Bone marrow macrophage iron grade and survival of HIV-seropositive patients.

OBJECTIVE: Increased iron stores predispose to certain microbial infections. This association might be especially important in patients whose immune system is impaired by HIV. This study examined the relationship between iron stores and the survival times of patients with HIV infection. DESIGN: Retrospective analysis of iron stores, as determined directly in bone marrow aspirates, and of hospital records. SETTING: The George Washington University Hospital, an urban academic tertiary care institution. PATIENTS: Three hundred and forty-eight HIV-seropositive adults who had diagnostic bone marrow aspirates between January 1985 and June 1996. MEASUREMENTS: Bone marrow macrophage iron stores were graded on a scale of 0 to 5. For analysis of the influence of iron stores on survival, we compared patients with grades 4-5 iron stores (markedly or massively increased; n = 188) to those with grades 0-2 iron stores (normal or decreased; n = 130). RESULTS: Infections caused by Candida spp., Pneumocystis carinii, and Mycobacterium spp. were more common in patients with high macrophage iron grades than in patients with low or normal iron grades (P < or = 0.006). The adjusted estimated rate of death (hazards ratio) was higher in patients with high iron stores compared with patients with low or normal iron stores, both from the time of the bone marrow study (ratio of 2.1; 95% confidence interval 1.3-3.5; P = 0.003) and the determination of HIV-seropositivity (ratio of 2.8; 95% confidence interval 1.4-4.9; P = 0.001). CONCLUSION: High iron stores, as determined by bone marrow macrophage iron grade, may be associated with shorter survival times in patients with HIV infection.

Human herpesvirus-8-associated body cavity-based lymphoma in human immunodeficiency virus-infected patients: a unique B-cell neoplasm.

Human immunodeficiency virus (HIV)-related body cavity-based lymphomas (BCBLs) are known to exhibit unusual clinical, immunophenotypic, and genotypic features, and have recently been found to harbor DNA sequences of a new human herpesvirus, designated Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8). The authors have encountered eight cases of HHV-8-associated BCBL in HIV-infected patients. A literature search revealed an additional 50 reported cases of HIV-related BCBL, as well as reports of several other disorders associated with HHV-8 DNA. Comprehensive analysis of the clinical and pathobiological features of all 58 known cases of HIV-related BCBL shows it to be a unique B-cell neoplasm with a strong propensity for body-cavity involvement without mass lesions and with little or no dissemination, poor prognosis, high grade usually immunoblastic morphology, late B-cell phenotype and genotype, no associated c-myc gene rearrangement, frequent presence of Epstein-Barr virus (EBV) genome, and uniform association with HHV-8 DNA. Considering these features in the context of other disorders associated with HHV-8 DNA, HHV-8 appears to play a causal role in BCBL, possibly in concert with EBV, and may induce this lymphoma through dysregulation of cytokines, particularly interleukin-6, or infection of an unusual B-cell subset. The characteristics of HHV-8-associated BCBL suggest a possible role for antiherpes or anticytokine agents in the treatment of this lymphoma.

The bone marrow in human immunodeficiency virus (HIV)-related disease. Morphology and clinical correlation.

To determine the true incidence of abnormalities in bone marrow specimens from patients infected with human immunodeficiency virus (HIV) and the clinical significance of these abnormalities regarding their cause and their role in the production of hematologic complications, 216 bone marrow biopsies, aspirates, and/or imprint preparations from 178 patients who either were seropositive for HIV infection or met the Centers for Disease Control (CDC) criteria for acquired immunodeficiency syndrome (AIDS) were studied. Detailed morphologic review was performed in a blind fashion as to clinical status. Extensive clinical, therapeutic, and laboratory data were collected for each patient. Statistical analysis was performed to detect significant correlations between morphologic findings and clinical/therapeutic/laboratory features. Among the most common bone marrow findings were hypercellularity (53% of specimens), myelodysplasia (69%), evidence of reticuloendothelial (RE) iron blockade (65%), megaloblastic hematopoiesis (38%), fibrosis (20%), plasmacytosis (25%), lymphocytic aggregates (36%), and granulomas (13%). A number of statistically significant correlations between morphologic findings and clinical features were noted. No significant association was detected between any morphologic finding and therapy with a variety of drugs. In 7 of 14 (50%) patients found to have marrow involvement by malignant neoplasm, the bone marrow represented the initial site of diagnosis of the neoplasm. Most of the bone marrow abnormalities associated with HIV infection appear to be related directly to the infection or its complications and not to therapeutic intervention. In certain clinical situations, bone marrow examination continues to be useful in the management of patients infected with HIV.

