Marshall E. Kadin

Ki-1 positive large cell lymphoma: a morphologic and immunologic study of 19 cases

In this report, we analyze the clinical, morphologic, and immunologic findings of 19 patients with Ki-1 + large cell lymphoma, a recently described malignant lymphoma which is usually of T-cell phenotype. Most patients in this selected series of 14 children and adolescents and five adults presented with peripheral lymphadenopathy or skin lesions. No patient had bone marrow involvement. Distinctive morphologic features of Ki-1 + large cell lymphoma are tumor cell pleomorphism, sinus infiltration, fibrosis, partial lymph node involvement, sparing of B-cell regions, and a prominent plasma cell infiltrate. Seventy-two percent of cases were of T-cell phenotype; the remaining cases expressed neither B- nor T-cell-specific markers. Virtually all cases were positive for la (HLA-DR), Tac (interleukin-2 receptor), and T9 (transferrin receptor), indicating that this lymphoma is frequently a tumor of activated T-cells. We conclude that a diagnosis of Ki-1 + large cell lymphoma should be considered in any pleomorphic tumor with the features described in this report.

Leukemia of large granular lymphocytes: association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia, and hemolytic anemia

Three patients had leukocytosis of large granular lymphocytes and chronic neutropenia. Clonal chromosomal abnormalities (trisomy 8 and trisomy 14) and lymphocytic infiltration of splenic red pulp, hepatic sinusoids, and bone marrow indicated the neoplastic nature of the large granular lymphocytes. Demonstration of a T3+, T8+, HNK-1 + phenotype and low natural killer cell activity that was augmented by interferon treatment showed the leukemic cells to be immature natural killer cells. Multiple autoantibodies were present and included rheumatoid factor and antinuclear, antineutrophil, antiplatelet, and antierythrocyte antibodies, suggesting a defect of B-cell immunoregulation. In addition, in-vitro studies showed impaired suppression of immunoglobulin biosynthesis by abnormal cells from one patient. Antineutrophil antibodies and absence of direct cell-mediated inhibition of granulocyte-macrophage colony formation supported a humoral immune mechanism for the neutropenia. In these patients the syndrome of splenomegaly, multiple autoantibodies with neutropenia, and lymphocytosis of large granular lymphocytes is due to a neoplastic proliferation of immature natural killer cells.

Hodgkin's Disease, Lymphomatoid Papulosis, and Cutaneous T-Cell Lymphoma Derived from a Common T-Cell Clone

BACKGROUND Lymphomatoid papulosis is a benign cutaneous eruption that in 10 to 20 percent of patients is associated with the development of lymphoma. The atypical cells of lymphomatoid papulosis histologically resemble the malignant cells of cutaneous T-cell lymphoma or the Reed-Sternberg cells of Hodgkins disease. We studied a patient in whom lymphomatoid papulosis developed in 1971, Hodgkins disease in 1975, and cutaneous T-cell lymphoma in 1985, to determine whether these diseases are clonally related. METHODS The T-cell-receptor alpha-chain gene was cloned and sequenced from a cell line derived from the advanced-stage cutaneous T-cell lymphoma, and the polymerase chain reaction was used to search for this rearrangement of the alpha-chain gene in tissues obtained earlier that were affected by Hodgkins disease or lymphomatoid papulosis. RESULTS The tumor-specific rearrangement of the alpha-chain gene was detected in the patients earlier tissues affected by lymphomatoid papulosis and Hodgkins disease, but not in control tissue, including uninvolved tissues from the staging laparotomy for Hodgkins disease. Cytogenetic studies revealed a translocation, t(8;9)(p22;p24), in cutaneous T-cell lymphoma lines and in a dermatopathic lymph node removed two years before the clinical onset of the cutaneous T-cell lymphoma. Immunohistochemical findings were consistent with an activated T-cell phenotype for the atypical cells of lymphomatoid papulosis, the Reed-Sternberg cells of Hodgkins disease, and the malignant cells of the T-cell lymphoma. CONCLUSIONS Lymphomatoid papulosis, Hodgkins disease, and cutaneous T-cell lymphoma can be derived from a single T-cell clone. A t(8;9) genetic translocation may be involved in the pathogenesis of lymphomatoid papulosis or its progression to malignant disease.

