Lymphoblastic lymphoma expressing natural killer cell-associated antigens: a clinicopathologic study of six cases.

We describe six patients with lymphoblastic lymphoma (LBL) whose neoplastic lymphoid cells expressed surface antigens associated with natural killer (NK) cells. The six cases were selected from a series of 38 specimens diagnosed as LBL based on morphologic criteria and further subclassified by the use of an extensive panel of monoclonal and polyclonal antibodies. Although the morphologic features in all six cases were similar to those previously reported for LBL, their expression of NK-associated antigens was unique. All cases were positive with anti-Leu 11b, an antibody which appears to define a specific subtype of lymphocytes considered to have NK function; and all cases expressed T11, a T-cell-restricted antigen. The most commonly encountered immunophenotype of our cases of LBL was: Leu 11b+, T11+, Leu7+, TdT+, Leu 3a+, Ia+, pre-B-, and B-. As compared with more classical LBL of T-cell type, LBL of NK-cell type in our series occurred primarily in females and non-whites. Whereas treatment of classical LBL by multi-agent chemotherapy may lead to long-term survival, only two of our six patients were long-term survivors. The data derived from this study raise the possibility that LBL with the antigenic phenotype of NK cells may represent a biologic subtype of LBL.

Antigenic phenotype of Langerhans cell histiocytosis: an immunohistochemical study demonstrating the value of LN-2, LN-3, and vimentin.

In order to determine the antigenic phenotype of the proliferating cells in Langerhans cell histiocytosis (LCH), we studied 15 such examples by using formalin- and B5-fixed, paraffin-embedded tissues. We used a panel of antibodies that are known to react with lymphocyte- and histiocyte-associated antigens. These included LN-1, LN-2, and LN-3 monoclonal antibodies (MoAbs), MoAbs to leukocyte common antigen (LCA), Leu-M1 antigen, vimentin, and epithelial membrane antigen (EMA), as well as polyclonal antibodies to lysozyme and S100 protein. The antigens encountered most frequently in LCH cells were S100 protein (93% of cases), vimentin (86%), and those detected by LN-2 (80%) and LN-3 (82%). Lysozyme was detected focally in two cases and diffusely in one case. The LCH cells were negative for LN-1, LCA, Leu-M1, and EMA. There was only one specimen in which S100 protein was not demonstrated; in this case, LN-3, vimentin, and T6 on frozen section were positive. The phenotype of LCH cells is similar to that of Langerhans' cells and interdigitating histiocytes. Our results demonstrate the value of using a panel of antibodies, including anti-vimentin MoAb, LN-2, and LN-3 for the immunophenotypic diagnosis of LCH in addition to an antibody to S100 protein.

Monocytoid B-cell lymphoma in a patient with human immunodeficiency virus infection. Demonstration of human immunodeficiency virus sequences in paraffin-embedded lymph node sections by polymerase chain reaction amplification.

There is a significantly increased incidence of malignant lymphoma in patients with acquired immunodeficiency syndrome (AIDS). The lymphomas are usually of a high grade and of B-cell phenotype. While the frequent presence of reactive monocytoid B lymphocytes in patients with AIDS-related lymphadenopathy has recently been documented in several studies, to our knowledge, there are no reported cases of monocytoid B-cell lymphoma, the neoplastic counterpart of monocytoid B lymphocytes, in patients with AIDS. We now describe a human immunodeficiency virus (HIV)-positive patient with HIV-related lymphadenopathy in whom monocytoid B-cell lymphoma developed during the course of his disease. The morphologic and immunologic features of the lymphoma were characteristic of monocytoid B-cell lymphoma, and the involved lymph node exhibited a reversed CD4/CD8 ratio. Moreover, using the polymerase chain reaction, we were able to demonstrate HIV genome in DNA extracted from the lymph node tissue. To our knowledge, this is the first report of a case of monocytoid B-cell lymphoma occurring in an HIV-positive patient and in which we were able, by using a sensitive molecular biologic technique, to demonstrate HIV sequence in paraffin-embedded, fixed lymph node sections.

Functional ACL bracing. A survey of current opinion and practice.

