German A. Gomez

An autopsy study of 1206 acute and chronic leukemias (1958 to 1982).

Autopsy data on 1,206 children and adult patients with acute myelocytic leukemia (AML) (585), chronic granulocytic leukemia (CGL) (204), acute lymphocytic leukemia (ALL) (308), and chronic lymphocytic leukemia (CLL) (109) obtained from 1958 to 1982 were reviewed. This analysis has shown that, whereas the proportion of patients with residual AML at any anatomic site decreased significantly and uniformly over the entire study period, significant corresponding decreases in patients with CGL and ALL occurred only since 1976 and 1978, respectively. No significant corresponding decreases were noted in patients with CLL at any time. Significant decreases were also noted over time in the rates of extramedullary site involvement by AML, CGL, and ALL. Whereas the lymphoreticular organs, kidneys, adrenals, and pituitary were most often involved at autopsy by CLL, the testes, leptomeninges, dura mater, uterus, large bowel, and pancreas were most often involved by ALL. In general, patients with AML and CGL showed the lowest relative rates of involvement of the various organs by leukemia during the 24‐year period. Whereas patients with AML and ALL showed significant decreases in the rates of involvement of nearly all anatomic sites during the most recent study periods, those with CGL and CLL showed corresponding decreases in only a few organ sites. The lower rates of organ involvement in patients with AML and ALL attest to the more aggressive eradication of leukemic cells by therapeutic regimens in these diseases over time. In particular, the significant decrease in the rate of meningeal involvement by ALL during the most recent period is probably attributable to central nervous system prophylaxis.

Prognostic Importance of Cytogenetic Abnormalities in Patients with Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia is recognized as having a variable prognosis, but its staging has depended exclusively on anatomical sites of involvement and the presence or absence of anemia and thrombocytopenia. The recent availability of techniques permitting cytogenetic analysis of malignant B lymphocytes led us to examine the karyotypic abnormalities in chronic lymphocytic leukemia and to correlate them with clinical stage, progression of disease, and survival. Of 53 patients with metaphases adequate for study who were followed for a minimum of one year, 21 (40 per cent) had abnormal karyotypes, of which trisomy 12 was the most frequent (25 per cent). Abnormal karyotypes were found to be significant correlates of advanced clinical stage (P less than 0.005) and of shortened survival (P less than 0.05). We conclude that cytogenetic analysis provides useful clinical and prognostic information in patients with chronic lymphocytic leukemia.

Bone marrow infiltration patterns and their prognostic significance in chronic lymphocytic leukemia: correlations with clinical, immunologic, phenotypic, and cytogenetic data.

Bone marrow biopsies were prospectively performed on 75 patients with chronic lymphocytic leukemia (CLL). There was a highly significant relationship (p less than 0.002) between clinical stages and bone marrow infiltration patterns. Ten (50%) of 20 patients with diffuse patterns died; the estimated median survival time for these patients was 87 months. In contrast, only six (11%) of 55 patients with nondiffuse patterns died; the estimated median survival time for these patients could not be computed. When both clinical stage and infiltration pattern were evaluated for survival, a highly significant association between clinical stage and survival time was still observed (p less than 0.003) whereas bone marrow infiltration pattern was no longer significant. A significant association was also observed between bone marrow infiltration patterns and absolute lymphocyte counts (p less than 0.0005), Fc-receptor-positive cells (p less than 0.002), 3H-thymidine uptake of leukocytes (p less than 0.01), serum alkaline phosphatase levels (p less than 0.05), monoclonal urinary-free light chain status (p less than 0.05), and cytogenetics of leukemic cells (p less than 0.05). These observations lead to the conclusion that in an overall prognostic evaluation of patients with CLL, although bone marrow histopathology may have no additional value over a well-established clinical staging system, as a whole, it may be of clinically predictive value in disease progression of patients with stage I and II.

Cytogenetic studies in 77 patients with chronic lymphocytic leukemia: correlations with clinical, immunologic, and phenotypic data.

Cytogenetic analyses by G-banding and/or Q-banding techniques of polyclonal B cell mitogen-stimulated peripheral blood lymphocytes in 77 patients with chronic lymphocytic leukemia were carried out in the present study. Adequate metaphases were obtained in 65 patients (84%). Of 29 patients with abnormal karyotypes, ten (34%) had trisomy 12 as the sole abnormality, eight (28%) had trisomy 12 in combination with other karyotypic changes, and the remaining 11 had various karyotypic changes other than trisomy 12. There was a significant relationship between the abnormal karyotype and disease status, clinical stage, lymphocyte count, bone marrow infiltration pattern, monoclonal IgM gammopathy, and urinary monoclonal-free light chain status. Six of seven patients (87%) with trisomy 12 only had stage 0-11 disease, whereas all eight patients with trisomy 12 with other changes had stage III or IV disease (P less than .02). However, of nine patients with other karyotypic changes without trisomy 12, five had stage 0-II and four had stage III or IV disease. These observations suggest that trisomy 12 may be the primary or the earliest karyotypic change in a majority of aneuploid patients with chronic lymphocytic leukemia, and that other karyotypic changes in addition to trisomy 12 may develop as a result of clonal evolution, dedifferentiation, or therapy. Of nine patients in whom autopsy studies were carried out, four were found to have diffuse histiocytic lymphoma or Richters syndrome (three with trisomy 12 in combination with other chromosome changes and one with normal karyotype). Our findings clearly demonstrate that cytogenetic study may be of value in the clinical and prognostic evaluation of patients with chronic lymphocytic leukemia.