A small-cell-predominant variant of primary Ki-1 (CD30)+ T-cell lymphoma

We describe nine patients with a primary Ki-1 (CD30)+ T-cell lymphoma containing numerous, often CD30-negative, small lymphocytes with irregular nuclei and a minor population of large CD30+ tumor cells. All previously described primary Ki-1+ lymphomas have been large-cell neoplasms. In this small-cell variant, the diagnosis of lymphoma was difficult to make because there was a predominance of small lymphocytes and, in some cases, clinical features suggested an inflammatory process. Patients were young (age range 0.3–40 years, median 14 years), and frequently had B symptoms (56%); sites of involvement were predominantly skin (78%) and lymph node (67%). The actuarial 2-year disease-free survival was 14%, and the overall survival was 51%. Two patients had a rapidly fatal course. In all cases histologic sections showed a predominance of small lymphocytes with marked nuclear irregularity and often a perivascular/intravascular distribution of CD30+ large cells. All cases had a T-cell phenotype. In four cases the large and small cells could be compared and had a similar aberrant T-cell phenotype. Large cells were CD30+, but only rare small cells expressed CD30. Cytogenetic studies revealed a t(2;5)(p23;q35) in four of four cases studied. Four patients had numerous large cells on repeat biopsies; two of these developed sheets of large CD30+ cells typical of anaplastic large-cell lymphoma (ALCL). These cases provide further evidence that primary Ki-1+ lymphoma has a morphologic spectrum that includes a small-cell variant. Although very different morphologically from previously described Ki-1+ ALCL, this small-cell variant is clearly part of the disease spectrum on the basis of clinical features, the presence of the t(2;5)(p23;q35), the aberrant T-cell phenotype in the small and large cells, as well as histologic progression seen in several patients.

Erythrophagocytic Tγ Lymphoma

CLINICOPATHOLOGICAL studies suggest that the T-cell lymphomas are heterogeneous with respect to clinical presentation, course, and morphology. Mycosis fungoides and the Sezary syndrome affect the s...

Ligand-independent signaling by overexpressed CD30 drives NF-κB activation in Hodgkin–Reed-Sternberg cells

Overexpression of CD30 and constitutive NF-κB activation characterizes tumor cells of Hodgkins disease (HD), Hodgkin and Reed-Sternberg (H–RS) cells. We report that in H–RS cells overexpression of CD30 leads to self-aggregation, recruitment of TRAF2 and TRAF5, and NF-κB activation, independent of CD30 ligand. CD30 and TRAF proteins co-localized in H–RS cell lines and in lymph nodes of HD. An adenovirus-vector carrying a decoy CD30 lacking the cytoplasmic region or a dominant negative IκBα mutant blocks NF-κB activation, down regulates IL-13 expression and induces apoptosis. Thus, in H–RS cells, ligand-independent activation of CD30 signaling drives NF-κB activation and this leads to constitutive cytokine expression, which provides a molecular basis for HD. Inhibition of NF-κB activation by adenovirus vector-mediated gene transfer may provide a novel strategy of cell- and target molecule-specific therapy for patients with HD.

Cutaneous T cell lymphoma with suppressor/cytotoxic (CD8) phenotype: Identification of rapidly progressive and chronic subtypes

We identified nine patients with cutaneous T cell lymphoma in whom the neoplastic cells expressed the CD8 (T8) suppressor T cell phenotype instead of the more common CD4 (T4) helper T cell phenotype. Five had rapidly progressive disease characterized by distinctive papulonodular skin lesions (four patients), involvement of palms or soles (four patients) or oral cavity (two patients), and poor response to standard topical therapy (four patients). Histologic examination showed extensive epidermotropism often associated with pagetoid features. Immunoperoxidase studies revealed a novel aberrant T cell phenotype characterized by lack of expression of CD4 and CD2 (T11) but positive staining for CD3 (T3) and CD7 (3A1). In contrast, the neoplastic cells from four patients with clinically more chronic CD8+ cutaneous T cell lymphoma, although also commonly epidermotropic, had a different aberrant T cell phenotype similar to that often seen in CD4+ mycosis fungoides; that is, there was lack of expression of CD7 but a positive reaction to staining for CD2. In two cases the tumor cells acquired the CD7 antigen or lost the CD2 antigen with progression of the disease. Two cases were analyzed with Southern blotting and both showed rearranged DNA bands that confirmed the presence of clonal populations of T cells. Our findings suggest the following: (1) CD8+ cutaneous T cell lymphoma can be rapidly progressive or chronic. (2) These two types cannot be reliably distinguished by histologic features. (3) Rapid progression was associated with a CD2-, CD7+ phenotype whereas chronicity was associated with a CD2+, CD7- phenotype.

