Serum levels of the soluble form of CD30 molecule as a tumor marker in CD30+ anaplastic large-cell lymphoma.

PURPOSE: To determine serum levels of the soluble form of CD30 molecule (sCD30) in patients with Ki-1/CD30+ anaplastic large-cell lymphoma (ALCL), and to evaluate its correlation with clinical features at presentation and its possible role as a tumor marker to monitor response to treatment and subsequent follow-up. PATIENTS AND METHODS: sCD30 serum levels were measured with an improved commercial sandwich enzyme-linked immunosorbent assay (ELISA) test kit in 24 patients with CD30+ ALCL at diagnosis and in 13 after treatment. RESULTS: Increased values (> 20 U/mL) at diagnosis were observed in 23 of 24 cases (median, 842.5 U/mL; range, 16 to 37,250) as compared with controls (P < .0001). These values were greater than those of 60 stage-matched cases of Hodgkin's disease (HD) (P < .0001). The highest median value was observed in patients with T-cell-type ALCL (1,690 U/mL), with a significant overall difference as compared with B- and null-cell types (P = .004). Phenotype maintained its significance when results were corrected for other parameters, such as age, sex, and stage (P = .03). sCD30 values returned to the normal range in complete remission (CR), but remained increased in one patient who only partially responded to treatment. Subsequent increases of sCD30 levels were recorded in four of four patients after relapse. CONCLUSION: sCD30 appears to be a new biologic serum tumor marker of possible use in the clinical setting of CD30+ ALCL.

Non-Hodgkin's lymphoma of the gastrointestinal tract: an analysis of clinical and pathologic features affecting outcome.

Clinical and histopathologic data from 87 patients with primary non-Hodgkin's lymphoma of the gastrointestinal (GI) tract diagnosed between 1974 and 1984 were reviewed. B-cell lymphomas of intermediate- or high-grade histology constituted 78% of lesions. Stage of disease varied with histologic grade, with a preponderance of advanced disease (stages IIIE and IV) in patients with low-grade lymphoma (15 of 21) (71%), compared with higher grade lesions (38%, P = .01). Among patients with nonlocalized (stages IIE through IV) lymphoma of intermediate- or high-grade histology, surgical resection of the primary focus afforded a higher rate of complete remission (CR) (70% v 50%) and sustained CR (61% v 21%, P = .04) after cytotoxic therapy compared with the nonresected cohort. The median survival in the resected group was 51 months + compared with 13 months in the nonresected patients (P = .012). Differences in outcome were attributable to a high risk of treatment-related complications (perforation and/or hemorrhage) (43% v 0%, P = .001) and local relapse (29% v 4%, P = .05) in nonresected individuals. Life-threatening local complications were not observed in patients with low-grade lymphoma managed solely with medical therapy. Histologic findings from surgically staged patients identified presence of extravisceral disease and intermediate- or high-grade tumor histology as features predictive of transmural invasion, enabling potential identification of patients who might be optimally managed by resection of the primary GI focus before initiation of cytotoxic therapy.

T-cell-rich B-cell lymphomas: diagnosis and response to therapy of 44 patients.

