The monoclonality of human B-cell lymphomas.

Human tissues involved with lymphoma have been examined in frozen sections for immunoglobulin-bearing cells by a technique involving double-label immunofluorescence with mixed anti-kappa and anti-lambda antibodies. F (ab')2 fragments of purified antibodies were employed to avoid any binding via Fc receptors. B cell lymphomas were shown to be composed of monoclonal populations of Ig bearing cells, whereas normal or reactive lymphoid follicles contained a mosaic of Ig-bearing cells derived from multiple clones. Nodules of lymphoma were often surrounded by normal polyclonal B cell populations. We anticipates that the approach described here will be useful in the diagnosis of lymphoma, differentiating it from reactive lymphoid hyperplasia by the demostration of monoclonality. In addition, it should provide a sensitive and reliable tool for investigating the immunobiology of human lymphoma.

Individual tumors of multifocal EB virus-induced malignant lymphomas in tamarins arise from different B-cell clones.

Cotton-top tamarins were inoculated with sufficient Epstein-Barr virus to induce multiple tumors in each animal within 14 to 21 days. The tumors consisted of large-cell lymphomas that contained multiple copies of the Epstein-Barr virus genome and generated Epstein-Barr virus-carrying cell lines showing no detectable consistent chromosomal abnormality. Hybridization of tumor DNA with immunoglobulin gene probes revealed that each lymphoma was oligo- or monoclonal in origin and that individual tumors from the same animal arose from different B-cell clones. Thus the virus induced multiple transformation events in tamarins in vivo to cause malignant tumors resembling the Epstein-Barr virus-associated lymphomas of patients with organ transplants.

Combined modality therapy for adults with small noncleaved cell lymphoma (Burkitt's and non-Burkitt's types).

Between June 1979 and June 1984 18 adult patients with small noncleaved cell lymphoma (SNCL) (diffuse undifferentiated lymphoma, Burkitt's and non-Burkitt's types of the Rappaport classification) were treated with high-dose cyclophosphamide, doxorubicin, vincristine, prednisone, midcycle high-dose methotrexate, and intrathecal methotrexate. Early in the course of treatment, hyperfractionated radiotherapy (125 cGy, every two days, for 1,500 to 2,250 centigray [cGy]) was administered to unresected masses greater than 10 cm in their greatest dimension. Chemotherapy was administered every 21 days for six to ten cycles. Treatment was generally well tolerated; however, one patient died of probable tumor lysis syndrome. With a median follow-up of 1.2 years, actuarial survival was 66.8% and relapse-free survival (RFS) was 71.3% for the entire group. All treatment failures and deaths occurred in patients with stage D disease. RFS projected at 2 years was 100% for stages A and AR and 60.6% for stage B, C, and D (P = .13 Gehan). Two-year RFS for patients with stage A, AR, B, or C disease was 100 v 41% for those with stage D disease. Patients with adverse prognostic features (n = 7)--unresected bulk measuring greater than 10 cm, pretreatment serum lactate dehydrogenase (LDH) 500 IU/L (normal, 200) or involvement of CNS or bone marrow--had a projected RFS of 28.6% compared with 100% for those patients without these features (P = .002 Gehan). Too few patients received induction radiotherapy to assert its role in therapy. By using aggressive multiagent therapy, cure can be expected in a high percentage of adults with SNCL. In the subset with adverse prognostic features, more effective therapy is necessary.

Follicular large-cell lymphoma: intermediate or low grade?

