Immunobiologic factors predictive of clinical outcome in diffuse large-cell lymphoma.

The prognostic importance of immunobiologic factors in diffuse large-cell lymphoma (DLCL) is studied in 105 consecutive DLCL patients. Multivariate results using the Cox proportional hazards model clearly indicate that the Ki-67 index (P = .002), a marker of cell proliferation activity, and the presence or absence of human leukocyte antigen-DR (HLA-DR) (P = .007) are strong predictors of survival even in the presence of established clinical factors of stage (P = .015) and symptoms (P = .050). Using these four variables, prognostic groups were formed identifying patient groups with varying degrees of risk. The group of patients with three or four risk factors present at the time of diagnosis had a median survival of 4 months compared with a median survival of 59 months for the group with no risk factors. Similarly, prognostic groups for disease-free survival (DFS) were constructed based on the proportional hazards model that involved B versus T phenotype (P = .035) and HLA-DR (P = .054). Median DFS for the patient group with one or two risk factors present was 11 months compared with 43 months with no risk factors present. This study suggests immunobiologic parameters are important predictors of clinical outcome in DLCL patients and are of value in identifying subgroups of patients who have not responded to currently available therapy. The practical significance of this study is to identify parameters that may suggest specific changes in therapy of patient subgroups.

Multiparameter analysis of acute mixed lineage leukemia: correlation of a B/myeloid immunophenotype and immunoglobulin and T-cell receptor gene rearrangements with the presence of the Philadelphia chromosome translocation in acute leukemias with myeloid morphology.

Morphological, immunological, cytogenetic, and molecular features of 28 cases of acute mixed lineage leukemia (AMLL), defined by the co-expression of lymphoid and myeloid cell surface antigens, were correlated in a multiparameter study. These 28 cases were identified in a series of 260 consecutive acute leukemia cases occurring predominantly in adults and were subdivided into 18 cases of AMLL with myeloid morphology and cytochemistry (AMLL-AML) and 10 cases of AMLL with lymphoid morphology and cytochemistry (AMLL-ALL). A lack of correlation was observed between the expression of B- or T-cell associated antigens with the presence of the expected immunoglobulin (Ig) or T-cell receptor (TCR) gene rearrangements in the AMLL cases with myeloid morphology. Only three of the 18 total AMLL-AML cases, each co-expressing B- and myeloid-associated cell surface antigens (B/My), had Ig heavy chain gene rearrangements with or without rearrangements of TCR genes. Ig light chain genes remained in the germline configuration. Strikingly, these three cases were the only AMLL-AML cases in our series to have the Philadelphia (Ph) chromosome translocation t(9;22)(q34;q11), suggesting that a significant percentage of acute leukemias with myeloid morphology and gene rearrangements may be Ph+ AMLL. The fact that three of the 10 B/My AMLL-AML cases in our series were Ph+ suggests that there may be an increased frequency of Ph chromosome, a translocation associated with a poor prognostic outcome, in B/My AMLL-AML occurring in the adult population. Although most AMLL cases with lymphoid morphology had Ig and TCR gene rearrangements associated with a variety of immunophenotypes and karyotypes, two Ph+ AMLL-ALL cases had many similar features (B/My immunophenotype; IgH with or without TCR rearrangements; Ig light chain genes germline) to their Ph+ AMLL-AML counterparts. However, the Ph+ AMLL-ALL cases differed from the Ph+ AMLL-AML cases by the expression of a more mature B-cell lineage immunophenotype and by their additional cytogenetic changes.

bcl-2 gene rearrangement in salivary gland lymphoma.