PURPOSE: Clinicopathologic features of 44 patients with well-documented T-cell-rich B-cell lymphomas (TCRBCLs) were reviewed to determine if there were distinguishing clinical characteristics and to evaluate the responsiveness to therapy. PATIENTS AND METHODS: Forty-one patients had de novo TCRBCL, while three patients had a prior diagnosis of diffuse large B-cell lymphoma. Seventeen TCRBCLs were identified from a retrospective analysis of 176 lymphomas diagnosed before 1988 as peripheral T-cell lymphoma (PTCLs). The initial pathologic diagnosis was incorrect in 36 of 44 cases (82%), usually due to the absence of adequate immunophenotypic and/or genotypic studies at the initial study. RESULTS: The median age of patients was 53 years (range, 17 to 92), and the male-to-female ratio was 1.4:1. B symptoms were present in 22 of 41 patients (54%); splenomegaly was detected in 11 patients (25%). Clinical stage at diagnosis was as follows: I (n = 8), II (n = 6), III (n = 15), IV (n = 14), and unstaged (n = 1). Although therapy was heterogeneous, the disease-free survival (DFS) and overall survival (OS) rates at 3 years for patients with de novo TCRBCL were 29% and 46%, respectively. A complete response (CR) to combination chemotherapy for intermediate-grade lymphomas was observed in 16 of 26 patients (62%); 11 of these patients (42%) had a continuous CR, compared with one of 14 patients (7%) who received radiation therapy or therapy for low-grade lymphoma or Hodgkin's disease (HD) (P < .05). However, there was no difference in OS between patients who received chemotherapy for intermediate-grade lymphoma versus other therapies (49% v 48%) due to a high response rate to salvage therapies, including seven patients without disease after marrow transplantation. CONCLUSION: TCRBCLs are difficult to recognize without immunoperoxidase studies. Patients with TCRBCL have clinical features similar to patients with other large B-cell lymphomas, except they may have more splenomegaly and advanced-stage disease; they should receive combination chemotherapy directed at large-cell lymphomas.

Effective therapy for poor-prognosis non-Hodgkin's lymphoma with 8 weeks of high-dose-intensity combination chemotherapy.

PURPOSE: Despite substantial advances in the treatment of aggressive non-Hodgkin's lymphoma, therapeutic results with conventional regimens remain poor in some subsets of patients. In an attempt to improve the prognosis of such patients we used an 8-week, multidrug chemotherapy regimen of high dose-intensity. PATIENTS AND METHODS: Between April 1986 and April 1991, 70 patients with advanced intermediate- or high-grade non-Hodgkin's lymphoma were treated. The median age was 41 years (range, 18 to 69). Fifty-one patients (73%) had stage IV disease; 37 (53%) were Shipp's category 3; 17 (24%) had small noncleaved-cell lymphoma; 35 (50%) had Eastern Cooperative Oncology Group (ECOG) performance status > or = 2; 24 (34%) had two or more extranodal sites involved; and 17 (24%) had bone marrow involvement. The 8-week regimen included cyclophosphamide, etoposide, doxorubicin, vincristine, bleomycin, methotrexate with leucovorin rescue, and prednisone. RESULTS: Sixty-two of 70 patients completed the regimen as planned. Fifty-seven patients (81%) obtained a complete response (CR) and the actuarial 5-year failure-free survival rate is 52%. Thirty-seven patients remain alive and disease-free a median of 35 months (range, 7 to 68) after therapy. Adverse prognostic factors included age more than 50 years, bone marrow involvement, and serum lactic dehydrogenase (LDH) more than 500 IU/L (normal range, 125 to 250). Myelosuppression was responsible for most of the treatment-related toxicity. Severe leukopenia (< 1,000/microL) occurred in all patients and lasted a median of 9 days. Seven patients (10%) died of myelosuppression-related complications; five of these patients were older than 60 years. CONCLUSION: This brief but intensive therapy was effective in treating poor-prognosis patients with non-Hodgkin's lymphoma. With this therapy, patients with small noncleaved-cell lymphoma or Shipp's category 3 disease had treatment outcome similar to the group as a whole. This therapy was not well tolerated by patients older than 60 years, and should not be given to this subgroup. Verification of these results in a randomized trial setting is indicated.

Peripheral T-cell lymphoma: a clinicopathologic study of 42 cases.

Clinical and histopathologic material from 42 patients with peripheral T-cell lymphoma (PTCL) was reviewed. The median age was 63.5 years (range, 11-97 years). The male:female ratio was 2.8:1. Prior immune or lymphoproliferative diseases occurred in 36% of the patients. PTCL was advanced at presentation with B symptoms (67%), generalized adenopathy (69%), and stage III/IV disease (79%). Suspected lung or pleural involvement (21%), hepatomegaly (29%), and splenomegaly (43%) were common; marrow involvement was documented in 37% of the patients at presentation and in 51% of patients during the illness. Hypercalcemia and eosinophilia occurred in 19% and 29% of patients, respectively. Among patients receiving combination chemotherapy (BCOP, CHOP, BACOP, COMLA), eight (24%) of 33 achieved a complete remission and only four (12%) of 33 had a sustained complete remission. The median survival for PTCL was 11 months. Because of the poor response to standard therapy, clinical trials should identify cases of PTCL and evaluate newer regimens in this subset of aggressive lymphoma.