PURPOSE: To evaluate the benefit of anthracycline-based chemotherapy, identify prognostic factors, and determine the value of the International Prognostic Factors Index for patients with follicular large-cell (FLC) lymphoma. PATIENTS AND METHODS: This retrospective study includes 96 patients with FLC lymphoma treated at Stanford University Medical Center between 1969 and 1991. Fifty-five patients received doxorubicin plus cyclophosphamide-containing chemotherapy regimens, 21 patients received other chemotherapy regimens, 15 patients received radiotherapy only, and five patients received no initial therapy. Thirty-four patients had stage I or II disease and 62 patients had stage III or IV disease. RESULTS: With a median follow-up duration of 5.2 years (range, 1 to 18), the actuarial 5- and 10-year overall survival rates were 75% and 54%, with actuarial 5- and 10-year freedom from progression (FFP) rates of 53% and 42%, respectively. Patients treated with chemotherapy regimens that contained both doxorubicin and cyclophosphamide had a superior actuarial 10-year FFP rate (55% v 25%, P = .06) and overall survival rate (65% v 42%, P = .04) compared with patients treated with other chemotherapy regimens. Only one patient treated with doxorubicin plus cyclophosphamide relapsed after 3 years. In the multivariate analysis, discordant lymphoma and treatment with chemotherapy regimens not containing both cyclophosphamide and doxorubicin predicted for worse FFP and overall survival rates. In addition, poor performance status and increasing areas of diffuse histology predicted for a worse survival, while anemia and male sex predicted for a worse FFP. The age-specific International Index was useful in predicting outcome; however, few patients with FLC lymphoma had high-risk features. CONCLUSION: The plateau in FFP implies that patients with FLC lymphoma enjoy sustained remissions after standard anthracycline-based chemotherapy. FLC lymphoma should continue to be approached as an intermediate-grade lymphoma with curative intent.

Similar outcome of treatment of B-cell and T-cell diffuse large-cell lymphomas: the Stanford experience.

Although previous studies have suggested a relatively poor prognosis for some patients with peripheral T-cell lymphoma, the clinical significance of immunologic phenotype in diffuse large-cell lymphoma (DLCL) remains controversial. One hundred one patients with a uniform morphologic diagnosis of DLCL treated at Stanford between 1975 and 1986 with cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), vincristine, and prednisone (CHOP), methotrexate, bleomycin, Adriamycin, cyclophosphamide, vincristine, and dexamethasone ([M]BACOD), or methotrexate, Adriamycin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) chemotherapy were studied with regard to immunologic phenotype. Immunologic analysis, performed on frozen or paraffin-embedded tissue, identified 77 cases of B-cell origin, 21 cases of T-cell origin, and three cases that lacked B-cell or T-cell markers. Analysis of complete remission (CR) rates (84% v 95%), 5-year actuarial freedom from disease progression (38% v 53%), and 5-year actuarial overall survival (52% v 79%) showed no statistically significant differences in prognosis between B- and T-cell patients, respectively. The 5-year actuarial survival of patients with stage IV T-cell DLCL (56%) also did not differ in a statistically significant way from stage IV B-cell patients (36%). We conclude that treatment selection for DLCL should not be based on immunologic phenotype alone.

The neurologic manifestations of sinus histiocytosis with massive lymphadenopathy.

Sinus histiocytosis with massive lymphadenopathy is a benign pseudolymphomatous disease with distinctive microscopic features. Painless cervical adenopathy is the most characteristic clinical finding, although other node groups and extranodal sites may be involved. Of 200 patients in a case registry, 8 had neurologic symptoms. The lesions included vertebral canal and intracranial infiltrates and a destructive vertebral body lesion. Two patients had both cord compression and intracranial disease; one of them died after 10 years of disease. Seven patients were alive 1 to 15 years after disease onset.

Lymphadenopathy as the initial manifestation of histiocytosis X.

Seventeen cases of histiocytosis X presenting as lymphadenopathy, in which the initial diagnosis was based on lymph node biopsy, are reviewed, the characteristic histopathologic findings described, and the differential diagnosis discussed. Clinical evaluation reveals a broad spectrum of associated manifestations varying from solitary eosinophilic granuloma of lymph node to a disseminated Letterer-Siwe-like syndrome. Follow-up confirms the essentially benign nature of this disorder when defined by strict histologic criteria. The implications of these findings on the continuing controversy surrounding histiocytosis X are discussed.

Breast involvement by extranodal Rosai-Dorfman disease: report of seven cases.

Seven cases of breast involvement by extranodal Rosai-Dorfman disease are presented. The patients were women and their ages ranged from 15 to 84 years. Three patients had disease confined to the breast; one had involvement of the breast and ipsilateral axillary lymph nodes, and two had bilateral breast involvement as well as disseminated systemic disease. In all cases the clinical and radiographic presentation of the breast lesion raised the possibility of a malignant tumor. All but one of the lesions were treated by excisional biopsy. Microscopically, the lesions were relatively circumscribed, often multinodular masses, located in the breast stroma, with or without associated involvement of the subcutaneous tissue and dermis. They were composed of sheets of S-100 protein-positive large histiocytes displaying lymphocytophagocytosis, scattered in a polymorphous background of mature lymphocytes and plasma cells. The microscopic differential diagnosis includes idiopathic granulomatous mastitis, infective granulomas, Langerhans' cell histiocytosis, Erdheim-Chester disease, fibrous histiocytoma, and malignant melanoma.