There is a wide spectrum of lymphoid hyperplasias and neoplasias that may arise in salivary gland tissue. Some lesions arise in the extranodal mucosal-associated lymphoid tissue (MALT) located in the salivary gland; others arise within the lymph nodes embedded in the gland parenchyma. It is difficult to distinguish the site and cell of origin in many salivary gland lymphoid lesions, but recent advances in the identification of specific gene rearrangements in lymphomas corresponding to normal follicular center cells have provided a molecular marker for these tumors. The genes involved are the immunoglobulin heavy chain gene (located on chromosome 14) and the blc-2 gene (located on chromosome 18). This specific chromosomal translocation [t(14;18)] has been sought in extranodal lymphomas of skin, stomach, and intestine. To date, primary lymphomas in these sites have lacked the t(14;18) translocation. We investigated the t(14;18) using molecular techniques in a series of morphologically and immunophenotypically defined malignant non-Hodgkin's lymphomas presenting in the salivary gland. Of the seven cases we examined, three had molecular evidence of a t(14;18) translocation. All three lesions had a nodular growth pattern. The four cases lacking bcl-2 rearrangement had diffuse growth patterns. In addition, all four bcl-2 germline cases had morphologic or clinical findings consistent with a MALT origin. In contrast to the data published to date for primary lymphomas of the stomach, skin, and intestine, our findings indicate that salivary gland lymphomas frequently contain bcl-2 gene rearrangement. In addition, there appear to be differences in the clinical findings of bcl-2 rearranged and bcl-2 germline salivary gland lymphomas.

Peripheral blood morphologic changes after high-dose antineoplastic chemotherapy and recombinant human granulocyte colony-stimulating factor administration.

The peripheral blood morphologic findings in 17 patients with cancer who had received high-dose cytotoxic chemotherapy followed by recombinant human-granulocyte colony-stimulating factor (rh-GCSF) were reviewed and compared with a control group of patients who received only high-dose chemotherapy. Both groups showed dysmyelopoiesis (abnormal granulation and nuclear lobulation) in the granulocytic series during the period of bone marrow recovery that followed the cytotoxic chemotherapy. Most of these morphologic abnormalities were more prominent in the rh-GCSF-treated group. Monocytic cells in both groups showed prominent vacuolation and immature nuclei. The percentages and absolute numbers of large granular lymphocytes were increased in the rh-GCSF group compared with the control group. No quantitative or qualitative abnormalities of eosinophilic or basophilic granulocytes were detected in either group. Both groups showed nonspecific red blood cell abnormalities, and large platelets were present in half of the control group smears. This report provides the first detailed peripheral blood morphologic description in patients treated with rh-GCSF and high-dose chemotherapy.

High-grade non-Hodgkin lymphoma relapsing as low-grade follicular lymphoma: so-called downgraded lymphoma.

Evolution of low-grade Non-Hodgkin Lymphoma (NHL) into a more aggressive neoplasm is a common, well-documented event in NHL. The reverse process, in which a less aggressive component becomes evident during the course of treatment for a higher-grade NHL, has only recently been recognized. This lymphoma "downgrading" has been reported at the time of relapse in both radiation- and chemotherapy-treated patients who initially presented with high- or intermediate-grade lymphoma. The etiology of this unusual transformation has not yet been determined. We present the clinical, morphologic, immunologic, and flow-cytometric features of a patient with diffuse immunoblastic lymphoma who achieved a complete response to chemotherapy and then relapsed with follicular small-cleaved-cell lymphoma 3 years later. Morphologic and immunophenotypic findings suggest that both immunoblasts and small cleaved cells were present in the initial biopsy. DNA content analysis of the initial and relapse biopsies suggests that the immunoblastic component was more susceptible than the small cleaved cells to the chemotherapy that the patient received. Successful eradication of the rapidly proliferating immunoblasts with survival of less rapidly proliferating small cleaved cells may account for the unusual histologic transformation seen in this case.

Partial hydatidiform moles: deoxyribonucleic acid content and course.

