Hun Kim's research while affiliated with University of California and other places

The clinical course of 41 previously reported patients with angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) on whom follow-up information has been obtained for five or more years is described. Of the 41 patients, 27 achieved a complete remission (CR). The durations of the CR ranged from two to 214 months, with a median of 48 months. Nine of these 27 complete responders are still alive and well without evidence of disease, whereas the remaining 18 patients have died of pneumonia, septicemia, immunoblastic lymphoma, or unrelated causes. These 27 patients had a significantly longer median survival (51 mos) than did the 14 patients who had partial or no response (9 mos) (P = 0.0006). Only two of these 14 patients who did not initially achieve a CR are alive (survivals, 66 months and 70 months). There was a trend suggesting that patients who received combination chemotherapy which included prednisone had a slightly longer survival than did the remaining patients (P = 0.087). Lymphocytopenia was evident in a higher proportion of dead patients than in those who remained alive (P = 0.089). Cancer 52:318-321, 1983.

A clinicopathologic analysis of 12 cases of a morphologically distinctive non-Hodgkin's malignant lymphoma which appeared to arise from the mantle zones of secondary lymphoid follicles is presented. In lymph node and spleen sections, atypical small lymphoid cells with slightly irregular and indented nuclear contours proliferated as wide mantles around non-neoplastic-appearing germinal centers. Surface marker analysis performed on lymph nodes revealed a monoclonal B-cell proliferation in two cases. Clinically, the patients usually had advanced disease (Stage III or IV) associated with splenomegaly. This lymphoma appears to be relatively low-grade, since nine of 12 patients are alive with a median follow-up period of 28.5 months. We believe that thie "mantle-zone lymphoma" represents a nodular or follicular variant of intermediate lymphocytic lymphoma.

A retrospective clinicopathologic study of lymphoblastic lymphoma was based on 95 patients from the files of the Repository Center for Lymphoma Clinical Studies. All patients were treated according to different protocols of Cooperative Oncology groups sponsored by the National Cancer Institute. The patients ranged in age from 4 to 84 years, with a median of 30 years. Sixty-eight patients were male and 27 female, with respective median ages of 27 and 50 years. The male-to-female ratio was 2.5:1. Forty patients had mediastinal masses; 30 (75%) of whom were male. The median survival of all patients was 17 months (range 1-100 months). To ascertain the influence of various clinical and morphologic parameters of survival, univariate and multivariate statistical analyses were performed. Patients older than 30 years of age had significantly lower incidences of mediastinal involvement (P = 0.01), number of mitotic figures (P = 0.04), and development of leukemia (P = 0.02) than patients younger than 30. Whereas lymphoblastic lymphoma is generally considered to be a disease of children and young adults, this study indicates that lymphoblastic lymphoma occurs in all age groups. These findings further suggest that lymphoblastic lymphoma may have a different biologic behavior in older patients.

A study was made of 80 patients whose lymph nodes were characterized by the presence of follicles throughout the lymph node. The patients were divided into two groups on the basis of the clinical follow-up information. The first group consisted of 20 patients who were alive and disease-free at the end of five years without therapy. The patients in this group were classified as having florid reactive follicular hyperplasia (FRFH). The second group of 60 patients had progressive, recurrent, clinically active disease and were classified as having follicular lymphoma (FL). Forty-six were dead of active disease, and 14 were alive with disease. Various morphologic parameters were evaluated at low and high magnification, and statistical comparisons were made between FRFH and FL. Although several criteria were helpful in distinguishing FRFH from FL, the single most valuable criterion was the type of pattern encountered. Follicles of variable size and shape lying adjacent to each other throughout the lymph node without or with very little intervening tissue are diagnostic of FL. This pattern was evident in 85% of the FL cases, but was not observed in any of the cases of FRFH.

