell receptor beta and gamma by molecular diagnostic studies. In all cases, IgH was negative. Follow-up was obtained in three cases. Two patients died within less than 1 year after the diagnosis. The third patient died within 18 months of the diagnosis. Our results suggest an aggressive clinical course for T-cell lymphomas that present in the breast.