Chromosomes and causation of human cancer and leukemia. XXXIV. A case of “hypereosinophilic syndrome” with unusual cytogenetic findings in a chloroma, terminating in blastic transformation and CNS leukemia

A 47‐year‐old white male developed massive hepatosplenomegaly, a pleural effusion, leucocytosis, and a left parasternal mass following a relatively symptomfree persistent hypereosinophilia for about 5 years. Bone marrow aspiration and biopsy and peripheral blood differential showed eosinophilia and a shift to the left with immature cells. A high serum B12 vitamin level and low LAP activity were found. Biopsy of the soft tissue mass revealed a granulocytic sarcoma (chloroma) with a hyperdiploid karyotype (49,XY,+10,+15,+19,3q‐), whereas the bone marrow cells had a normal male karyotype. The patient responded temporarily to chemotherapy but eventually developed CNS leukemia and went on to terminate in a frank blastic phase. This case illustrates hypereosinophilia and a myeloproliferative syndrome characterized by a somewhat indolent chronic course evolving into “eosinophilic leukemia” and granulocytic sarcoma, CNS involvement by leukemic cells and, finally, blastic transformation. It is possible that this case represents a variant of Ph1‐negative CML to which the term “chronic eosinophilic leukemia” could be justifiably applied.

Preferential inhibition by cytarabine of CFU-GM from patients with chronic granulocytic leukemia.

Granulocyte‐macrophage colony‐forming (CFU‐GM) cells from peripheral blood of normal subjects and patients with chronic granulocytic leukemia (CGL) were cultured in soft agar. Drugs under study were added in a liquid overlay 2 days after initiation of cultures, providing prolonged exposure to these agents thereafter. Dose‐dependent inhibition of colony growth was recorded with each of eleven agents examined, and at the higher concentrations tested, colony formation was often completely suppressed. Cytarabine showed selectivity against CFU‐GM from patients in the chronic stage of CGL (P = 0.006); the median 50% inhibitory concentration for 12 such patients was 3.4 ng/ml versus 11.8 ng/ml for 15 healthy subjects. Such selectivity was not found with busulfan, hydroxyurea, mercaptopurine, thioguanine, daunorubicin, vincristine, vinblastine, methotrexate, desacetylmethylcolchicine, and trimethylcolchicinic acid. One other group has also reported a preferential effect of cytarabine against colony‐forming cells from patients with CGL, and this appears to be the only drug for which such selective activity has been recorded to date. Cancer 59:197–202, 1987.

Post‐therapeutic acute malignant myeloproliferative syndrome and acute nonlymphocytic leukemia in non‐Hodgkin's lymphoma correlation with intensity of treatment

In a prospective randomized study of treatment with radiation therapy (RT) or RT + chemotherapy (CT) for patients with non‐Hodgkins lymphoma Stages I‐III, one patient developed an acute malignant myeloproliferative syndrome (AMSS) and four others acute nonlymphocytic leukemia (ANLL). There was correlation between the intensity of treatment and development of this complication: Among patients treated with local radiation with or without chemotherapy no cases of AMMS or ANLL were observed. However, patients treated with total lymphoid irradiation alone (TLI) had an observed to expected ratio of 162. Among patients treated with TLI plus CT this ratio increased to over 1000. The cytogenetic, clinical, and hematologic abnormalities of these patients are discussed.

Treatment of early--stages I and II--nodular, poorly differentiated lymphocytic lymphoma.

Twenty-nine patients with Stages I and II nodular, poorly differentiated lymphocytic lymphoma were treated with radiation therapy or radiation therapy plus chemotherapy. Twenty-two patients with Stage I received radiation to the involved field, the other seven with Stage II received total lymphoid radiation. Complete remission was achieved in all 29. There were no differences in remission duration or survival according to treatment modality. Five of 29 (17%) patients relapsed. No relapses were observed after 5 years. Ten patients died; one patient died of lymphoma, and nine others died in continuous complete remission of various other causes. Sixty-six percent of the patients were alive at 74–160 months (median 118 months). Involved field radiation with or without chemotherapy was well tolerated, producing acceptable toxicity. Substantially more toxicity was observed after total lymphoid irradiation and although cures were also achieved, less toxic treatment programs should be investigated. The low rate of relapse observed in early stages of this lymphoma in this and in other studies is suggestive that cures might be achieved in nearly one-half of the patients presenting in early stage.

Primary prostatic involvement in non-hodgkin lymphoma

We report 3 cases of primary extranodal lymphoma of the prostate, an unusual extranodal presentation rarely diagnosed antemortem. Symptoms of prostatism associated with an enlarged hard prostate with pyuria and hematuria in younger patients should suggest the diagnosis. Urine cytologic examination should aid in the diagnosis of this condition.

Postoperative respiratory complications in patients with Hodgkin's Disease: Relationship to the size of the mediastinal tumor☆

Postoperative respiratory complications were investigated in patients with Hodgkins disease, stages I-III, presenting with a mediastinal mass. By measuring the ratio between the widest diameter of the mediastinal mass and the width of the thorax at T5-6 (mediastinal thoracic ratio, MTR) in a PA chest X-ray, patients were divided into three groups: I: MTR less than 0.35 (41 patients); II: MTR 0.35-0.49 (33 patients); and III: MTR greater than 0.50 (23 patients). Five patients of group II and eight of group III received preoperative radiation therapy (RT) to the mediastinum due to severe clinical or radiological findings associated with the mediastinal mass. No patient of group I received preoperative RT. Without preoperative RT, group III had a significantly higher incidence of respiratory complications (7/15) compared to groups I (7/41) and II (2/28). Respiratory complications were not significantly different after preoperative RT in group III (1/8) compared to that observed in groups I plus II without preoperative RT (9/69).