Since most studies designed to prove the efficacy of functional anterior cruciate ligament (ACL) bracing have been equivocal, we felt it would be helpful to know the practices of orthopedic sports medicine physicians. Physicians were questioned about their brace prescription practices via a mailed survey. The response rate was 56% (114/205). Most physicians use functional braces for ACL patients, prefer custom braces, and brace patients for 9 months after reconstruction. Thirty-six percent reported having recently made changes in their brace prescription practices, including using bracing less often. There was no effort made in this study to determine the best bracing practice. Researchers must continue studying brace efficacy in an effort to provide some rationale for bracing regimens.

Time trends in Hodgkin's disease incidence. The role of diagnostic accuracy.

A prior study of Hodgkin's disease (HD) incidence using national cancer survey data (1969-1980) identified unprecedented rate declines among white persons older than 40 years, and rate increases among young adults aged 15 through 39. These trends could be due to improved diagnostic accuracy. To investigate this hypothesis, the authors updated incidence rates in whites by age, sex, and histologic subtype through 1984; quantified diagnostic accuracy in corresponding detail using Repository Center for Lymphoma Clinical Studies data, which include original and expert review diagnoses on lymphoma patients; and recalculated HD incidence rates (1969-1984) corrected for diagnostic error. Updated HD incidence rates through 1984 continued to decline in older adults and showed persistent increases for young adults with the nodular sclerosis (NS) histologic subtype. The percentage of original HD diagnoses confirmed on review (confirmation rate) decreased with age and increased over time; in older adults, these patterns opposed observed incidence trends. However, for young adults, confirmation rates of NS, the most common subtype at these ages, were high and changed little over time. After adjustment for diagnostic error, incidence rates for older adults were lower than previously observed and showed no secular changes. However, young adults with NS had slightly larger rate increases than in uncorrected data. Thus, contemporary changes in HD incidence for whites primarily involve growing risk to persons at the start of adult life. These patterns are compatible with trends in suspected sociodemographic risk factors that suggest an infectious etiology for HD.

Monocytoid B-cell lymphoma. Clinicopathologic study of 21 cases of a unique type of low-grade lymphoma.

The morphologic and immunologic features of three cases of an unusual and distinct B-cell lymphoma were recently described and termed monocytoid B-cell lymphoma (MBCL) because of the striking resemblance of the neoplastic cells to reactive monocytoid B-lymphocytes. The morphologic spectrum and the clinical behavior of MBCL were investigated in a series of 21 patients. This study indicates that patients with MBCL usually present with lymphadenopathy and Stage I or II disease. MBCL also occurs at extranodal sites including the salivary gland. Because four of the patients with MBCL had Sjögren's syndrome with characteristic laboratory profiles, these results raise the possibility that there may be a relationship between MBCL and Sjögren's syndrome. Eight patients were male and 13 female (M:F = 1:1.6), and MBCL primarily involved the elderly (median age, 66 years). The most striking clinical findings were high percentages of complete remissions and long survival times indicating that MBCL is a low-grade lymphoma. Of 21 patients investigated, 18 were in complete remission at the time of completion of this study. Two patients died with the disease and one was lost to follow-up. Patients with localized MBCL may have a better survival rate than those with generalized disease. Like other low-grade lymphomas, MBCL can progress to a higher grade lymphoma of large cell type. Unlike other low-grade lymphomas, in MBCL splenomegaly, bone marrow involvement, and leukemic conversion are uncommon.

Can we improve breast pathology reporting practices? A community-based breast pathology quality improvement program in New Hampshire.

We implemented a regional quality assurance program in New Hampshire (NH) to evaluate breast pathology practices and attempt to improve the completeness of information provided in breast surgical pathology reports. We also assessed the degree to which NH pathologists agree with National Guidelines. The program's objective was to promote a consistent standard of care for patients whose breast pathology is interpreted in NH. Using a sequential survey technique, we were able to obtain consensus on breast tissue report content that was similar to National Guidelines. We also found that 52% of the reporting elements improved in the post-intervention period, although only one reached statistical significance. In conclusion, pathology interpretation is the "gold standard" for determining both screening effectiveness and subsequent treatment of breast cancer, yet variability in breast tissue reporting exists. It is critical that more research be done to improve breast pathology interpretation and reporting practices.