Effective treatment of small-noncleaved-cell lymphoma with high-intensity, brief-duration chemotherapy.

Small-noncleaved-cell (SNC) lymphoma is a high-grade, biologically aggressive neoplasm notable for poor response to therapy, high relapse rate, and less than a 20% long-term survival. We treated 20 patients with SNC lymphoma with a novel chemotherapeutic regimen using intensive doses of chemotherapy at frequent intervals in the inpatient setting. All patients were previously untreated. Sixteen patients (80%) had stage IV disease. Most patients (95%) had at least one other characteristic associated with poor prognosis (bulky [greater than 10 cm] disease, multiple extranodal sites, poor performance status), and 85% had two or more characteristics associated with poor prognosis. Seventeen patients (85%) achieved a complete response (CR) to therapy, including all three patients with human immunodeficiency virus (HIV)-associated disease. There have been three relapses, all occurring less than 18 months after treatment, and two of three relapses occurred in patients who were unable to complete therapy. At a median follow-up of 29 months, 13 patients (65%) remain disease-free; the calculated 5-year actuarial disease-free survival is 60%. Toxicity, chiefly myelosuppression, was severe but manageable. There were two treatment-related deaths, both in elderly patients with poor performance status and advanced-stage disease. These data suggest that such a dose-intensive approach improves the response and survival of patients with SNC lymphoma.

Clinical features of 31 patients with Ki-1 anaplastic large-cell lymphoma.

Thirty-one patients were diagnosed by morphologic and immunophenotypic features as having primary Ki-1 anaplastic large-cell lymphoma (Ki-1 ALCL). the median age was 35 years (range, 4 months to 78 years); the male:female ratio was 18:13. B symptoms were observed in 13 patients. Peripheral adenopathy was present in 26 patients, while mediastinal adenopathy occurred in five. There was extranodal disease in 13 patients; the most common extranodal site was skin with seven affected. Seventeen patients had stage III/IV disease. Immunophenotypes were T cell in 24 patients and B cell in four patients; immunophenotype could not be determined in three patients. Cytogenetic abnormalities in chromosomes 2, 5, and 7 were detected in three patients. Although therapy was heterogeneous, the actuarial 2-year survival was 73%. Two-year disease-free survival was 39% for all patients; for stages I and II, it was 62% compared with 20% for stages III and IV (P = .001). Complete remission (CR) occurred in 21 of 23 patients receiving combination chemotherapy; however, nine relapses, including six of seven stage IV patients, occurred within 21 months of diagnosis. Preliminary observations suggest that Ki-1 ALCL may have a quiescent phase in the rare patient with only localized skin disease. However, the disease generally behaves as an intermediate- to high-grade lymphoma, and patients with Ki-1 ALCL should receive curative-intent combination chemotherapy.

Large-cell lymphomas: clinical and prognostic features.

We reviewed the clinical and pathologic features in 186 patients with large-cell lymphomas seen at Vanderbilt University Hospital between 1970 and 1986. Ninety-two cases (49%) were large noncleaved-cell lymphoma (LNCCL), 61 cases (33%) were large-cleaved-cell lymphoma (LCCL), 17 cases (9%) were peripheral T-cell lymphoma (PTCL), and 16 cases (9%) were immunoblastic sarcoma of B cells (IBS-B). These subsets of large-cell lymphoma did not differ with respect to median age, distribution by stage, or incidence of bone marrow involvement. Significant differences between groups were noted with regard to male:female ratio, incidence of symptoms, incidence of extranodal disease, and pattern of adenopathy. However, when LCCL was excluded from the analysis, none of these differences were significant. By univariate analysis, age, stage, marrow involvement, extranodal disease, B symptoms, elevated serum lactic dehydrogenase (LDH), and diffuse pattern were unfavorable prognostic features in large-cell lymphoma. However, when cases were stratified by cell of origin, nodular versus diffuse pattern was of no prognostic significance. Nodularity was favorable only because 71% of nodular and nodular-diffuse cases were LCCL, while the majority of diffuse cases were LNCCL. Although IBS-B is considered a "high-grade" lymphoma, we found no evidence for inferior survival in these patients compared with LNCCL or LCCL. In fact, survival was better in IBS-B than in LNCCL or LCCL, although this difference was not significant. However, survival was significantly inferior in PTCL (median, 11 months) compared with the other subsets of large-cell lymphoma (median, 46 months; P = .038, log-rank test). Since the association of PTCL and an inferior survival has most often been noted in the context of "second-generation" chemotherapy, we believe that this association may be therapy-dependent and may be minimized by the use of more aggressive chemotherapy regimens.

