Robert J. Lukes

Immunologic characterization of human malignant lymphomas

The immunologic and morphological approach of our recently proposed functional classification of malignant lymphomas based on the T and B cell systems and lymphocyte transformation has been reviewed. Preliminary results of our retrospective morphological studies indicate: 1) Over 70% of non‐Hodgkins lymphomas involve cleaved or noncleaved follicular center cell (FCC) or B cell types. 2) Nodularity is observed only with FCC types and suggest origin in follicular centers as a block or a “switch on” (derepression) in B cell lymphocyte transformation. 3) Lymphomas of “true” histiocytes appear rare and need to be redefined with functional studies since those previously regarded as histiocytic are indistinguishable morphologically from transformed lymphocytes. 4) Lymphomas of large transformed lymphocytes, “immunoblastic sarcoma” of B and T cell types, have been observed to develop in abnormal immune states and senescence and represent a distinctive entity. Ideal characterization of lymphomas using integrated morphological, cytochemical, and immunologic membrane marker studies has been outlined, and preliminary results of this approach provide support for our new proposal.

Non-Hodgkin's lymphoma in 90 homosexual men: relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome

We describe the histologic and clinical features of non-Hodgkins lymphoma diagnosed between January 1980 and December 1983 in 90 homosexual men from San Francisco, Los Angeles, Houston, and New York. The median age was 37 years, with an age distribution identical to that for cases of AIDS reported to the Centers for Disease Control. Sixty-two per cent of the patients had high-grade (aggressive) subtypes of lymphoma, 29 per cent had subtypes of intermediate grade, and 7 per cent had low-grade subtypes. Histologic subtypes and malignant cell phenotypes were consistent with a B-cell origin. All but two men had extranodal lymphoma: central-nervous-system, bone-marrow, bowel, and mucocutaneous sites were most commonly involved. Thirty-five of 66 evaluable men (53 per cent) had complete responses to combination chemotherapy or radiotherapy or both, and thus far, 19 (54 per cent) of them have had a relapse. Mortality and morbidity were closely related to prodromal manifestations; death or illness have occurred in 19 (91 per cent) of the 21 men who presented with AIDS, in 26 (79 per cent) of the 33 who presented with generalized lymphadenopathy, and in 5 (42 per cent) of the 12 who had no prodromal manifestations. Mortality rates analyzed according to histologic grade were higher than currently reported rates in other patient populations. Kaposis sarcoma or severe opportunistic infections characteristic of AIDS developed in 14 of 33 men (42 per cent) who presented with generalized lymphadenopathy and in 3 of 12 (33 per cent) without prodromal manifestations. We conclude that non-Hodgkins lymphoma in members of an AIDS risk group is a serious manifestation of AIDS and the AIDS-related complex.

Immunoblastic Lymphadenopathy a Hyperimmune Entity Resembling Hodgkin's Disease

Immunoblastic lymphadenopathy, although it resembles Hodgkins disease, is a distinct, hyperimmune disorder apparently of the B-cell system. In 32 cases, it was characterized by a morphologic triad: proliferation of arborizing small vessels; prominent immunoblastic proliferations; and amorphous acidophilic interstitial material. Clinically, it is manifested by fever, sweats, weight loss, occasionally a rash, generalized lymphadenopathy and often hepatosplenomegaly. There is a consistent polyclonal hyperglobulinemia and often hemolytic anemia. The course of the disease is usually progressive, with a median survival of 15 months in 18 fatal cases. The cellular proliferation appears benign morphologically in the pretherapy biopsies and in 10 of 12 available autopsy cases. In three cases the process evolved into a lymphoma of immunoblasts, immunoblastic sarcoma. The basic process appears to be a non-neoplastic hyperimmune proliferation of the B-cell system involving an exaggeration of lymphocyte transformation to immunoblasts and plasma cells that may be triggered by a hypersensitivity reaction to therapeutic agents.

Natural history of Hodgkin's disease as related to its pathologic picture

This paper evaluates the significance of the clinical stages and histologic features of Hodgkins disease in 377 U. S. Army cases from World War II with a 15‐ to 18‐year follow‐up. From this study 6 histologic types have emerged: (1) lymphocytic and/or histiocytic (L & H), nodular; (2) lymphocytic and/or histiocytic (L & H), diffuse; (3) nodular sclerosis; (4) mixed; (5) diffuse fibrosis and (6) reticular. There is a definite relationship between histologic types, clinical stages and survival. The L & H types are expressions of lymphocytic proliferation and diffuse fibrosis and reticular types represent lymphocytic depletion while the mixed is intermediate between these extremes. Nodular sclerosis appears to be a regional expression of Hodgkins disease in the mediastinum and is of major prognostic significance in stage I. The histologic types are regarded as expressions of an attempted host response and possibly evidence of the dramatic interplay between the host and the factors responsible for the development of Reed‐Sternberg cells. The authors suggest that the Hodgkins disease process represents the attempted induction of malignant neoplasia and that the evolution of the histologic process is a manifestation of the natural history of the disease.

Development of B-cell lymphoma in homosexual men. Clinical and immunologic findings.