Report cards or instrument panels: who needs what?

BACKGROUND: The report card movement in health care is a positive response to legitimate customer needs and requirements for comparative information on quality and costs. At the same time, providers have a legitimate concern about potential problems with gathering and using valid data in a prudent manner. Report cards have problems that often detract from their potentially constructive uses. In response to this concern, the authors propose that instrument panels--a newer concept in health care--compared to the static, judgmental image of report cards project an action-oriented, decision-making image. EXAMPLES: Descriptions are given of three types of instrument panels based on work in progress in the Dartmouth-Hitchcock health care system, a regional, integrated delivery system that serves the population of New Hampshire and parts of Vermont and Massachusetts: a 450-physician group practice (The Hitchcock Clinic), which provides more than one million visits per year in more than 25 locations; a tertiary health care facility (Mary Hitchcock Memorial Hospital) with more than 300,000 patient days; and prepaid health plan (Matthew Thornton Health Plan) with approximately 120,000 members. SUMMARY: It would be wise and efficient for providers to design instrument panel data collection systems that can feed directly into report cards, leading to the triple benefit of enhancing accuracy, reducing total costs, and increasing overall utility to both providers and their customers.

Antigenically defined subgroups of lymphoblastic lymphoma. Relationship to clinical presentation and biologic behavior.

A large panel of monoclonal antibodies and polyclonal antisera were used to ascertain the immunophenotypic characteristics of 36 lymphoblastic lymphomas (LBL). Results showed that this group of lymphomas have significant immunologic heterogeneity. Of the 36 cases, 33 were positive for T-cell antigens; among these, 22 cases were classified as T-cell LBL (TLBL, Group 1) based on their expression of T-cell-restricted and T-cell-associated antigens, and five expressed the common acute lymphoblastic leukemia antigen in addition to T-cell-associated antigens (Group 2). Six cases showed strong reactivity with anti-Leu-11 antibody, which defines a specific subtype of lymphocytes considered to have a natural killer (NK) function (Group 3). Two additional cases had a "pre-B" cell phenotype (Group 4), as determined by reactivity with BA-1 and BA-2 monoclonal antibodies, which react with immature and pre-B-lymphocytes. The neoplastic cells in the remaining case showed monoclonal surface membrane immunoglobulin of the IgMD heavy chain and kappa light chain type (Group 5). Despite immunophenotypic heterogeneity, the morphologic features were essentially similar in all cases. When the clinical features for each immunologic group were compared, however, two statistically significant findings resulted: (1) the frequency of mediastinal masses was highest in TLBL (Group 1, P less than 0.01), and (2) the male-female ratio was significantly lower in patients with LBL expressing NK-associated antigens (Group 3) than in the other groups of patients (P less than 0.01). Our data indicate that LBL can be divided into several immunologic subtypes; larger, prospective clinicopathologic studies are required to determine the clinical significance of the immunophenotypic classifications of LBL.

Variability in interpretation of immunohistologic findings in lymphoproliferative disorders by hematopathologists. A comprehensive statistical analysis of interobserver performance.

Eight hematopathologists independently reviewed 56 consecutive cases of benign and malignant lymphoproliferative disorders (LPD) to determine: (1) the degree of interobserver agreement on the interpretation of immunologic findings on fresh-frozen sections alone and on that of the immunologic findings in conjunction with corresponding hematoxylin and eosin (H & E)-stained histologic sections; (2) whether prior knowledge of morphologic characteristics influences the interpretation of immunohistologic sections; (3) whether immunologic phenotype could be predicted reliably based solely on study of histologic sections; and (4) the significance of immunologic data as an aid in the interpretation of histologic sections. The study was carried out in three independent review sessions consisting of (1) review of immunohistologic sections only, (2) review of the same immunohistologic sections together with histologic sections, and (3) review of the histologic sections alone. A consensus diagnosis was defined as agreement of five or more pathologists on the final diagnosis and identification of the immunophenotype. When the authors compared the total number of major disagreements in the first review session with those in the second, the accuracy of the determination of immunophenotype in the second session was clearly superior (P less than 0.05). Similarly, the total number of major disagreements in the second review session was significantly lower than that in the third review session (P less than 0.001). When histologic diagnoses in the second session were compared with those in the third session, it became apparent that the immunologic data helped the pathologist to correct major misinterpretations in 14 cases (25%). This study is the first to demonstrate quantitatively that (1) knowledge of morphologic features influences and greatly enhances the accuracy of the interpretation of immunologic findings, (2) the immunophenotype of LPD cannot be predicted based on morphologic findings alone, and (3) immunologic findings improve the accuracy of interpretation of histologic findings in situations in which a diagnosis cannot be made from morphologic features only.