Intensive chemotherapy with cyclophosphamide, carmustine, and etoposide followed by autologous bone marrow transplantation for relapsed Hodgkin's disease.

Fifty-six consecutive patients with advanced Hodgkin's disease considered incurable with further conventional chemotherapy were entered into a protocol that included high-dose cyclophosphamide (7.2 g/m2), carmustine (BCNU; 0.6 g/m2), and etoposide (VP16-213; 2.4 g/m2) (CBV) followed by autologous bone marrow transplantation (BMT). Prior combination chemotherapy had failed in all the patients, and all but five had been previously treated with both mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and doxorubicin, bleomycin, and vinblastine with or without dacarbazine (ABV[D]). Thirty-four eligible patients received short-course conventional chemotherapy and/or involved-field radiotherapy before CBV. However, formal restaging was not performed after these conventional therapies; ie, the therapies were not used to select responding patients for transplantation, and all who received such therapy subsequently received CBV and autologous marrow grafts. Forty-four patients (80%; 95% confidence interval [CI], 69% to 91%) achieved a complete response after CBV and BMT. Performance status at protocol entry and the use of conventional cytoreduction therapy before CBV correlated with response. Median follow-up is now 3.5 years (range, 2.5 to 5.0 years). Kaplan-Meier estimates for overall and event-free survival 5 years after transplant are 53% (95% CI, 37% to 67%) and 47% (95% CI, 33% to 60%), respectively. In a univariate analysis, patients with a normal performance status and those without constitutional ("B") symptoms at protocol entry had an improved overall and event-free survival. In a multivariate analysis, only a normal performance status remained significant. Disease progression occurred in 17 patients at an actuarial rate of 39% (95% CI; 26% to 56%) and occurred at previous sites of active disease in all but one patient; our analysis did not identify prognostic factors for progression. Toxic deaths, caused by either neutropenic sepsis or interstitial pneumonitis (IP), occurred in 12 patients (21%; 95% CI, 10% to 32%). CBV with autologous marrow support can produce durable remissions in a substantial number of patients with Hodgkin's disease considered incurable with conventional measures. Regimen refinements may even further improve the therapeutic index of BMT in this malignancy.

High-dose cytarabine and daunorubicin as consolidation therapy for acute myeloid leukemia in first remission: long-term follow-up and results.

In an effort to increase the proportion of patients with acute myeloid leukemia (AML) remaining in continued complete remission (CCR), we administered intensive postremission consolidation therapy with high-dose cytarabine (Ara-C) and daunorubicin. Eighty-seven patients, with a median age of 38 years (range, 7 to 71), received consolidation therapy after first complete remission was obtained with standard induction chemotherapy that included conventional doses of Ara-C. Consolidation therapy consisted of from one to three cycles of high-dose Ara-C (3 g/m2 intravenously [IV] over 1 hour every 12 hours for 12 doses) followed by daunorubicin (30 mg/m2/d IV bolus for 3 days). After completion of the high-dose Ara-C and daunorubicin, no further therapy was administered. Myelosuppression encountered with consolidation resulted in a median duration of neutropenia and thrombocytopenia of 3 weeks. Four patients (5%) died during consolidation due to infection and/or hemorrhage; 59% of patients experienced severe but nonfatal infectious or extramedullary organ toxicity. With a median follow-up of more than 3.5 years from diagnosis, the proportion of patients, by Kaplan-Meier product-limit estimate, remaining in CCR is 49% (95% confidence limits, 37% to 61%). In a Cox multivariate analysis, only age significantly (P less than .001) influenced the probability of remaining in CCR. The probability of remaining in CCR was 83%, 50%, and 23% for age groups of 25 or less, 26 to 45, and more than 45 years, respectively. These survival curves all have stable long-term plateaus, suggesting cure. In this study, the administration of brief, intensive nonmarrow ablative chemotherapy resulted in a large proportion of patients with AML remaining in CCR, results similar to those reported with allogeneic bone marrow transplantation. Relapse of acute leukemia was still the major reason for therapy failure, suggesting that more effective or additional postremission therapy will be required to further improve the likelihood of cure especially for older patients.