Partial moles are either diploid (46 chromosomes) or triploid (69 chromosomes). In 35 cases ploidy was measured by flow cytometry for nuclear deoxyribonucleic acid quantitation, indicating approximate chromosome number. Six of the 35 were triploid (17%) and the balance was diploid (83%). No complications occurred in the triploid group, while five of 25 (20%) diploid cases with evaluable follow-up had nonfatal sequelae. Complications included persistent mole treated by recurettage and four cases requiring chemotherapy (human chorionic gonadotropin titer plateau, clinical metastasis, overt choriocarcinoma, and placental site trophoblastic tumor). A combined morphologic and genetic classification of partial moles is recommended for identification and risk assessment. Deoxyribonucleic acid cell cycle fractions of the diploid partial moles may be helpful in the identification of patients at high risk for complications. A proliferation index greater than 3.6 separated the cases with sequelae from most of the uncomplicated cases (sensitivity 100%, specificity 95%).

Castleman's disease in POEMS syndrome with elevated interleukin-6.

POEMS syndrome is a rare multisystem affliction known for its signs, from which it also takes its acronym name "peripheral neuropathy, organomegaly, endocrinopathy, monoclonal (M) protein, and skin lesions." Our study chronicles the course of this syndrome in a young woman with Castleman's disease (angiofollicular lymph node hyperplasia). Cerebrospinal fluid (CSF) and serum interleukin-6 (IL-6) levels were abnormally elevated at various times during a 9-month period. The authors conclude that the plasma cell dyscrasia associated with the POEMS syndrome of this patient was Castleman's disease. Elevation of serum IL-6 levels might contribute to the pathogenesis of the POEMS syndrome.

An ultrastructural morphometric and immunophenotypic evaluation of Burkitt's and Burkitt's-like lymphomas.

Six cases of Burkitt's lymphoma (BL) and 12 cases of Burkitt's-like lymphoma (BLL) were classified by using strict histologic and cytologic criteria. These cases were processed for electron microscopy and analyzed by using computerized image analysis techniques. Form factor (4 pi A/P2) was used to measure nuclear contour irregularity. The mean of the standard deviation (SD) of nuclear area and form factor was used to assess pleomorphism. Overall, there were 8 similarities and 10 statistically significant dissimilarities out of 18 parameters analyzed. The similarities (p greater than 0.05) between the BL and BLL groups included the means of form factor, nuclear area/cytoplasmic area, SD of nuclear area/cytoplasmic area, number of nuclear pockets/100 nuclei, percentage of cells with nuclear pockets, number of lipid droplets/micron 2 of cytoplasm, percentage of cells with lipid droplets and number of mitochondria/micron 2 of cytoplasm. The dissimilarities (p less than 0.05) included the means of nuclear perimeter, SD of nuclear perimeter, nuclear area, SD of nuclear area, cellular area, SD of cellular area, cytoplasmic area, SD of cytoplasmic area, SD of form factor, and nucleolar frequency. Multiparameter analysis clearly separated these 18 patients into two distinct groups and confirms that the subtleties used in the histologic classification of these lymphoma subtypes are meaningful. Sixteen cases of BL and BLL were snap-frozen in isopentane and analyzed by using 16 lymphoid surface markers. All of the immunoglobulin-positive BL were of the mu isotype, whereas the BLL cases were divided between mu (6 cases) and gamma expression (4 cases). All 4 of the BL evaluated manifested CALLA expression, whereas 3 of the 11 BLL evaluated coexpressed CALLA. One BL case was of a pre-pre-B phenotype and one BLL case was of pre-B phenotype. The BL and BLL were compared to 49 cases of SIg (+) large cell lymphomas. The high incidence of coexpression of lambda, CALLA, and Ki-67 in BL and BLL separates these lymphomas, as a group, from the large cell lymphomas. We have also determined from this study that the separation of patients into distinct BL and BLL subtypes is clinically relevant. The BL group were all children (median of 6.5 years) compared with the BLL group who were all adults (median of 63 years). The complete remission rate was higher in the BL (67%) than in the BLL group (25%).4off