Alpha-2 interferon therapy of hairy-cell leukemia: a multicenter study of 64 patients.

Sixty-four patients with hairy-cell leukemia (HCL) (61 had undergone prior splenectomy) were treated with alpha-2 interferon (Intron A, Schering Corp, Kenilworth, NJ) subcutaneously three times per week at a dosage of 2 X 10(6) U/m2. Three patients (5%) demonstrated a complete response (CR) with apparent eradication of hairy cells from the bone marrow, 45 patients (70%) showed a partial response (PR) defined as normalization of all three blood counts associated with decreased involvement in the bone marrow, and nine patients (14%) showed a minor response that included improvement in at least one blood count. Three patients had no response, three patients died before completing 1 month of therapy, and one patient refused further therapy after 1 month of therapy. The median platelet count returned to normal by the second month of treatment. The median hemoglobin returned to greater than 12 mg/dL by the fourth month of treatment, and the median granulocyte count to greater than 1,500/mu by the fifth month of treatment. Bone marrow biopsy analysis during interferon therapy demonstrated a decrease in median hairy-cell index by more than half. Transfusion of both RBCs and platelets were decreased within 4 months of initiating treatment. Serious infections, which averaged four per month in 16 of the 64 patients before interferon therapy, were rarely observed after the first month of treatment. Treatment-induced toxicity was mild, consisting primarily of influenza-like symptoms, fatigue, and minor skin disorders. Alpha-2 interferon therapy is highly effective in reversing the course of progressive HCL and should be considered the treatment of choice for a minimum of 12 months in patients who have progressive disease post-splenectomy.

Extralymphatic involvement in diffuse non-Hodgkin's lymphoma.

Between 1961 and 1982, 543 patients with diffuse histiocytic, mixed, or undifferentiated lymphoma were treated at Stanford University, Stanford, Calif. Of this group, 281 (52%) had extralymphatic lesions and the 111 patients with stage IE and IIE disease were subjected to analysis. Most patients (94) had diffuse histiocytic lymphoma. Lymphangiography was performed in 77%, bone marrow biopsy in 91%, and diagnostic or staging laparotomy in 52% of the patients. All but five patients were treated with megavoltage irradiation and 35 patients received combination chemotherapy. Median follow-up was 4.0 years. Kaplan-Meier actuarial survival at five and 10 years was 46% and 36%, respectively. Freedom from relapse (FFR) at five years was 49% with no relapses beyond that point. The most common extralymphatic sites were the gastrointestinal tract, the head and neck region, and the lung. Prognosis could not be correlated with the specific sites of involvement. Patients with bulky disease (greater than 10 cm) or more than three sites of involvement had a significantly lower survival and FFR. There was no significant difference in outcome for patients treated with irradiation or combined modality therapy. Most patients (62%) relapsed in distant extralymphatic sites.

Morphological subclassification of follicular lymphoma: variability of diagnoses among hematopathologists, a collaborative study between the Repository Center and Pathology Panel for Lymphoma Clinical Studies.

A collaborative study between the Repository Center for Lymphoma Clinical Studies and the members of the lymphoma pathology subcommittee of the major cooperative oncology groups was undertaken in an effort to ascertain the reproducibility and the interobserver agreement for the cytologic diagnosis of follicular lymphomas. A group of 105 patients with follicular lymphomas were subclassified by seven hematopathologists according to two methods. In the first method, cases were subclassified according to the Rappaport, Lukes, and Collins, and Working Formulation systems. In these systems, follicular lymphomas are subclassified by estimation of the different cell populations without the actual counting of cells. With this method, great variability in diagnosis was noted. For example: (1) The consensus diagnosis was that of poorly differentiated lymphocytic lymphoma (PDL) in 39 cases, but among the individual pathologists the number of cases thus diagnosed ranged from 24 to 65; (2) In 40 cases, the consensus diagnosis was follicular lymphoma, mixed-cell type; however, all seven pathologists independently agreed on this subtype in only one case; (3) A major disagreement was noted in 39 cases (37%), in which both diagnostic extremes (small cleaved and large noncleaved) were expressed. In the second method, only precise counts of different cells were made, according to a modification of the method recommended by Berard. With this counting method, diagnoses were independently derived based on the counts provided by the seven pathologists for large cleaved, small noncleaved, and large noncleaved cells. The variability in the results was wide also with this second method. For example, the average number of large cells found by each pathologist was ascertained, and the ranges were determined. The average range was 28 cells, which was considered high. The same determinations were performed only for large noncleaved cells, and the range was found to be 15 cells, which was also considered high. When the diagnoses derived from counts of only large noncleaved cells were compared with the traditional, more subjective diagnoses, fairly close agreement was obtained. In summary, the great variability in diagnoses of follicular lymphomas among pathologists may be attributed to the difficulties inherent in accurate determination of cell size and of the precise percentages of different cells. Until solutions to these problems are developed, one can subclassify follicular lymphomas according to the Berard method or the estimation method.