Pegfilgrastim after high-dose chemotherapy and autologous peripheral blood stem cell transplant: phase II study.

Pegfilgrastim is equivalent to daily filgrastim after standard dose chemotherapy in decreasing the duration of neutropenia. Daily filgrastim started within 1-4 days after autologous stem cell transplant (ASCT) leads to significant decrease in time to neutrophil engraftment. We undertook a study of pegfilgrastim after high-dose chemotherapy (HDC) and ASCT. In all, 38 patients with multiple myeloma or lymphoma, eligible to undergo HDC and ASCT, were enrolled. Patients received a single dose of 6 mg pegfilgrastim subcutaneously 24 h after ASCT. There were no adverse events secondary to pegfilgrastim. All patients engrafted neutrophils and platelets with a median of 10 and 18 days, respectively. The incidence of febrile neutropenia was 49% (18/37). Neutrophil engraftment results were compared to a historical cohort of patients who received no growth factors or prophylactic filgrastim after ASCT. Time to neutrophil engraftment using pegfilgrastim was comparable to daily filgrastim and was shorter than in a historical group receiving no filgrastim (10 vs 13.7 days, P<0.001). Pegfilgrastim given as a single fixed dose of 6 mg appears to be safe after HDC and ASCT. It accelerates neutrophil engraftment comparable to daily filgrastim after ASCT. Pegfilgrastim may be convenient to use in outpatient transplant units.

High-dose cytosine arabinoside and etoposide: an effective regimen without anthracyclines for refractory childhood acute non-lymphocytic leukemia.

The purpose of this report is to describe the tolerability and activity of the combination of high-dose cytosine arabinoside (Ara-C) given at the maximum tolerated dose of 36 g/m2, together with high doses of etoposide in relapsed and refractory childhood acute leukemias. Eighteen children with relapsed or refractory acute leukemia were treated with Ara-C 3 g/m2 every 12 h on days 1-6, followed by etoposide 400 mg/m2 on days 7-9 (HDAC/VP-16). Eight children with refractory disease received HDAC/VP-16 as salvage induction therapy after failing conventional induction regimens; four of five refractory ANLL patients (80%) had a complete response (CR) after HDAC/VP-16 therapy. Ten patients received HDAC/VP-16 as post-remission intensification therapy; five patients (four ANLL, one relapsed ALL) remain in second CR at 56, 26, 9, 5 and 2 months. Toxicities were primarily hematologic and dermatologic. Seven patients (39%) developed bacterial or fungal infections; four patients developed grade 3 or 4 acral erythema. No patient died of therapy-related toxicity. The combination of 36 g/m2 cytosine arabinoside and 1200 mg/m2 etoposide is an effective regimen for children with relapsed or refractory acute nonlymphocytic leukemia, with tolerable toxicities; the absence of anthracyclines makes this regimen suitable for patients who have previously received maximal doses of anthracyclines or who have evidence of cardiac dysfunction. Further evaluation of this regimen in acute nonlymphocytic leukemia is presently being investigated.

High-dose cytosine arabinoside and daunorubicin as consolidation therapy for acute nonlymphocytic leukemia in first remission: an update.