Signet ring cell lymphoma. A rare morphologic and functional expression of nodular (follicular) lymphoma.

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 nanlysis 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 immunoperoxidase 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.

Lymphoid hyperplasia of the gastrointestinal tract. A study of 26 cases and review of the literature.

Based on a study of 26 cases and a review of the literature, lymphoid hyperplasia of the gastrointestinal tract can be categorized into four clinicopathologic groups: focal lymphoid hyperplasia of the stomach, focal lymphoid hyperplasia of the small intestine, focal lymphoid hyperplasia of the rectum, and nodular lymphoid hyperplasia of the gastrointestinal tract. The focal lesions are single, variably circumscribed, and produce thickening of the wall of the affected part of the viscus. While a substantial number of the gastric lesions are associated with chronic peptic ulcers, ulceration is absent or insignificant in focal lesions located in the intestine. The extent of the infiltrate may range from involvement of the mucosa and submucosa only to infiltration of the full thickness of the wall. Nodular lymphoid hyperplasia of the gastrointestinal tract produces multiple discrete mucosal nodules in a variable segment of the small intestine, large intestine, or both. Gastric involvement is rare. The lymphoid infiltrate is confined to the lamina propria and superficial submucosa. Nodular lymphoid hyperplasia is most commonly encountered incidentally during radiologic examination or at autopsy, but it also occurs in association with hypogammaglobulinemia, especially late-onset acquired hypogammaglobulinemia. Lymphoid hyperplasia of the gastrointestinal tract can be distinguished from malignant lymphoma by the polymorphic nature of the infiltrate, the absence of significant cytologic atypia, and the presence of reactive follicles within the lesion.

Necrotizing lymphadenitis. A study of 30 cases.

Thirty patients with necrotizing lymph-adenitis, a disorder initially described in Japan and commonly misdiagnosed as malignant lymphoma, have been studied, in addition, stains for immunologic markers were performed. The patients included 21 United States residents and most commonly were young women with a subacute illness characterized by persistent, painless cervical adenopathy with or without fever. The excised lymph nodes were moderately enlarged and typically showed focal, well-circumscribed, paracortical, necrotizing lesions, and abundant karyorrhectic debris, scattered fibrin deposits, aggregates of large mononuclear cells, and a paucity of plasma cells and neutrophils. Immunohistochemical stains on frozen tissue sections were positive for 63D3 and Leu-2a, indicating an admixture of of histiocytes/macrophages and cytotoxic/suppressor T-lymphocytes in the necrotizing lesions. The etiology of necrotizing lymphadenitis and its distinction from other causes of reactive lymphadenitis are discussed. To our knowledge, this disorder has not previously been reported in the United States.

Differential diagnostic features of nodular L & H Hodgkin's disease, including progressive transformation of germinal centers.

The histologic features in 171 cases of nodular lymphocyte-predominant (L&H) Hodgkin's disease are presented and the association with an abnormal form of follicular hyperplasia termed "progressively transformed germinal centers" (PTGC) by Lennert is discussed. PTGC may closely resemble the nodules of L&H Hodgkin's disease and in 18% of our cases the two processes coexisted in the same lymph node. In addition, two patients had lymph node biopsies showing PTGC prior to biopsies showing nodular L&H Hodgkin's disease and three patients with histologically proved Hodgkin's disease were found to have PTGC in subsequent lymph node biopsies. Immunologic studies on frozen tissue sections from three cases of nodular L&H Hodgkin's disease showed that the neoplastic nodules contained abundant dendritic reticulum cells and B-lymphocytes with scattered T-lymphocytes. These findings suggest that the association between PTGC and nodular L&H Hodgkin's disease is more than coincidental and that this form of Hodgkin's disease preferentially involves B-cell areas of the lymph node, in contrast to the T-zone distribution in other forms of this disorder.

The varied histopathology of lymphadenopathy in the homosexual male.