Hairy cells and monocytoid B lymphocytes: are they related?

The normal tissue counterpart of hairy cell leukemia is unknown. Because of the morphologic similarities of hairy cells to reactive and lymphomatous monocytoid cells, we compared the phenotypic characteristics of seven spleens involved by hairy cell leukemia with four reactive lymph nodes containing benign monocytoid B cells and three lymph nodes diagnosed as monocytoid B cell lymphoma. The hairy cells had a phenotype of surface Ig+, B1/Leu-14+, Leu-M5+, PCA-1+, Tac+, B2-, BA-1-, BA-2-, J5-, T10-, T11-, Leu-1-, Leu-2a-, Leu-3a-. The immunophenotype of both the reactive and neoplastic monocytoid B lymphocytes was virtually identical to the hairy cells. The major difference was that monocytoid B cells failed to react with anti-Tac and that PCA-1 expression was inconsistent. Despite these variances, the immunophenotypic similarities are remarkable, particularly the common expression of B1/Leu-14 and Leu-M5 (S-HCL3), and suggest a possible lineage relationship between hairy and monocytoid B cells.

Factors predicting for response and survival in adults with advanced non-Hodgkin's lymphoma.

Knowledge of the prognostic factors that characterize a disease can assist in planning and analyzing clinical trials. The present study was conducted to determine the characteristics related to response and survival in patients with stage III and IV non-Hodgkin's lymphoma who were treated with combinations of cyclophosphamide, vincristine sulfate, and prednisone. Considering each characteristic individually and using stepwise regression analysis, tumor bulkiness, prior therapy, sex, and pretreatment lymphocyte count were selected as the four most important prognostic variables. Tumor architecture (diffuse or nodular pattern) and cell type, hemoglobin level, and symptoms although not important in predicting response were found to be important in predicting survival. The hemoglobin level had only marginal importance in predicting response. Factors found not be important were age, stage, symptoms, cell type, nodularity, marrow involvement, prior extensive radiotherapy, and bone involvement. A logistic regression equation has been derived that can be used to predict response rate.

The diagnosis and differential diagnosis of hairy cell leukemia in bone marrow and spleen.

In this study we reviewed the morphologic features of marrow biopsies and aspirates as well as splenic sections derived from 28 patients with hairy cell leukemia. Marrow biopsies proved reliable in establishing and/or confirming the diagnosis in every patient, when available for review. Regardless of the degree of marrow involvement, the hairy cell infiltrates consistently exhibited wide spacing of their nuclei due to relatively abundant pale to clear cytoplasm. Hairy cells appeared homogeneous and bland, without mitotic activity or prominent nucleoli; nuclear contours characteristically were ovoid and to a lesser extent slightly indented or reniform. The splenic histology of hairy cell leukemia was equally distinctive. The splenic red pulp was diffusely infiltrated by a uniform population of cytologically monotonous mononuclear cells that expanded the red pulp cords, filled the sinuses, and generally led to atrophy or obliteration of the white pulp. Moreover, the clear cytoplasm of hairy cells usually was highlighted in sinusoidal blood-filled lakes. Despite the employment of these characteristic morphologic criteria for the diagnosis of hairy cell leukemia in marrow and spleen, these pathologic changes may vary and may be simulated in part by a variety of other hematologic disorders. Accuracy of diagnosis requires not only knowledge of the usual pathologic features of hairy cell leukemia but also knowledge of the unusual. Awareness of these pathologic variations will aid in the improvement of diagnosis and will provide a foundation for understanding the clinical and biologic aspects of hairy cell leukemia.