Effect of analytic uncertainty of conventional and point-of-care assays of activated partial thromboplastin time on clinical decisions in heparin therapy.

The authors assessed the capability of assays of activated partial thromboplastin time (aPTT) for supporting clinical decision algorithms for heparin therapies of varying complexity. Blood samples were collected prospectively in three explicit management strategies from 100 sequential patients for whom heparin dosage was adjusted for therapeutic monitoring, femoral venous sheath removal after cardiac catheterization, or heparinization after thrombolytic therapy. In two- and three-way decision algorithms, conventional and point-of-care aPTT assays agreed with heparin assays in approximately two thirds of cases, and the two aPTT assays agreed in 80% or more of all cases. In six-way decision algorithms, the two aPTT assays agreed in only about half of all cases. The authors conclude that the reliability of point-of-care aPTT assays is similar to that of conventional assays. Both techniques can support two- and three-way decision algorithms but not some more complex patient classifications.

Urine sediment analysis by the Yellow IRIS automated urinalysis workstation.

The Yellow IRIS automated urinalysis workstation (International Remote Imaging Systems, Chatsworth, CA 91311) performs urine sediment analysis with the use of Automated Intelligent Microscopy (AIM). It ranks and counts particles based on size. A split sample study using 268 individual urine specimens was performed comparing sediment analyte detection by the Yellow IRIS with that achieved by a standard manual method. The detection ratio ("positive" specimens detected by the Yellow IRIS divided by "positive" specimens detected by the manual method) for the presence of various analytes, as well as the presence of abnormal numbers of analytes, was determined. The significance of each detection ratio was tested by calculating the McNemar's statistic, which is useful in the evaluation of nonparametric data collected by two different methods on identical specimens. Results were considered abnormal if the red blood count was greater than or equal to three per high-power field, the white blood cell count was greater than or equal to five per high-power field, or squamous epithelial cells were greater than or equal to five per high-power field. The results indicate that the Yellow IRIS enhances the detection of urinary sediment components.

Usefulness of molecular detection of human herpesvirus-8 in the diagnosis of Kaposi sarcoma by fine-needle aspiration.

Kaposi sarcoma (KS), a multifocal angioproliferative disorder, occurs most commonly in patients with AIDS, in whom it remains an important cause of morbidity and mortality. KS is often in the differential diagnosis in HIV-infected patients undergoing fine-needle aspiration (FNA). FNA diagnosis of KS is usually made by morphologic observation of scant tissue fragments composed of bland spindle cells and crush artifact. Human herpesvirus-8 (HHV-8) has been identified by polymerase chain reaction (PCR) amplification of DNA samples isolated from various epidemiologic forms of KS. In an attempt to improve the accuracy of KS diagnosis by FNA, we analyzed for the presence of HHV-8 DNA in 13 spindle-cell lesions evaluated by FNA: KS, 8 cases; granulomatous inflammation due to Mycobacterium avium-intracellulare, 1; nodular fasciitis, 1; dermatofibrosarcoma protuberans, 1; dermatofibroma, 1; benign spindle-cell lesion of nerve sheath origin, 1; and 2 lesions with lymphoid hyperplasia. DNA isolated from archival Wright-Giemsa-stained glass slides was used for the PCR amplification of the HHV-8 DNA sequences. All of the cases diagnosed as KS and 1 of the lymphoid hyperplasia cases were PCR-positive for HHV-8 DNA, while all other cases of spindle-cell lesions were negative. The molecular demonstration of HHV-8 DNA may be a useful adjunct in the diagnosis of KS by FNA.

Comparison of PCR with southern hybridization for the routine detection of immunoglobulin heavy chain gene rearrangements.

The development of a reliable polymerase chain reaction (PCR) technique for the routine detection of clonal immunoglobulin heavy chain (IgH) gene rearrangements would represent an attractive alternative to Southern hybridization analysis because of the relative simplicity of PCR protocols, and because the requirements for both quality and quantity of DNA would be considerably less stringent. To assess the utility of PCR for the routine detection of clonal IgH gene rearrangements, samples from 123 adult patients were evaluated and analysis by PCR amplification using IgH Framework 1 or Framework 3 variable region consensus primers was compared with analysis by restriction endonuclease digestion and Southern hybridization with genomic, IgH probes. The authors found that 90% of IgH genes found to be rearranged by Southern hybridization are detected by the PCR technique. An additional 9 patient samples had clonal IgH gene rearrangements that were detectable by PCR alone. Eight of these nine patients had a history of a clonal hematopoietic process at either the morphologic or molecular level, and six had a history of a B-cell malignancy. It is likely that these specimens contained clonal lymphoid populations undetected by the Southern hybridization technique. Thus, the diagnostic sensitivity and specificity of the PCR method for the detection of B-cell tumors were 91% and 95%, respectively. The combination of improved analytical sensitivity and specimen flexibility of the IgH PCR assay could make it the method of choice for the routine detection of clonal IgH gene rearrangements, if minor improvements in the diagnostic sensitivity of the assay can be achieved.