High-dose (HD) cytosine arabinoside (ara-C) is more effective treatment than conventional-dose ara-C regimens for patients with relapsed acute nonlymphocytic leukemia (ANLL). Previously, we have reported that HD-ara-C administered during the first remission of ANLL has resulted in long remission durations and a high proportion of patients with long-term disease-free survival. In this update, those patients have been observed further and additional patients have been treated, affirming the initial conclusions. Since August 1979, 55 adult patients with ANLL in first remission received one to three courses of HD-ara-C (3 g/m2 by one-hour infusion every 12 hours for 12 doses on days 1 to 6) alone or with daunorubicin (30 mg/m2 for two or three doses on days 7 to 9). Three patients died of sepsis or hemorrhage during consolidation and 19 patients have relapsed from 5 to 48 months after diagnosis. The remaining 33 patients remain in continued complete remission (CCR) from 5 to 75 months. Denoting all deaths in remission as relapse, the actuarial probability of CCR is 51% at 75 months with an apparent plateau in the survival curve. Of the first 22 patients is 27 months. Using univariate and multivariate analysis, age is the only statistically significant prognostic parameter with the actuarial CCR of ages less than 25, 25 to 44, and greater than 44 being 100%, 48%, and 23%, respectively. Due to its heightened antileukemic activity, HD-ara-C allows brief but effective consolidation of ANLL in first remission with long-term disease-free survival comparable with other approaches including bone-marrow transplantation.

Re-treatment of aplastic anemia with antithymocyte globulin or antilymphocyte serum.

Twenty-two patients with aplastic anemia were treated with antilymphocyte serum or antithymocyte globulin at Vanderbilt University and affiliated hospitals from 1980 to 1986. The median age was 42 (eight to 73 years); the male:female ratio was 8:14. Nineteen patients had severe aplastic anemia, and three had moderate disease. Twenty patients received antilymphocyte serum initially while two patients received antithymocyte globulin. Fifteen patients received fluoxymesterone 10 mg by mouth three times a day with antilymphocyte serum, and all received prednisone during the course of antilymphocyte serum or antithymocyte globulin. There were seven responses (31.8 percent) to the first course with four complete responses and three partial responses. Six of 15 patients who received fluoxymesterone showed a response, compared with zero of five treated without androgens (p less than 0.05). Eight patients with no initial response and a patient who experienced a relapse after a complete response were re-treated with either antithymocyte globulin (six) or antilymphocyte serum (three), with four of nine patients (44 percent) having a response (three complete responses, one partial response). Overall, 10 of 22 patients (45 percent) had a response (six complete responses, four partial responses). Median survival for those without a response is six months. Median survival for those with a response has not been reached, with follow-up ranging from 18 to 70 months. This study shows the benefit of a second cycle of antilymphocyte serum or antithymocyte globulin and a possible role for concomitant androgens in this treatment of aplastic anemia.

Lymphocyte-depleted Hodgkin's disease. Clinicopathologic review of 25 patients.

Clinicopathologic material from 25 patients with lymphocyte-depleted Hodgkin's disease was reviewed. The median age of the patients was 57 years. The patients had no prior diagnosis of Hodgkin's disease and were divided according to pathologic subtype of lymphocyte-depleted Hodgkin's disease: 11 diffuse fibrosis, 10 reticular, and four not otherwise specified. The clinical presentation included B symptoms of fever, weight loss, or night sweats (92 percent), subdiaphragmatic disease (88 percent), frequent marrow involvement (56 percent), and advanced-stage disease (100 percent). Four of 11 patients with diffuse fibrosis had peripheral adenopathy as compared with seven of 10 patients with the reticular subtype (p = 0.3); 10 of 11 patients with diffuse fibrosis had marrow involvement compared with two of nine patients with the reticular subtype (p = 0.006). Among patients who received chemotherapy, median survival was longer in the diffuse fibrosis subtype (nine patients, 39 months) than in the reticular subtype (10 patients, 10 months), p = 0.005. Of the 17 patients who received more than one cycle of combination chemotherapy with mechlorethiamine, vincristine, procarbazine, and prednisone, the median survival was 36 months with 11 (65 percent) complete remissions. In eight patients, disease remains in remission (12 to 127 months) with five patients surviving beyond five years. These results indicate that lymphocyte-depleted Hodgkin's disease has at least two clinicopathologic subtypes and is curable if adequate therapy can be given.