Surgical pathology of the spleen: an approach to the differential diagnosis of splenic lymphomas and leukemias. Part I. Diseases of the white pulp.

In order to facilitate diagnostic accuracy in the pathologic examination of the spleen, the differential diagnosis of the various splenic lymphomas and leukemias are divided into those diseases which primarily affect the white or red pulp. Enlargement of the splenic white pulp is due to either lymphoid hyperplasia, with or without the formation of germinal centers, or lymphomas and other lymphoproliferative disorders including chronic lymphocytic leukemia. Differentiation depends on recognition of germinal centers and the polymorphous nature of the lymphoid proliferation in reactive conditions, in comparison to the general monomorphous type of white pulp expansion found in the majority of lymphomas and lymphoproliferative disorders. Many of the reactive conditions are associated with a clinical hypersplenic state, while splenic lymphomas and lymphoproliferative disorders are frequently asymptomatic and discovered only at laparotomy. Macroscopic and microscopic evidence of enlargement of the white pulp may be absent in spleens of normal weight that are involved by lymphoma. In that situation, diagnosis requires meticulous examination of the white pulp for the demonstration of cytologic atypia.

Surgical pathology of the spleen: an approach to the differential diagnosis of splenic lymphomas and leukemias. Part II. Diseases of the red pulp.

The diseases which chiefly pertain to the differential diagnosis of splenic lymphomas and leukemias primarily involving the red pulp have been separated into five histologic categories. These include the various forms of congestion, infections, benign and malignant histiocytic proliferations, leukemias and myeloproliferative disorders, and the rare nonhematopoietic tumors of the spleen. Many diseases with major involvement of the red pulp present as hypersplenism of unknown etiology. Accurate diagnosis is particularly dependent on an awareness of the specific histologic manifestations of malignant histiocytosis and the different leukemias in contrast to benign disorders, such as infectious mononucleosis which may simulate malignancy in the splenic red pulp. For each histologic category, therefore, the relevant morphologic features are reviewed, pathophysiologic mechanisms and clinical manifestations correlated, and criteria for differential diagnosis emphasized.

Dermatopathic lymphadenopathy. Comparison of cases associated and unassociated with mycosis fungoides.

Thirty-three biopsies showing dermatopathic lymphadenopathy were obtained from patients with documented cutaneous mycosis fungoides and were studied together with an equal number of dermatopathic lymph nodes derived from patients without evidence of mycosis fungoides. The nodes were evaluated for a variety of histologic features including mitotic figures, immunoblasts, and in particular for the number of atypical cerebriform lymphocytes. Atypical lymphocytes were found to be equally as frequent among both groups of dermatopathic lymph nodes without any statistically significant differences in quantitation or distribution. Similarly, no other morphologic variable was found which would allow an objective distinction of dermatopathic lymphadenopathy from patients with or without mycosis fungoides.

Localized reactive lymphoid hyperplasia of the spleen simulating malignant lymphoma. A report of seven cases.

Since 1976, we have discovered isolated, solitary nodules in seven spleens due to reactive lymphoid hyperplasia. Six cases were encountered at staging laparotomy for malignant lymphoma and one case was observed in a spleen resected because of autoimmune hemolytic anemia. Macroscopically, the nodules were strongly suggestive of splenic involvement by lymphoma; microscopically, however, splenic lymphoma was not demonstrated in any case. In four spleens, the nodules were formed by focal aggregation of reactive germinal centers. In three other cases, the nodules were manifestations of a localized proliferation of lymphocytes, including immunoblasts and plasma cells. The immunoblasts raised the question of splenic involvement by Hodgkin's disease, but Reed-Sternberg cells were not identified. The etiology of localized splenic lymphoid hyperplasia is unknown, but the lesion is likely analogous to florid reactive follicular and diffuse hyperplasia observed in a solitary enlarged lymph node stimulating malignant lymphoma.