Burkitt's and Burkitt‐like lymphoma in children and adolescents: a review of the Children's Cancer Group Experience

Summary. Historically, the survival of children and adolescents with Burkitts and Burkitt‐like lymphoma had been poor. Recently, short and intensive chemotherapy appears to have improved disease outcome. We therefore reviewed the results of four successive Childrens Cancer Group trials conducted on 470 children with disseminated Burkitts and Burkitt‐like lymphoma. Of the patients studied, the median age was 8 years (0–21 years), the male:female ratio was 4:1, 58% had lactate dehydrogenase (LDH) ≥ 500 IU/l, 23% had M2 or M3 bone marrow (BM), and 12% demonstrated central nervous system involvement. In a multivariate analysis, the 4‐year event‐free survival (EFS) in patients ≥ 15‐years‐old compared with < 15‐year‐old was 34 ± 7 versus 59 ± 2% (P < 0·05), the 4‐year EFS of M2/M3 compared with M1 BM was 38 ± 5 versus 63 ± 3% (P < 0·001), and the 4‐year EFS with LDH ≥ 500 IU/l compared with LDH < 500 IU/l was 49 ± 3 versus 71 ± 4% (P < 0·001). Furthermore, patients treated on the most recent protocol, which was short and more intensive, had a significantly improved survival compared with those on previous trials (4‐year EFS 80 ± 6 versus 54 ± 2%, P < 0·001). In summary, the outcome for childhood Burkitts and Burkitt‐like lymphoma has recently improved with the use of short and intensive B‐cell non‐Hodgkins lymphoma‐directed therapy.

Methotrexate is effective therapy for lymphomatoid papulosis and other primary cutaneous CD30-positive lymphoproliferative disorders

BACKGROUND The spectrum of primary cutaneous CD30+ lymphoproliferative disease consists of lymphomatoid papulosis (LyP) at one extreme and CD30+ peripheral T-cell lymphoma (Ki-1+ lymphoma) presenting in the skin at the other extreme. Methotrexate has been reported to be effective in LyP, but the experience has been limited to single case reports or small series. OBJECTIVE The objective was to determine the effectiveness of methotrexate in the treatment of primary cutaneous DC30+ lymphoproliferative disease. METHODS We reviewed our 20-year experience with the use of methotrexate in 45 patients with relatively severe LyP, Ki-1+ lymphoma, and interface presentations. RESULTS During induction of methotrexate therapy patients received maximum doses ranging from 10 to 60 mg/week (median, 20 mg/week). Clinical improvement usually occurred quickly, typically at doses of 15 to 20 mg weekly, and satisfactory long-term control was achieved in 39 patients (87%) with maintainance doses given at 10 to 14-day intervals (range, 7 to 28 days). After methotrexate was discontinued, 10 patients remained free of CD30+ lesions from more than 24 months to more than 227 months (median, more than 127 months). The median total duration of methotrexate therapy for all patients exceeded 39 months (range, 2 to 205 months). Adverse effects were generally mild and transient and included fatigue (47%), nausea (22%), weight loss (13%), diarrhea or gastrointestinal cramping (10%), increased serum hepatic transaminase levels (27%), anemia (11%), or leukopenia (9%). Early hepatic fibrosis was found in 5 of 10 patients, all of whom had been treated for more than 3 years (range, 38 to 111 months). CONCLUSION Low-dose methotrexate (25 mg or less given at 1-to 4-week intervals) is an effective and well-tolerated treatment of selected patients with primary cutaneous CD30+ lymphoproliferative disease.

Activity of TNF-related apoptosis-inducing ligand (TRAIL) in haematological malignancies

T‐cell cytotoxicity is primarily mediated by two cell surface proteins, Fas ligand (FasL) and tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL), and intracellular perforin and granzyme granules. FasL‐deficient and perforin‐deficient T lymphocytes maintain cytotoxicity but fail to induce graft‐versus‐host disease (GVHD) when transplanted into mice, suggesting that GVHD and graft‐versus‐tumour (GVT) effects can be dissociated, and that TRAIL is not involved in the pathogenesis of GVHD. Because TRAIL could mediate a favourable GVT effect it became important to study the spectrum of its activity and to investigate factors that can dissociate its expression from FasL. TRAIL induced apoptosis in 11/41 (27%) tumour specimens of haematological origin compared to 16/41 (39%) induced by FasL. Although eight specimens were sensitive to both FasL and TRAIL, no synergism was observed between these two ligands. TRAIL induced apoptosis in a dose and time dependent manner with an ED50 of 0.5 μg/ml and EDmax of 1 μg/ml. TRAIL activity was not reduced by the over‐expression of the multidrug resistant (MDR) protein, and was not enhanced by 9‐cis retinoic acid (RA), which can down‐regulate bcl‐2 protein. Both ligands were simultaneously up‐regulated in normal peripheral blood lymphocytes in response to IL‐2, IL‐15 and anti‐CD3 antibody, whereas IL‐10 had no effect. Together, our data show that (1) TRAIL can mediate cell death in a variety of human haematological malignancies, (2) resistance to TRAIL is not mediated by MDR protein, (3) the lack of synergy between TRAIL and FasL suggests that either one is sufficient to mediate T‐cell cytotoxicity, and (4) within the panel of cytokines tested, the expression of TRAIL and FasL could not be dissociated.