Giant lymph node hyperplasia involving the thymus with associated nephrotic syndrome and myelofibrosis.

Giant lymph node hyperplasia (GLH) is an unusual form of benign lymphoid hyperplasia which, although it often occurs in the mediastinum, has not previously been reported to involve the thymus. In this report, a case of GLH with involvement of the thymus and with associated nephrotic syndrome and myelofibrosis is presented. The significance of the association of these conditions with GLH is discussed, including the possibility that some or all of the patient's abnormalities may have been related via an abnormal immune mechanism.

Polymerase chain reaction detection of immunoglobulin gene rearrangement and bcl-2 translocation in archival glass slides of cytologic material.

Cytologic evaluation of lymph node fine-needle aspirates and serous effusions is a rapid and useful means for establishing the diagnosis of a variety of lymphoproliferative disorders. However, in some instances, cytologic findings are not sufficient to establish a diagnosis of lymphoma, thus necessitating the use of ancillary procedures, the most frequent of which is immunophenotyping. In this respect, the usefulness of molecular markers, such as clonal immunoglobulin gene rearrangements or chromosomal translocations, have been less well evaluated. Follicular lymphoma constitutes an interesting disease for such a study because these tumors possess characteristic histopathologic features and contain two potential molecular markers, that is, a clonal immunoglobulin gene rearrangement and a bcl-2 gene translocation [t(14;18)]. In the present study, we evaluated, retrospectively, the cytologic material from four lymph node fine-needle aspirates and one pleural effusion of five patients with biopsy-proven follicular lymphoma. In four of the cases, definitive diagnosis of lymphoma had not been possible solely from cytologic evaluation. DNA was isolated from archival air-dried samples present on glass slides and amplified by the polymerase chain reaction (PCR) for detection of either a clonal immunoglobulin heavy chain gene rearrangement or bcl-2 translocation (major breakpoint region). An immunoglobulin heavy chain gene rearrangement was detected in four of five patients, and two patients had the bcl-2 translocation by PCR. The effusion case was identical by gel electrophoresis with product amplified from a lymph node biopsy of the same patient and DNA extracted directly from fresh pleural effusion cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Low grade lymphomas in the elderly.

Aging is considered to play an important role in the pathogenesis of non-Hodgkin's lymphoma (NHL). Recent epidemiological studies, both in the United States and worldwide, show an increasing incidence of NHL, with the increase also marked in the elderly population. Two hundred thirty-two patients with NHL, aged 60 years and older (44 percent female and 56 percent male), have been analyzed retrospectively. These patients represented 39 percent of all NHL cases seen over a seven-year period at a single institution. Among the elderly cases, 81 (35 percent) were classified as low-grade NHL, with 44 (19 percent) small lymphocytic lymphoma/chronic lymphocytic leukemia, 2 (1 percent) small lymphocytic lymphoplasmacytoid, 13 (6 percent) diffuse small cleaved including mantle cell, and 22 (9 percent) follicular small cleaved and mixed cell types. Although the indolent lymphomas are currently treated similarly, recent studies indicate differences in pathogenesis and survival among the classic subtypes. Also, several new low-grade clinicopathologic entities have been described. The clinical, morphologic, immunophenotypic, and genetic features of the classic and newer low-grade lymphomas are discussed.

Clinically unsuspected Hodgkin disease presenting initially in the bone marrow of patients infected with the human immunodeficiency virus.

BACKGROUND: Hodgkin disease (HD) in patients infected with the human immunodeficiency virus (HIV) is an aggressive neoplasm that often exhibits high stage and extranodal involvement at the time of presentation. Because of the propensity of HIV-associated HD to involve the bone marrow early in the course of the neoplasm, bone marrow examination may often represent the initial source for the diagnosis. In most cases, however, there is a clinical suspicion of HD before bone marrow examination. METHODS: Three cases are presented in which HD was not clinically suspected and the initial diagnosis of the neoplasm was suggested by atypical lymphohistiocytic lesions identified on routine bone marrow examination, later to be confirmed by lymph node biopsy. RESULTS: In none of the cases was HD clinically suspected before bone marrow examination; in two cases, fever was the only clue that the patients may have HD. It was found on bone marrow biopsy that all three patients had lymphohistiocytic aggregates with large atypical mononuclear cells suggestive but not diagnostic of HD. CONCLUSIONS: Bone marrow examination may provide the initial evidence of HD in HIV-infected patients, even when there is little or no clinical indication of the neoplasm.