Serious infections, neoplasms, and immunologic abnormalities have been found in homosexual men. We describe the development of malignant lymphoma in six such patients, three of whom had persistent, generalized lymphadenopathy. In biopsies done before the lymphoma developed, the lymphadenopathy was characterized morphologically by a distinctive pattern of B-cell follicular hyperplasia. All lymphomas were of B-lymphocytic origin, including B-cell immunoblastic sarcoma; small noncleaved, Burkitt-like lymphoma; and plasmacytoid lymphocytic lymphoma. Extranodal presentation with B symptoms occurred in five patients. Median age of our patients was 33 years. Three patients had histories of repeated systemic infections. The peripheral blood lymphocyte count was depressed in four, with depression of OKT 4+ (helper phenotype) cell levels and reversal of the T-helper: T-suppressor ratio in all. We conclude that these patients are at risk for the development of abnormalities of the B-lymphocytic system, manifested by abnormal hyper-B-cell response in enlarged reactive lymph nodes and aggressive, extranodal B-cell lymphomas.

Correlation of histopathology with other prognostic indicators in Hodgkin's disease.

The Rye Conference histologic classification of Hodgkins disease has been applied retrospectively to a series of 176 previously untreated cases of Hodgkins disease. Three different pathologists independently and unanimously agreed in two‐thirds of the cases on assignment of cases to one of the four categories: lymphocyte predominance, nodular sclerosis, mixed cellularity, and lymphocyte depletion. The classification was found to be effective in predicting prognosis even within clinical staging groups. Nodular sclerosis emerges as the largest histologic group and has a favorable prognosis. The usual manner of spread in Hodgkins disease was to adjacent lymph node groups. Noncontiguous dissemination, when it occurred, was more than twice as frequent in the mixed cellularity and lymphocyte depletion types, compared to nodular sclerosis. Nodular sclerosis involving lung has shown a favorable prognosis, unlike mixed cellularity. Survival appears to be increased in all histologic categories after intensive wide‐field megavoltage radiotherapy.

Hodgkin's disease in siblings.

An incidence survey of Hodgkins disease in Greater Boston during 1959-1973 detected five sibling pairs under the age of 45. The expected number is 0.7; thus, siblings of young adults with Hodgkins disease have about a sevenfold excess risk of the disease (P = 0.0008). Eight sibling pairs, not in the incidence series, were also identified. Among all 13 pairs, 12 were sex concordant; the number expected is 6.8 (P = 0.01). The literature includes 46 sibling pairs under 45 of which 30 are sex concordant. The expected number is 23.9 (P = 0.05). Combining the present and the literature series suggests that siblings of the same sex as an affected person have a risk of Hodgkins disease double that of siblings of the opposite sex. The sex concordance suggests that the excess Hodgkins disease among siblings of affected persons is due either to inter-personal transmission of an etiologic agent by prolonged or intimate contact or to common-source exposures.

Primary central nervous system lymphoma in homosexual men. Clinical, immunologic, and pathologic features☆

Primary central nervous system lymphoma constitutes one of the criteria for the acquired immune deficiency syndrome (AIDS), yet a paucity of information is currently available regarding the clinical, immunologic, or pathologic features of these patients. Six homosexual men presenting with primary central nervous system lymphoma were evaluated. Five of these patients presented with altered mental status. All lymphomas were intracranial. B cell immunoblastic sarcoma was found in five. Immune phenotyping studies performed in five patients revealed monoclonal lambda light chain in three, whereas one expressed only IgG heavy chain, and one demonstrated another B cell (LN-1) surface antigen. Hypodense, contrast-enhancing lesions were apparent on computed axial tomographic scanning of the brain, in sharp contrast to isodense or hyperdense lesions reported in primary central nervous system lymphomas without underlying immunodeficiency. Immunologic abnormalities in these patients were similar to those in AIDS presenting as Kaposis sarcoma or with opportunistic infections. In spite of therapeutic interventions, survival was short, and only one patient is currently alive.

An immunohistological study of immunoglobulin content of primary central nervous system lymphomas

Paraffin sections of surgical and autopsy material from 24 cases of primary CNS lymphoma were examined for the presence of cytoplasmic immunoglobulin by an immunoperoxidase technique. Definite staining for cytoplasmic immunoglobulin was observed in 13 cases, and in eight of these the pattern of staining was consistent with current concepts of monoclonality. In every case the histological diagnosis of malignant lymphoma was confirmed, and cases were subclassified by both the Lukes‐Collins and the Rappaport classifications. Morphologically 12 of the 24 cases resembled immunoblastic sarcoma occurring outside the CNS. Other cases showed features of follicular center cell lymphoma or plasmacytoid lymphocytic lymphoma. Of those cases with positive immunoglobulin staining of tumor cells, the majority showed some plasmacytoid features. It was concluded that the primary CNS lymphomas resemble their counterparts occurring outside the CNS, and that at least a proportion are derived from the B lymphocyte.

Primary mediastinal lymphoma in adults

The incidence of primary mediastinal lymphoma in adults was investigated in 184 patients with non-Hodgkins lymphoma. This entity was defined as disease within the mediastinum in patients who presented with symptoms due to an enlarging mediastinal mass. Of 184 patients, 17 presented with primary mediastinal lymphoma. All had a diffuse histologic pattern. The most common pathologic type was poorly differentiated lymphocytic lymphoma, diffuse (PDL-D), (11 cases). In nine of these 11 cases the patients had tumors of convoluted lymphocytes. The presentation was rapid in onset, with heart failure, pericarditis, dyspnea and superior vena caval syndrome predominating. Eleven of the 17 were clinical stage I or II, but eight of these had widespread disease on pathologic staging or rapid dissemination soon after diagnosis. In conclusion (1) primary mediastinal lymphoma is always diffuse in histology. (2) The most frequent pathologic type is PDL-D, with convoluted morphology. (3) Compression of vital intra-thoracic structures is common. (4) Although seemingly localized at presentation, this entity usually implies disseminated disease.