In order to investigate the natural history of so-called "Lennert's lymphoma" and to reevaluate whether non-Hodgkin's lymphoma with a high content of epithelioid histiocytes represents a clinicopathologic entity, we reviewed the histopathologic and clinical features of 60 patients in whom pretreatment diagnostic tissues had shown a diffuse and florid epithelioid histiocytic reaction identical to that originally described by Lennert and Mestdagh. Our study indicates that so-called "Lennert's lymphoma" is a heterogeneous group of disorders, which, in our series, included Hodgkin's disease (27 patients), non-Hodgkin's lymphoma (24 patients), angioimmunoblastic lymphadenopathy (1 patient), and atypical lymphoepithelioid cell proliferations of uncertain etiology and pathogenesis (8 patients). Most of the patients with Hodgkin's disease had Stage I or II disease without B symptoms, whereas patients with non-Hodgkin's lymphoma usually had Stage III or IV disease, commonly with B symptoms. The median survival was 79 months in the Hodgkin's disease group, compared with 12 months in patients with non-Hodgkin's lymphoma (P less than 0.0001). In patients with atpical lymphoepithelioid cell proliferations, the survival pattern was unpredictable, and the number of patients was too small for a meaningful statistical comparison. Progression to malignant lymphoma in 1 of the 8 patients with atypical lymphoepithelioid cell proliferations, however, underscores the malignant potential of this disorder. One patient with angioimmunoblast lymphadenopathy had generalized disease and constitutional symptoms. In Hodgkin's disease with a prominent epithelioid histiocytic reaction, the gross and microscopic features were similar to those observed in Hodgkin's disease in which this reaction was lacking. In non-Hodgkin's lymphoma, however both the macroscopic and microscopic features differed from those of the usual non-Hodgkin's lymphomas. Moreover, subdivision into poorly differentiated lymphocytic, mixed, and histiocytic types did not reveal any differences in median survival among these subtypes. Non-Hodgkin's lymphoma with a multifocal epithelioid histiocytic reaction previously included in the heterogeneous group called "Lennert's lymphoma" appears to be a distinct clinicopathologic entity.

Using the substrate 2-naphthylthiol acetate (NTA), we developed a reproducible method of demonstrating a non-specific esterase while retaining nuclear and cytoplasmic details at the ultrastructural level. The NTA esterase had a distribution and pattern of staining similar to those of esterases demonstrable at the light microscopic level by the α-naphthyl acetate or naphthol AS-D acetate esterase reaction. The NTA esterase appeared as intensely electron-dense granules of varying size and shape in the cytoplasm. The granules were most abundant in the cells of the histiomonocytic series. The large number of diffusely scattered granules in the cytoplasm of the histiocytes and monocytes made it possible to separate these cells from other haematopoietic elements. There was usually no direct relationship between the NTA esterase positivity and the amount or the location of lysosomes or mitochondria, although in some histoocytes the granules appeared to the associated with lysosomes. The NTA esterase-positive granules were usually more numerous than lysosomes and were located outside the lysosomal granules. Some of the lymphocytes outside the germinal centres and most of the lymphocytes in the blood showed a punctate positivity in the form of 1–4 electron-dense dots. Plasma cells were usually negative but, in rare cases, contained an occasional single dot-like reaction product similar to that in some of the lymphocytes. Granulocytes were always negative. The method described in this paper can be used effectively for identification and study of human haematopoietic cell lines at the ultrastructural level.

Nodular lymphomas and diffuse lymphomas of corresponding cellular composition have been shown to arise from follicular center cells. This paper describes a rare functional and morphological expression of malignant lymphomas arising from follicular center cells, namely, immunoglobulin production, an observation for which no detailed description or analysis is available in the literature. Furthermore, the unusual signet ring-like appearance of the lymphoma cells, which is due to retention of immunoglobulins within the cytoplasm, may result in an erroneous interpretation of metastatic adenocarcinoma or liposarcoma. Therefore, we are presenting a detailed analysis of light microscopic, histochemical, immunocytochemical, and ultrastructural observations. The lymphomas of all seven patients in our series showed nodular growth patterns; in all but one, diffuse areas were also observed. Five of the lymphomas were classified as poorly differentiated lymphocytic type and two as mixed cell type, according to Rappaport's classification. In four of the seven patients, the majority of the neoplastic cells had a clear vacuolated cytoplasm, and in three of these cases, a few of the neoplastic cells showed immunoper-oxidase positivity for monoclonal IgG. This group in particular closely simulated metastatic carcinoma composed of so-called signet ring cells. In the remaining three cases, most of the neoplastic cells contained PAS-positive, Russell body-like monoclonal IgM. Ultrastructurally, the monoclonal IgG appeared as even-sized electron-dense spherules or irregular electron-dense clumps, while the monoclonal IgM appeared as membrane bound, homogeneous, electron-dense material. The implications of these findings and the morphologic features which are helpful in the identification of these lymphomas are discussed.