Leu-M1 antigen in human neoplasms. An immunohistologic study of 400 cases.

Several studies have shown that the Leu-M1 antigen, a monocyte/granulocyte-related marker, is consistently expressed by the neoplastic cells of patients with Hodgkin's disease (HD). It has been suggested that reactivity of Reed-Sternberg cells with Leu-M1 can be used in support of a morphologic interpretation of HD, and that it is helpful in the differential diagnosis of HD from morphologically similar lesions. To evaluate the significance of the Leu-M1 positivity of Reed-Sternberg cells in the diagnosis of HD, we investigated the distribution of Leu-M1 antigen in a series of patients with HD, non-Hodgkin's lymphomas, and nonhematopoietic neoplasms. We were able to demonstrate the presence of Leu-M1 antigen not only in the majority of patients with HD, but also in 12 of 18 (67%) peripheral T-cell lymphomas, as well as in a variety of nonhematopoietic neoplasms, which included 113 of 199 carcinomas, most of them (58%) adenocarcinomas. Only one of 34 sarcomas showed a focal positive reaction. Leu-M1-related antigen was not detected in any of 18 mesotheliomas, 15 germ cell tumors, 13 melanomas, three schwannomas, or three astrocytomas. Our study indicates that Leu-M1 positivity has no value in supporting the diagnosis of HD in situations where the histologic diagnosis of HD is doubtful. However, since anti-Leu-M1 reacted positively in the majority of adenocarcinomas but was absent in mesotheliomas, melanomas, and most sarcomas, this antigen could serve as a new marker that may be helpful in situations in which carcinoma is a part of the differential diagnosis.

Differentiation of chronic lymphocytic leukemia from Hodgkin's disease using immunologic marker studies.

Four consecutive lymph node biopsies from one patient showed features typical of lymphocyte-pre-dominant Hodgkin's disease. When the patient developed lymphocytosis of the peripheral blood and a staging bone marrow biopsy was found to have nodular lymphoid infiltrates atypical for Hodgkin's disease, the fourth node biopsy was performed in order to perform immunologic marker studies. A monoclonal cell population was identified and the lymph nodes were interpreted as chronic lymphocytic leukemia mimicking lymphocyte-predominant Hodgkin's disease. The diagnostic usefulness of immunologic marker studies stressed.

Lymphoblastic lymphoma expressing natural killer cell-associated antigens: a clinicopathologic study of six cases.

We describe six patients with lymphoblastic lymphoma (LBL) whose neoplastic lymphoid cells expressed surface antigens associated with natural killer (NK) cells. The six cases were selected from a series of 38 specimens diagnosed as LBL based on morphologic criteria and further subclassified by the use of an extensive panel of monoclonal and polyclonal antibodies. Although the morphologic features in all six cases were similar to those previously reported for LBL, their expression of NK-associated antigens was unique. All cases were positive with anti-Leu 11b, an antibody which appears to define a specific subtype of lymphocytes considered to have NK function; and all cases expressed T11, a T-cell-restricted antigen. The most commonly encountered immunophenotype of our cases of LBL was: Leu 11b+, T11+, Leu7+, TdT+, Leu 3a+, Ia+, pre-B-, and B-. As compared with more classical LBL of T-cell type, LBL of NK-cell type in our series occurred primarily in females and non-whites. Whereas treatment of classical LBL by multi-agent chemotherapy may lead to long-term survival, only two of our six patients were long-term survivors. The data derived from this study raise the possibility that LBL with the antigenic phenotype of NK cells may represent a biologic subtype of LBL.

Hemangiopericytoma of the esophagus.

A case of hemangiopericytoma arising in the esophagus is described. The light microscopic features were typical, and ultrastructural examination confirmed the presence of pericyte-like cells and excluded smooth muscle and fibroblastic differentiation. Areas of necrosis and a focus of mitotic activity within the tumor suggested the possibility of an uncertain future course.

