John M. Flexner

Malignant lymphoma of peripheral T-lymphocyte origin: immunologic, pathologic, and clinical features in six patients.

In a continuing study of patients with lymphoproliferative diseases, six adult patients were encountered with a distinctive malignant lymphoma of peripheral T‐lymphocyte origin. Cell suspensions from lymph nodes of these patients contained a pleomorphic, cytologically atypical population of lymphocytes, of which an average 58% marked as T cells in the E‐rosette test. The average percent of surface immunoglobulin‐bearing B cells in these suspensions was 6%; they were of polyclonal distribution. Lymph node biopsies revealed a malignant lymphoma with certain characteristic features of the organization of the infiltrate, the morphology of the lymphoid cells, and the nature of non‐lymphoid cellular elements. The average age of the patients was 67 years; they presented with generalized lymphadenopathy, anorexia, and significant loss of weight. Four patients had lung and/or pleural involvement by lymphoma at presentation. The immunologic, pathologic, and clinical features of these patients serve to characterize this recently recognized malignant lymphoma further.

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.

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.

Malignant lymphomas of follicular center cell origin in humans. V. incidence, clinical features, and prognostic implications of transformation of small cleaved cell nodular lymphoma

Seventy‐five cases of small cleaved cell nodular lymphoma (SCC‐N) were reviewed. Thirty‐four cases underwent repeat biopsy a median of 54 months after diagnosis (range, 7–116 months) because of progressive or recurrent disease. Histologic conversion to a transformed (noncleaved) cell lymphoma was found at re‐biopsy in 13 of 34 cases (38%). Neither age, gender, stage, visceral sites of disease, nor symptoms at presentation were predictive of subsequent conversion. Similarly, none of the clinical features analyzed at the time of rebiopsy were predictive of whether the rebiopsy would show stable histology or transformation. Documentation of transformation was of significant prognostic value. Although rebiopsies were performed at the time of progressive disease, survival following re‐biopsy was 37.5 months for patients found to have cleaved cell lymphoma at re‐biopsy, and only 2.5 months for those with transformed cell lymphoma at re‐biopsy. Two of the cases which had immunoglobulin surface markers studied at diagnosis and at transformation, showed retention of heavy and light chain markers. This implies that the change in appearance involves the original neoplastic clone and was not due to a second neoplasm. Development of transformed cell lymphoma is one of the most common features of the aggressive phase of indolent lymphoma. Repeat biopsy in all patients with indolent lymphoma who have relapsing or progressive disease is recommended. Cancer 53:1109‐1114, 1984.

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-Hodgkins 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.

Clinical value of empirical amphotericin B in patients with acute myelogenous leukemia

From August 1977 to October 1978, 23 patients with acute myelogenous leukemia (AML) received induction therapy at Vanderbilt University Hospital. Six patients died of documented fungal infection, predominantly aspergillus pneumonia; the complete remission rate was only 40%. Based on this experience we began using amphotericin B empirically in any AML patient remaining febrile or having recurrent fever after a week of broad spectrum antibiotics. Of 22 patients treated from October 1978 to August 1980, none died of fungal infection during induction therapy; the remission rate increased significantly to 77%. Chemotherapy and supportive care were otherwise unchanged during this period. While the first group was older, the improvement in remission rate was also seen in patients younger than 60 years of age. Since fungal infection may be difficult to document, this study suggests that empirical amphotericin B is reasonable therapy in leukemic patients remaining febrile or having a recurrent fever following a week of broad spectrum antibiotics, if the institution has a high incidence of fungal infections.

Peripheral T-cell Lymphomas: Clinical Features and Prognostic Factors of 92 Cases Defined by the Revised European American Lymphoma Classification

The purpose of this study was to better define the clinical features and natural history of peripheral T-cell lymphomas (PTCL) entities included in the Revised European American lymphoma (REAL) classification. Cases of PTCL were retrieved from the records of the Department of Pathology and classified according to the REAL classification. In addition, cases of anaplastic large cell lymphoma (ALCL) were divided into classical, small cell, and primary cutaneous subtypes, and immunostaining for the anaplastic large-cell kinase (ALK) protein was performed on all cases of ALCL. Clinical features, response to therapy and survival were abstracted. Ninety-two cases of PTCL with adequate clinical information were retrieved. There were 40 cases of ALCL (30 classical, 7 small cell variant, 3 primary cutaneous), 28 PTCL, unspecified, 13 angioimmunoblastic T-cell lymphoma and 11 with other entities. The patients had a median age of 48 years with a range of 6-84 and had an estimated overall survival (OS) of 49% and progression-free survival (PFS) of 22% at 5 years. The International Prognostic Index (IPI) was a significant prognostic factor for both progression-free and OS. Histology was a significant predictor of PFS with anaplastic large cell having the best prognosis. ALK expression was not associated with an improved progression-free or overall-survival in patients with systemic T-cell ALCL. In conclusion, the REAL classification describes distinct PTCL entities. The IPI is the most important predictor of progression-free and OS in patients with PTCL. ALK expression may not provide prognostic information for systemic ALCL.

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 Hodgkins 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.

Malignant lymphomas of follicular center cell origin in man.III. Prognostic Features

Prognostic features were evaluated in 92 patients with follicular center cell (FCC) lymphomas. Cleaved‐cell lymphomas (N = 73) were associated with significantly better survival than transformed cell lymphomas, 58 months vs. 6 months (p < .001). Among the cleaved‐cell group neither age, sex, heavy or light chain surface immunoglobulin, nor bone marrow involvement was a statistically significant prognostic indicator of survival. With stratification by cell of origin, survival in patients with cleaved‐cell lymphoma having a nodular histologic pattern was statistically equivalent to survival in patients having a diffuse histologic pattern (p = .22). FCC lymphomas of small cleaved cells had a better median survival than lymphomas of large cleaved cells (61 months vs. 33 months) but this only approached statistical significance (p = .08). Patients with symptoms had a median survival of 40 months as compared to 72 months in patients asymptomatic at presentation (p = .07). Involvement of lungs, pleura, or gastrointestinal tract, or extensive hepatic involvement was associated with a median survival of 16 months as compared to 63 months in patients in whom these features were absent (p < .001). Classification of lymphomas with respect to imune origin has clinical significance as it allows the identification of patients with B‐cell neoplasms who may have a clinical course similar to that usually associated with nodular lymphomas despite having a diffuse histologic pattern. Although in cleaved FCC lymphomas marrow involvement apparently has no prognostic value, involvement of other stage IV sites has grave prognostic implications; therefore, use of the term stage IV without specification of involved site may be of limited meaning in patients with these lymphomas.

Non-Hodgkin's Lymphoma After Treatment of Hodgkin's Disease: Association with Epstein-Barr Virus

Non-Hodgkins lymphoma occurs infrequently as a late complication of obscure cause after treatment of Hodgkins disease. We investigated the possible role of Epstein-Barr virus in the pathogenesis of such secondary malignancies of B-cell lineage. Two patients, aged 25 and 43 years, developed high-grade non-Hodgkins lymphomas 12 and 8 years after radiation therapy for Hodgkins disease. Serologic profiles in these patients showed evidence of acute and past Epstein-Barr virus infections, respectively. Molecular hybridization analysis showed the presence of multiple cellular equivalents of virus genome in tumor specimens from each patient. Our findings suggest that Epstein-Barr virus may play an integral role in the pathogenesis of non-Hodgkins lymphoma of B-cell lineage that develops after treatment of Hodgkins disease.