Paracortical nodular T-cell lymphoma. Identification of an unusual variant of peripheral T-cell lymphoma.

Peripheral T-cell lymphomas (PTCLs) are regarded as diffuse proliferations. We describe an unusual paracortical nodular growth pattern in four nodal PTCLs that were initially interpreted as atypical lymphoid hyperplasia in three patients and small B-cell lymphoma with plasmacytic differentiation in a fourth. The nodules were vague to easily discernible and produced minimal to partial architectural distortion. Sinuses were often open, and scattered cortical lymphoid follicles with atretic to hyperplastic germinal centers were present. Clusters of tumor cells abutted some follicles in all cases, and in one case they exhibited focal T-zone expansion. Hypervascularity was not prominent, but a few nodules surrounded epithelioid venules, imparting an angiofollicular appearance. The nodules were composed primarily of small lymphocytes with irregular nuclei admixed with scattered large transformed cells, both cell types having clear cytoplasm. Paraffin immunoperoxidase showed that the nodules were composed of T cells. Dendritic cell networks were present only in follicular centers. Southern blot analysis found T-cell receptor gene rearrangements and a germline immunoglobulin gene configuration in all four nodes. These paracortical clear cell nodules of clonal T cells may be a special type of PTCL. Alternatively, they may represent early foci of lymphoma or they may be a subgroup of T-zone lymphoma. Paracortical nodular PTCL must be differentiated from atypical hyperplastic lesions and some B-cell lymphomas.

Splenic marginal zone lymphoma. A distinct B-cell neoplasm.

The splenic marginal zone is a morphologically and perhaps immunologically distinct B-cell compartment. Lymphomas arising from cells of the splenic marginal zone are rare. Here we describe the morphologic, immunologic, and clinical features of 14 cases. Patient age ranged from 35 to 79 years (median, 68 years) with a male-to-female ratio of 1:1.8. The spleen was uniformly enlarged (median, 1,540 g; range, 388-3,845 g) in all patients, the neoplastic infiltrate had a nodular pattern in three cases, nodular and diffuse in seven cases, and diffuse in four cases. The neoplastic cells had small to medium-sized nuclei with round, oval, or slightly indented contours, small eosinophilic nucleoli, and a moderate amount of pale cytoplasm. Extrasplenic involvement was present in 12 patients. Lymph nodes often had a vaguely nodular pattern and preservation of sinuses; bone marrow was infiltrated focally (seven cases) or diffusely (one case). Five patients had hepatic involvement. Ultrastructurally, neoplastic cells differed from other small B cells and resembled normal marginal zone cells by having long, serpentine rough endoplasmic reticulum profiles. All lymphomas marked as B cells and light chain restriction was demonstrated in 12 cases. Bcl-2 protein expression was present in all cases. Most cases (70%) were negative for DBA.44 (CD72). Plasmacytic differentiation was present in three cases. In conclusion, splenic marginal zone lymphoma is a B-cell neoplasm with distinctive clinical, morphologic, immunologic, and ultrastructural characteristics.

Lymphocyte-depletion Hodgkin's disease. Histopathologic diagnosis of marrow involvement.

Lymphocyte-depletion Hodgkin's disease (LDHD) is a rare and often misdiagnosed form of HD. Although marrow involvement is frequent in this disease, most pathologists are not familiar with the marrow lesion of LDHD, since the underlying disease is so unusual. In order to characterize the marrow lesion produced by LDHD, we reviewed biopsies or aspirates from the initial presentation of 22 patients meeting all the clinical and pathologic criteria for LDHD. These included 11 cases of the diffuse fibrosis subtype, eight cases of reticular subtype, and three cases not subclassified. Fifty-four percent of cases, primarily of the diffuse fibrosis subtype, had marrow involvement. Aspirations and biopsies were positive with essentially the same frequency. LDHD produces a characteristic consolidated lesion readily recognized on low-power examination and composed of amorphous, nonbirefringent eosinophilic background material, an inflammatory infiltrate, and Reed-Sternberg (RS) cells. Involvement may be focal and RS cells are generally scarce, requiring examination of multiple sections of well-fixed and stained material. Uninvolved marrow tends to be normocellular and frequently has increased numbers of eosinophils. The original diagnosis of LDHD often may be made from marrow examination alone. Early recognition of marrow involvement is important in facilitating prompt treatment and providing accurate staging without laparotomy.