Lymphoid hyperplasia and malignant lymphoma occurring in the ocular adnexa (orbit, conjunctiva, and eyelids): a prospective multiparametric analysis of 108 cases during 1977 to 1987.

We performed a prospective multiparametric correlative clinical, histopathologic, and immunologic analysis of 117 ocular adnexal lymphoid proliferations developing in 108 patients between October 1977 and July 1987. The ocular adnexal lymphoid proliferations were distributed among the 108 patients as follows: orbit 69 (64%), conjunctiva 30 (28%), and eyelids nine (8%). The 117 ocular adnexal lymphoid proliferations were classified as follows: polyclonal lymphoid hyperplasia, 32 (22 orbit, nine conjunctiva, one eyelid) (27%); monoclonal B cell lymphoma, 81 (48 orbit, 25 conjunctiva, eight eyelid) (69%); null cell lymphoma, one (orbit) (1%); and histologically indeterminate, three (one each: orbit, conjunctiva, eyelid) (3%). Patients presenting with ocular adnexal polyclonal lymphoid hyperplasia and monoclonal B cell lymphoma, and patients developing unilateral and bilateral ocular adnexal lymphoid proliferations did not differ significantly with respect to age, sex, presenting complaints, duration of symptoms, or ophthalmic findings. Classifying ocular adnexal lymphoid proliferations into benign and malignant categories by histopathologic criteria and into polyclonal and monoclonal B cell categories by immunophenotypic criteria was not useful in predicting eventual outcome, including the occurrence of extraocular lymphoma. However, the clinicopathologic characteristics did differ according to the anatomic site of involvement and histopathology of the ocular adnexal lymphoid proliferations. Lymphoid infiltrates of the conjunctiva were associated with a lower incidence of extra-ocular lymphoma (20%) than were those of the orbit and eyelid, 35% and 67%, respectively (statistically significant, P less than .03). Ocular adnexal small lymphocytic and intermediate lymphocytic lymphomas were less often associated with extra-ocular lymphoma than were ocular adnexal lymphomas of all other histologic types, 27% and 46%, respectively (P less than .09). However, the single most important and statistically significant prognostic factor in these patients was the extent of disease at the time of presentation with an ocular adnexal lymphoid proliferation (P less than .001). Eighty-six percent of patients presenting with a unilateral or bilateral clinical stage lE ocular adnexal lymphoid proliferation, regardless of the histopathology or the immunophenotype, had a benign indolent clinical course and failed to develop ocular or extra-ocular lymphoma during a median follow-up period of 51 months. The results of this study substantially improve our understanding of extranodal small lymphocytic proliferations in general, and those of the ocular adnexa in particular.

Neoplastic B cells with cerebriform nuclei in follicular lymphomas.

Three cases of follicular lymphoma in which the follicular center cells exhibited pronounced nuclear irregularities, i.e., convoluted and cerebriform shapes, are described. The cytoplasm in B5-fixed sections was scanty to abundant and showed pale to clear staining, with interlocking cell borders. Although the architectural pattern in these cases suggested B-cell lymphoma, the cytologic features suggested a T-cell phenotype. Immunologic studies of frozen sections by immunohistochemical techniques in all three cases, as well as cell suspension studies in two cases, showed that the follicular center cells, including those with convoluted and cerebriform nuclei, were clearly monoclonal B cells, as evidenced by the presence of only one immunoglobulin light chain on the surfaces. The results of this study suggest that the follicular architectural pattern is a more reliable predictor of the immunologic phenotype than are the cytologic features.

Monoclonal small (well-differentiated) lymphocytic proliferations of the gastrointestinal tract resembling lymphoid hyperplasia: a neoplasm of uncertain malignant potential.