Interleukin-2 diphtheria fusion protein (DAB486IL-2) in refractory rheumatoid arthritis. A double-blind, placebo-controlled trial with open-label extension.

OBJECTIVE: This pilot phase II, double-blind, placebo-controlled trial of 1 month duration, with a 2-3-month open-label extension, evaluated the safety, tolerability, biologic effects, and efficacy of interleukin-2 diphtheria fusion protein (DAB486IL-2) in refractory rheumatoid arthritis (RA). METHODS: Forty-five RA patients were enrolled in the trial, and were randomized, after a 3-4-week disease-modifying antirheumatic drug washout, to receive a daily intravenous dose of either DAB486IL-2 or placebo (saline) for 5 days. A blinded, third-party observer evaluated arthritis activity. Clinical response was defined as > or = 25% improvement in swollen and tender joints and > or = 25% improvement in at least 2 of 6 additional parameters. The double-blind phase was 4 weeks; placebo patients could cross over to receive open-label treatment for a maximum of 3 monthly DAB486IL-2 cycles. RESULTS: In the double-blind phase, 4 of 22 patients (18%) in the treated group and none in the placebo group (P = 0.05) met the criteria for clinical response. During the open-label treatment phase, 11 of 36 patients (31%) and 11 of 33 patients (33%) had a clinical response after completing 2 and 3 courses of DAB486IL-2, respectively. Adverse events included transient fever/chills (45%), nausea/vomiting (50%), elevated (< or = 3 x normal) transaminases (55%), and increased joint pain (45%). Twelve patients (8 placebo, 4 DAB486IL-2) did not complete 3 treatment cycles. No apparent differences were noted in CD4+ CD25+ cells of responders versus nonresponders, or of DAB486IL-2-treated versus placebo-treated patients. CONCLUSION: Clinical responses were noted in patients treated with DAB486IL-2 (18%) compared with placebo (0%) in the double-blind phase. In the open-label phase, 33% of patients completing 3 monthly DAB486IL-2 cycles had improvement in arthritis activity. Further studies of IL-2 diphtheria fusion proteins are warranted to elucidate factors that may predict clinical response and define mechanism(s) of action.

Small lymphocytic lymphoma: a clinicopathologic analysis of 268 cases.

We analyzed specimens from 268 patients with small lymphocytic lymphoma (SL) to identify prognostic factors significant for survival. These patients were staged and treated according to the protocols of the Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, Southeastern Cancer Study Group, and the Southwest Oncology Group. Univariate analysis showed that a large-cell grade greater than I, WBC greater than 10,000/microL, hemoglobin (Hgb) less than 11 g/dL, age greater than or equal to 55 years, and failure to respond to treatment were all poor prognostic factors. Multivariate analysis showed that large-cell grade, age, degree of capsular invasion, and symptom type were independently associated with survival. Separate analyses of cases with and without leukocytosis indicated differences in survival. In patients without leukocytosis, age, presence or absence of anemia, and treatment response were significant prognostic variables; in patients with leukocytosis, large-cell grade, presence or absence of anemia, symptom type, and treatment response were significantly related to survival. Multivariate analysis showed that age was the only significant independent prognostic variable in patients without leukocytosis; in patients with leukocytosis, symptom type, large-cell grade, and bone marrow involvement were independently associated with survival. We conclude that several parameters, both clinical and pathologic, should be assessed at the initial diagnosis of SL to predict prognosis better.