Transformation of the small cell variant Ki-1+ lymphoma to anaplastic large cell lymphoma: pathologic and clinical features.

The disease spectrum of anaplastic large cell lymphoma (ALCL) includes a biologically aggressive small cell variant (SCV). The SCV may progress to ALCL, but little is known about the transformation process and its significance. The goals of this study were (1) to identify the clinical and pathologic features that characterize ALCL arising in SCV and (2) to determine whether some cases with ALCL histologic appearance at the outset arose from an SCV. Seventeen SCV were reviewed, and four cases (24%) transformed to ALCL as shown by subsequent biopsy. The ALCLs were predominantly monomorphic (3 cases) rather than pleomorphic (1 case). Residual SCV was detected at transformation in 3 of 4 cases. Twenty-one de novo T-cell ALCLs were reviewed for an SCV component; such a component was identified in two ALCLs with monomorphic features, suggesting a preceding SCV phase. There was no change in the immunophenotype between the SCV and ALCL, all marking as EMA+ T cells. Expression of p80 was detected in 3 of 4 (75%) SCV with transformation and 10 of 12 (77%) SCV without transformation. Chromosomal abnormalities involving the sex chromosomes and 6, 7, 9, and 15, in addition to the characteristic t(2;5)(p23;q35), were present in 2 cases at transformation. Times to transformation ranged from 1 to 146 months (mean: 63 months) after diagnosis. Transformation to ALCL signaled a rapid clinical course, with 75% of patients dying in less than a year; one patient remains alive at 15 months. In summary, some ALCLs, particularly those with monomorphic features, arise from an SCV. Transformation to ALCL signals a rapid course, with death occurring in less than a year in most cases. Necrosis in the SCV may be predictive of transformation. Chromosomal abnormalities in addition to the t(2;5)(p23;q35) are present at transformation, suggesting that multiple genetic alterations are involved in disease progression.

T-cell-rich B-cell lymphomas. A clinicopathologic study of 19 cases.

T-cell-rich B-cell lymphomas (TCRBCLs) are recently described, unusual non-Hodgkin's lymphomas that have a diffuse morphology, a predominance of reactive T-cells, and a minority of neoplastic B-cells. The clinical and pathological features of 19 TCRBCLs, all of which demonstrated B-cell clonality, are presented. These lymphomas generally affected older patients by widespread disease and usually were nodal in origin. Treatment varied, but continuous complete remissions (eight patients) were achieved only in those receiving chemotherapy directed at intermediate-grade lymphomas. Although morphologically heterogeneous, all cases resembled peripheral T-cell lymphomas (PTCLs); several TCRBCLs also contained Reed-Sternberg-like cells. Flow cytometry or frozen-section immunoperoxidase failed to detect monotypic immunoglobulin (Ig) in eight of eight cases tested. In contrast, paraffin immunoperoxidase was very useful diagnostically, showing large L26 (CD20-associated) positive cells scattered singly or in small clusters among numerous small T-cells (UCHL1[CD45RO] positive) in all cases. Monotypic cytoplasmic Ig was present in 16 of 19 cases, one of which exhibited plasmacytic differentiation. Southern blot analysis demonstrated relatively faint Ig JH and/or JK bands, indicating a small monoclonal B-cell population in nine of 11 cases, one of which also showed a bcl-2 rearrangement. No T-cell receptor gene rearrangements were observed. These results showed that TCRBCLs may be easily confused with PTCLs or occasionally confused with Hodgkin's disease. TCRBCLs are probably heterogeneous biologically; some cases are of follicular center cell origin. These lymphomas respond to chemotherapy directed at intermediate-grade lymphomas, apparently have a better prognosis than PTCLs, and seem to represent morphological variants of different types of large B-cell lymphomas.