Three histologically benign-appearing or diagnostically equivocal small lymphocytic proliferations of the gastrointestinal tract were examined by fresh-frozen section immunohistologic techniques. In one case, a dense infiltrate in the small intestine, consisting of small lymphocytes with round nuclei, was limited almost entirely to the mucosa. In another case, a localized colonic polyp was formed by mucosal and submucosal lobules of benign-appearing lymphoid aggregates with centrally located germinal centers. The third case, a penetrating gastric ulcer, was surrounded by histologically hyperplastic lymphoid tissue which included germinal centers. The small lymphocytes in all three cases were strongly positive for B-cell-associated antigens (B1, B2, BA-1), and all exhibited monoclonal light-chain restriction. Even though treatment consisted only of surgical resection of the lesions, no patient has had progressive disease during follow-up periods ranging from 24 to more than 50 months. We believe that the infiltrates in these cases are analogous to the morphologically benign monoclonal small lymphocytic proliferations common to the lung and orbit and that they have an uncertain, but probably low, malignant potential.

Monocytoid B-cell lymphoma in patients with Sjögren's syndrome: a clinicopathologic study of 13 patients.

A recent clinicopathologic study of a series of patients with monocytoid B-cell lymphoma (MBCL) indicated that there is a frequent association between MBCL and Sjögren's syndrome (SS) and raised the possibility of a relationship between these two disease entities. To further investigate the possible relationship of MBCL and SS, we studied pathologic and clinical characteristics of 13 patients with MBCL who had clinically documented SS. In all patients, the lymphoma had the characteristic morphologic features of MBCL, and immunologic and molecular hybridization studies confirmed the B-cell nature of the lymphoma. Twelve of the 13 patients were female, with a median age of 66 years at diagnosis. Eleven had localized disease and presented with either salivary gland or cervical lymph node enlargement; one patient presented with a breast mass, and another with generalized lymphadenopathy and hepatosplenomegaly. In five of 13 patients, the MBCL was associated with or progressed to large cell lymphoma. In two patients, there was bilateral involvement of the parotid gland; one had a synchronous high-grade lymphoma in both parotid glands. In two patients, bone marrow biopsies showed involvement by MBCL. Eleven patients are alive 2 to 55 months after the diagnosis of MBCL. One patient died with the disease 8 months after the initial diagnosis. Another patient died of an unrelated cause without evidence of disease 16 months after the diagnosis of MBCL. We conclude that there is a more than fortuitous association between MBCL and SS. This concept is consistent with previously reported observations of reactive monocytoid B cells in patients with benign lymphoepithelial lesions of salivary glands, which may result from selective homing of reactive monocytoid B lymphocytes to the benign lymphoepithelial lesions and their subsequent neoplastic transformation.

Mitotic counts in follicular lymphomas.

Increased mitotic activity is associated with significantly shorter patient survival in some of the subtypes of diffuse non-Hodgkin's lymphomas. This study on 105 cases of follicular lymphoma was undertaken to determine the clinical significance of mitotic activity in follicular lymphomas. For each case, two pathologists independently counted mitotic figures in 20 random high-power fields. The difference of the average mitotic counts over 20 high-power fields for the two pathologists showed a Gaussian distribution with a median difference of -0.26 counts per high-power field and a standard error of 0.10 per cent. In 94 cases (91 per cent), the difference was less than two mitotic counts per high-power field, indicating good interobserver agreement. There was a statistically significant difference in mitotic counts between subtypes of follicular lymphoma as well as a gradient among subtypes, with the lowest mitotic activity in the poorly differentiated lymphocytic subtype and highest in the undifferentiated subtype. A multivariate statistical analysis of clinical and pathologic variables showed that mitotic figures were not of prognostic significance.

Splenic lymphoid hyperplasias versus lymphomas/leukemias. A diagnostic guide.

An accurate diagnosis of a lymphoid infiltrate in the spleen is based on several essential factors. 1. The spleen must be well fixed and the sections of high technical quality. 2. The pathologist has to be congnizant of the predominant distributional features, whether primarily in the white or in the red pulp, of the various lymphoid infiltrates that result in splenomegaly. 3. A differential diagnostic scheme also should be based on the predominant histologic pattern and cell type. 4. Immunophenotypic and occasionally molecular genetic studies are imperative for refinement and verification of the histologic diagnosis.