We review the clinical features and histopathologic changes observed in 69 cases of lymphadenopathy in homosexual men. The most common pattern seen was that of florid reactive follicular hyperplasia (43 cases). A peculiar and distinctive lysis of the germinal centers, a phenomenon we have termed "follicle lysis," was noted in 25 cases. Eighteen of these lymph nodes also contained sinusal collections of "monocytoid" cells and neutrophils and six showed focal dermatopathic changes. Seven cases were characterized by a lymphocyte-depleted pattern with only occasional regressively transformed germinal centers. Nine patients were found to have involvement of their lymph nodes by Kaposi's sarcoma; malignant lymphomas were encountered in 10 patients (eight with Hodgkin's disease and two with non-Hodgkin's lymphomas). Polykaryocytes (multinucleated giant cells) were observed in germinal centers or interfollicular areas within the lymph nodes of four patients. Limited clinical follow-up was available but the lymphocyte-depleted group appeared to have a more aggressive clinical course (three patients in this group developed pneumocystis pneumonia, two had mycobacterial infections and one cutaneous Kaposi's sarcoma). The diverse nature of these findings and the potential for treatment of certain patients (i.e., those with malignant lymphomas and mycobacterial infections) underlines the importance of lymph node biopsy in all cases of unexplained lymphadenopathy in homosexuals and other individuals susceptible to the acquired immunodeficiency syndrome (AIDS). The histopathologic findings may also serve to identify a subgroup of these patients at increased risk to develop more severe AIDS-related complications.

Inflammatory pseudotumor of lymph nodes. Additional observations and evidence for an inflammatory etiology.

Inflammatory pseudotumor of lymph nodes (IPT), a recently described benign cause of lymphadenopathy, was studied in 14 patients using paraffin-section immunohistochemistry. All biopsies showed a proliferation of spindle cells (small blood vessels, histiocytes, and "activated" fibroblasts resembling myofibroblasts) containing a mixture of inflammatory cells without atypia and involving the connective tissue framework (hilum and sinuses) of the lymph node. Ten patients had additional histologic features of IPT originally described (extranodal extension, obliterative vasculitis, and endothelial infiltration), and nine of these had associated fever of unknown origin, which in some was relieved by biopsy alone. Additional features observed focally in some cases but not previously described included lymph node parenchymal infarction, fibrinoid vascular necrosis, karyorrhexis, and involvement of only part of the lymph node. Immunostaining showed the lymphoid infiltrate to be predominantly of T-lineage (except for plasma cells), only a minority of which marked as T-helper cells. Numerous mononuclear cells resembling histiocytes were identified, some of which had a spindled shape but reacted with an antibody (KP1) of myelomonocytic specificity. Large fibroblastic cells expressed alpha-muscle actin but not desmin, similar to myofibroblasts in granulation tissue. The morphologic and immunohistologic features were similar to those in inflammatory pseudotumors of spleens and livers also studied, but the lack of simultaneous lymph node involvement argued against a common etiology. The findings suggest that the mass lesion of IPT is produced in response to localized lymph node inflammation or injury and further exclude hematolymphoid or mesenchymal neoplasia as a cause.

Interfollicular Hodgkin's disease.

An unusual pattern of focal involvement of lymph nodes by Hodgkin's disease is described which we have named "interfollicular Hodgkin's disease." It is characterized by florid reactive follicular hyperplasia which overshadows involvement of the interfollicular zones by Hodgkin's disease. The pattern can be mistakenly diagnosed as one of the many causes of reactive follicular hyperplasia. The seven cases studied did not appear to differ clinically from other more recognizable forms of Hodgkin's disease. The importance of this pattern of lymph node involvement by Hodgkin's disease rests on its misdiagnosis as a benign lesion and not on any unusual clinical features.

T-cell signet-ring cell lymphoma. A histologic, ultrastructural, and immunohistochemical study of two cases.

The histologic, ultrastructural, and immunologic characteristics of two signet-ring cell lymphomas of T-cell derivation are presented. Histologically, both lymphomas were diffuse large cell lymphomas with many neoplastic cells containing cytoplasmic vacuoles imparting a signet-ring configuration. Ultrastructural examination revealed the vacuoles to consist of electron-lucent spaces containing variable numbers of microspherules. Immunohistochemical studies showed that both lymphomas expressed T-cell phenotypes with no reactivity with antibodies to B-cell antigens. In contrast to previous reports which have shown signet-ring cell lymphomas to be invariably B-cell in derivation and usually follicular center cell type, this study demonstrates that these lymphomas may also be of T-cell origin.