Malignant histiocytosis occurring in patients with acute lymphocytic leukemia.

Five cases of malignant histiocytosis (MH) in patients being treated for acute lymphocytic leukemia (ALL) have been previously reported. Two additional cases are described here, all known cases are reviewed, and the phenomenon is discussed. The most tenable explanation for this phenomenon appears to be that ALL and MH may have been interrelated in these patients with both diseases originating from a common stem cell.

Thymic carcinoma: clinical findings in two patients with extrathoracic metastases.

Two patients with widely metastatic thymic carcinoma form the basis for this review. Evidence of local tumor invasion at initial operation may be the best predictor of risk for relapse. Combination chemotherapy including cisplatin may be of benefit for some patients with metastatic disease.

Human herpesvirus-8/Kaposi's sarcoma-associated herpesvirus in organ transplant patients with immunosuppression.

Several recent studies have demonstrated Kaposi's sarcoma-associated herpes virus (KSHV), also known as putative human herpes virus-8 (HHV-8), DNA in various epidemiologic forms of Kaposi's sarcoma (KS), including AIDS-associated, classic, and endemic types. Risk of developing KS in non-HIV-infected immunosuppressed hosts, such as patients following solid organ transplantation, is also significantly higher compared to normal individuals. We have retrospectively evaluated 28 organ transplant patients with KS (23 cutaneous and five visceral) for the presence of KSHV genome by polymerase chain reaction (PCR) amplification of DNA isolated from formalin-fixed, paraffin-embedded archival tissue samples. 27/28 KS patients were positive for the presence of KSHV. In four KS patients, tissue samples with no histologic evidence of KS were also analysed for KSHV. No evidence of positivity in three samples was noted, but one patient had weak positive amplification products on DNA samples isolated from a gastric biopsy with chronic gastritis and lymph node with sinus histiocytosis. These data support the association of KSHV with KS developing in non-HIV-infected immunosuppressed patients, similar to other forms of KS, and suggest that KSHV may play a significant role in the development of all forms of KS.

DNA analysis and S-phase fraction determination by flow cytometric analysis of infiltrating lobular carcinoma of the breast.

Flow cytometric analysis was performed on 50 infiltrating labular carcinomas (ILCs) of the breast from 50 patients with clinical follow-up (average duration, 4.1 yr) who had been treated between 1976 and 1991. The patients were classified as alive with no evidence of disease, alive with disease, or dead of disease. Ploidy and S-phase fraction (SPF) were compared with clinical outcome, histologic pattern (classical versus variant patterns), nuclear grade 1 or 2, axillary lymph node status, tumor size, percentage of signet ring cells, and estrogen receptor status. There was no association between aneuploid or diploid ILC and disease recurrence (of those patients classified as alive with no evidence of disease plus dead of disease, 4 (40%) of 10 were aneuploid and 15 (38%) of 40 were diploid), survival (of those classified as alive with no evidence of disease plus alive with disease, 9 (90%) of 10 were aneuploid and 36 (90%) of 40 were diploid), or any of the other factors evaluated. However, ILCs with a high SPF were more likely to recur than those with a low SPF (a high SPF was found in 9 [56%] of 16; a low SPF was found in 9 [30%] of 30), but this relationship was not statistically significant (P = 0.08). When only diploid ILCs were considered, there was a statistically significant association between high SPF and recurrence (a high SPF was found in 9 [64%] of 14, a low SPF was found in 6 [24%] of 25, P = 0.033). After the stratification of the diploid ILCs by the stage of disease, this relationship persisted only in Stage 1 (recurrence: a high SPF was found in 3 [75%] of 4; a low SPF was found in 1 [9%] of 11, P = 0.033). There was no association between SPF and any of the other factors evaluated. Our study indicates that ILC is usually diploid and that SPF may be a prognostic indicator that is limited to Stage 1 disease.

High Ia (HLA-DR) and low CD11b (Mo1) expression may predict early conversion to leukemia in myelodysplastic syndromes.