Detailed pathologic and clinical findings in 19 patients with malignant lymphoma with a high content of epithelioid histiocytes (MLEH) are presented. The essential morphologic features for inclusion in this study comprised a diffuse architectural pattern; obliteration of normal nodal architecture; small, poorly defined clusters of epithelioid cells scattered throughout the stroma; and proliferation of atypical small and large lymphoid cells in varying proportions. Males predominated and the patients' ages ranged from 23 to 75 years, with a median age of 49 years. All patients had cervical adenopathy. Generalized adenopathy and splenomegaly occurred in approximately half. Hepatomegaly was less frequent, but the liver was histologically involved in four of seven patients in whom biopsies were performed. Skin rashes developed in two, but Waldeyer's ring involvement was noted in only one patient. More than half of these patients had „B” symptoms. Staging procedures disclosed that 74% were pathologic Stage IV. In seven surgically staged patients, the histologic features in the initial diagnostic lymph node biopsy were reproduced in the involved tissues at laparotomy. All patients received a variety of single agent and/or combination chemotherapy. Four patients received radiotherapy in addition to chemotherapy. The median survival was 15.6 months. Thirteen patients have died, all with clinical evidence of residual lymphoma. The cause of death in six was infection. In two of the four autopsies, the epithelioid cell component was absent and the microscopic features were indistinguishable from diffuse lymphoma of mixed cell type. While this disorder shares certain clinical and histologic features with Hodgkin's disease and with angioimmunoblastic lymphadenopathy, our observations lead us to the conclusion that MLEH, as defined in this paper, should be considered a variant of a non-Hodgkin's lymphoma and a distinct clinicopathologic entity.

The Lukes and Collins classification is based on the premise that malignant lymphomas (ML) should be classified on the basis of immunologic markers and that the B, T or „undefined” nature of these tumors can be morphologically recognized. The difficulties of achieving this are discussed in this study. The „undefined” type of these investigators posed a particular problem since it appears to be a heterogeneous group which includes ML currently classified as „histiocytic,” lymphoblastic and undifferentiated. The prognosis appeared to be closely related to cytologic types in both the Rappaport and the Lukes and Collins classifications. In the follicular center cell (FCC) lymphomas the overall median survival of patients with follicular lymphomas was longer than that of patients with diffuse lymphoma (p < 0.0001). Extending this comparison to cell types we found longer median survivals of follicular lymphomas in each subgroup but with variable statistical significance. For all cleaved cell lymphoma the p value was 0.02, for the small cleaved cell type 0.16, for the large cleaved cell type 0.09 and for the large noncleaved cell type 0.1. The lymphomas which we identified as being of the diffuse large cleaved FCC type seemed to have a relatively favorable prognosis in comparison to other diffuse large cell lymphomas (p ρ 0.08). However, within this latter group a morphologic separation into large noncleaved FCC, immunoblastic, and true histiocytic seemed difficult. For the purpose of this study, however, we attempted to apply the designation of immunoblastic sarcoma to tumors composed of large lymphoid cells with plasmacytoid features, but found no differences in survival when comparing it with diffuse large noncleaved FCC tumors.

Composite lymphomas (CL), comprising two distinctly different and well-delineated varieties of lymphoma occurring in a single anatomic site or mass, are unusual. This series represents an analysis of 20 patients with such lesions. There were 13 men and 7 women, and the patients' ages varied from 31 to 85 years. In 12 patients, the composite lymphomas consisted of different types of non-Hodgkin's lymphomas, whereas a combination of Hodgkin's disease and non-Hodgkin's lymphoma was observed in the remainder. The most frequent combination (7/20) was that of diffuse histiocytic lymphoma (DH) and nodular, poorly differentiated lymphocytic lymphoma (NLPD), according to the criteria of Rappaport. The composite pattern was present in lymph nodes in 12 patients, spleen in three, retroperitoneum in one, liver in two, and both spleen and lymph nodes in two patients. In 13 patients in whom NLPD was one histologic component, the identical histology was reflected in additional lesions distant from the composite site, in 10. The belated discovery of a composite pattern in one patient emphasized the need for a thorough examination of all the material available when one encounters two different histologic types of lymphoma in different sites. Of 11 patients who died, eight had DH as one component, and in seven of these, death occurred within 20 months after the diagnosis of a composite lymphoma. Clearly, prognosis relates to the recognizably more aggressive component. Nevertheless, recognition of CL at one site is important to account for varying histologic features in widely disseminated lesions.