Coexistence of nodular lymphocyte predominance Hodgkin's disease and Hodgkin's disease of the usual type.

Recent literature suggests that usual Hodgkin's disease (nodular sclerosing and mixed cellularity types or UHD) and nodular lymphocyte predominance Hodgkin's disease (NLPHD) may be distinct clinical and pathologic entities. Thus, coexistence of NLPHD and UHD in the same patient is expected to be rare. We undertook a review of cases accessioned as NLPHD and UHD in the Laboratory of Surgical Pathology at Stanford University Hospital between January 1980 and May 1992 and found five patients with UHD that predated, followed, or coexisted with lesions histologically typical of NLPHD. All of the patients were male with ages ranging from 10 to 30 years at presentation (median, 22 years; mean, 22.2 years). The sites initially involved by disease were primarily peripheral lymph nodes in the region of the head and neck: cervical (three), supraclavicular (one), submandibular (one). One patient presented with mixed-cellularity Hodgkin's disease (MCHD), two with nodular sclerosis Hodgkin's disease including the cellular phase, one with NLPHD, and the remaining patient presented with a composite malignancy comprising MCHD and NLPHD. Development of the second lymphoma was associated with a somewhat more variable distribution of nodal involvement. The morphologic features in each biopsy specimen resembled either typical NLPHD or UHD, except for one case in which cells with features of both Reed-Sternberg cells and lymphocytic and histiocytes cells were identified. However, the immunophenotypic profiles obtained with a panel of monoclonal antibodies remained distinct for all cases studied. None of the cases showed reactivity with antibodies against the Epstein-Barr-virus latent membrane protein. Thus, NLPHD and UHD maintain a distinct phenotype, even when occurring in the same patient. A second conclusion is that the utility of Leu-7 (CD57) reactivity in distinguishing NLPHD applies to problematic as well as classic cases. Finally, Epstein-Barr virus is not implicated in NLPHD cases associated with UHD.

Langerhans' cell granulomatosis (histiocytosis X) associated with malignant lymphomas.

We present six patients in whom Langerhans' cell granulomatosis (histiocytosis X) was found in lymph nodes also harboring malignant lymphomas: Hodgkin's disease in five and non-Hodgkin's lymphoma in one. This brings to 12 the total number of such reported cases. Whether this represents a chance association of the two processes or a peculiar reaction of Langerhans' cells to the lymphoma is unknown. The focal intimate intermingling of the two processes and the inability to identify LCG as an incidential finding in other cancers suggests that this phenomenon may represent a peculiar reaction to the lymphoma.

Floral variant of follicular lymphoma. Immunological and molecular studies support a neoplastic process.

In recent reports of the so-called "floral variant" of follicular lymphoma, an unusual variant of follicular lymphoma mimicking progressive transformation of germinal centers, questions have been raised regarding whether this process represents a malignant lymphoma. We studied 19 examples of the floral variant of follicular lymphoma and report our light microscopic, immunohistochemical, and molecular diagnostic findings. Morphologic changes consisted of effacement of normal lymph node architecture by follicles composed of atypical lymphocytes. The follicles were surrounded by prominent mantle zones that invaginated irregularly into the follicle centers, often imparting a "floral" appearance. Sufficient material was available for immunophenotypic or genotypic studies in 15 biopsies. Twelve of 15 cases studied by immunohistochemistry demonstrated phenotypes supporting a diagnosis of lymphoma. Five demonstrated light-chain restriction; one was an immunoglobulin-negative B-cell neoplasm; and six, in which only formalin-fixed, paraffin-embedded tissue was available, demonstrated overexpression of the bcl-2 protein. Southern blot analysis revealed evidence of clonal immunoglobulin heavy-chain gene rearrangement in all five cases tested. Overall, 12 of the 15 biopsies studied with these techniques showed immunologic or genotypic support for malignant lymphoma. The results of this study demonstrate that the floral variant of follicular lymphoma does indeed represent a malignant lymphoma.

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.