The FAB classification of myelodysplastic syndromes (MDS) has been useful in predicting prognosis; however, additional methods are required to detect patients at high risk for early conversion to acute nonlymphoblastic leukemia (ANLL). Using a panel of monoclonal antibodies to myelomonocytic surface antigens (MMSA) and flow cytometry, we studied bone marrow cells from 26 patients with MDS of all five FAB subtypes. The MMSA studied included Ia (HLA-DR), CD11b (Mo1), CD14 (Mo2, My4), CD13 (My7), and CD33 (My9). Marrows were considered "positive" for a given MMSA if the percentage of reactive cells exceeded the upper limit of the normal range. Twenty-four of twenty-six patients (92.3%) were CD13 (My7)+, suggesting that CD13 may serve as a diagnostic marker for MDS. Ten of twelve patients who developed ANLL during a median follow-up of 44 weeks were Ia(HLA-DR)+. The Kaplan-Meier estimated median time to leukemia (TTL) was 16 weeks for Ia+ patients and 88 weeks for Ia- patients (P = 0.004). All six patients who developed ANLL before 16 weeks from diagnosis were Ia+, while none of the Ia- patients converted to ANLL before 24 weeks. Nine of thirteen patients with low CD11b (Mo1) expression (< 53% reactive cells) developed ANLL, compared with only two of 11 patients with high CD11b expression (> 53% reactive cells). Kaplan-Meier estimated TTL was 29 weeks for patients with low CD11b, compared to 160 weeks for patients with high CD11b (P < 0.05). Patients who met both criteria, Ia+ and low CD11b, represented the poorest prognostic subgroup, with median TTL of 13 weeks compared with 88 weeks for the others (P = 0.017). Ia and CD11b patterns were not specific for MDS subtype, and their expression did not correlate with blast count. These data suggest that MDS patients whose bone marrow cells demonstrate high Ia (HLA-DR) and low CD11b (Mo1) expression represent a poor prognostic subgroup with short TTL. These patients may be candidates for early aggressive or investigational treatment.

T-cell lymphoma occurring in the oropharynx.

Two cases of documented T-cell lymphoma occurring in the oropharynx are described. Both patients presented with cervical lymphadenopathy and involvement of oropharyngeal tissues. Although classification of these patients' lesions in relation to other known T-cell lymphomas was difficult, the location of the lesions in both cases and certain morphologic features in one case at least suggested that the malignant cells may have arisen from peripheral T-lymphocytes. In both patients, the neoplastic cells showed a tendency to impinge upon the oral epithelium, in keeping with the pattern of involvement of epithelial tissues seen in several varieties of T-cell lymphoproliferative disorders. The possibility that these oropharyngeal T-cell lymphomas may represent a distinct type of T-cell neoplasm is raised.

Prolymphocytic leukemia: treatment with combination chemotherapy to include doxorubicin.

Prolymphocytic leukemia (PL) is a clinically distinct leukemic disorder. Cytochemical and surface marker characteristics help to differentiate PL from other types of leukemia, including chronic lymphocytic leukemia (CLL). In contrast to patients with CLL, those with PL frequently require early therapeutic intervention. Standard treatment regimens for CLL as well as splenectomy and splenic irradiation have not been effective in the treatment of PL. Combination chemotherapy with cyclophosphamide, Doxorubicin, vincristine, and prednisone (CHOP) has produced impressive clinical responses in patients with PL. The treatment of a patient with PL is discussed and the literature is reviewed.

Richter's transformation of lymphoma complicating Gaucher's disease.

A case of lymphoma in a middle-aged woman with Gaucher's disease, a mu-kappa monoclonal gammopathy, peripheral lymphocytosis, and massive splenomegaly is described. There was no evidence of Gaucher's disease in the splenectomy specimen. Instead, the splenic architecture was effaced by a small lymphocytic lymphoma (SLL), with a few foci of large cell lymphoma (LCL). Immunoperoxidase studies showed that both lymphomatous components had a mu-kappa immunophenotype. Flow cytometric analysis of peripheral blood and spleen lymphocyte surface markers confirmed monoclonality. The intensity of surface immunoglobulin expression and the results of other cell marker studies in the SLL component were consistent with a stage of differentiation beyond that typical of chronic lymphocytic leukemia (CLL). The presence of abundant cytoplasmic immunoglobulin in the SLL and the association with monoclonal gammopathy were more consistent with Waldenström's macroglobulinemia or plasmacytoid lymphocytic lymphoma. The immunohistochemical and flow cytometric findings suggest that the SLL component evolved clonally or underwent Richter's transformation to LCL. Although Gaucher's disease has been associated with a variety of B-cell disorders, the subsequent transformation to a high-grade lymphoma has not been previously reported.