Faculty Bibliography

We report on a patient with systemic mastocytosis with an activating point mutation of the c-kit gene. This mutation was identical to the c-kit mutation recently described by other groups. Additionally, we found that in this patient the mutation was also present in myeloid and erythroid lineages, indicating a multilineage involvement and suggesting a clonal origin of the disease similar to that described in other myeloproliferative disorders. The erythroid involvement was further demonstrated by the presence of erythropoietin-'independent' erythroid progenitor cells

Large-cell variants are uncommon in mantle cell lymphoma (MCL). Here we describe the pathologic and clinical findings in five patients with large-cell lymphoma related to MCL (L-MCL), and compare them to a group of classic small-cell MCL (s-MCL) cases. Histologically, the MC origin of the large cells was evinced by their association with a small mantle cell component in the same tissue, or their distribution in a classic mantle zone pattern, or their development in a patient with previous s-MCL. The large cells were either pleomorphic mantle cells (case 1) or transformed blast-like cells (case 2-5). The median nuclear diameter, median nuclear area and proliferation index of L-MCLs and s-MCLs, were statistically different. Immunophenotypic characterization of four specimens of L-MCL and 10 of s-MCLs with a large panel of antibodies showed the classic findings of MCL, i.e. the IgM+ D+/-, CD5+, CD10-, CD23- phenotype in all cases except two (one CD5- and one CD23+), and the association with a loose follicular dendritic cell network. Two of four L-MCLs and 5/10 s-MCLs demonstrated rearrangements of the bcl-1 gene by Southern blot or by polymerase chain reaction (PCR); 2/4 L-MCLs and 1/9 s-MCLs had p53 mutations on single-strand conformation polymorphism analysis; none of the 14 specimens showed rearrangement of bcl-2 by PCR or bcl-6 and c-myc by Southern blot. All patients with 'transformed' histology (versus 37% of all others) died of lymphoma; their survival (15-18 months; median 17) was much shorter than that of all the others (28-117+ months; median 43) (P=0.0035). All three patients with p53 anomalies, two of whom had tumours with transformed histology, died of their disease in a short time (15, 18 and 28 months). In contrast, the presence of bcl-1 rearrangements did not have prognostic implications. This study documents the existence of large-cell variants of MCL and the poor prognosis associated with the 'transformed' cytologic type and/or p53 abnormalities

Sinus histiocytosis with massive lymphadenopathy (SHML) is a rare benign disease of unknown etiology. It is rarely associated with malignant lymphoma. This report documents the first case of a T-cell lymphoma, which developed in a patient with a 10-year history of SHML. The disease was complicated by hypereosinophilia and massive retroperitoneal lymphadenopathy. Histological examination of a cervical lymph node biopsy during the terminal phase identified a lymphoma composed of cells with morphological plasmacytoid features. Ultrastructurally, the tumor cells showed poorly developed cytoplasm, nuclei with peripheral chromatin clumping, and inconspicuous nucleoli. Cytogenetic studies showed two related clones. On immunohistochemical staining tumor cells were positive with monoclonal antibodies (mAb) CD3 and CD45RO. Southern blotting analysis identified clonal rearrangements in the T-cell receptor (TCR) alpha, beta and gamma genes. Thus, T-cell lineage of the tumor cells was established. In situ hybridization of interleukin-2 (IL-2) and interleukin-5 (IL-5) cDNA probes on tissue sections identified the synthesis of IL-5 by the eosinophils, suggesting an autocrine pathway of eosinophilopoiesis leading to hypereosinophilia in this patient

BACKGROUND--The full spectrum of bullous diseases associated with underlying cancers remains to be fully defined. OBSERVATION--We describe a patient with a mixed bullous disease exhibiting combined features of cicatricial pemphigoid and pemphigus and associated with a B-cell lymphoma producing an IgM paraprotein to intercellular antigens in human skin. The patient had the clinical features of cicatricial pemphigoid and the histologic and immunofluorescence abnormalities of both cicatricial pemphigoid and pemphigus. These included oral and cutaneous erosions; ocular scarring; subbasal and acantholytic intraepidermal bullae; and circulating and tissue-fixed basement membrane zone and intercellular antibodies. The antibodies were directed to a 140-kd antigen in dermal extracts of skin split with 1 mol/L of sodium chloride and to antigens with approximate molecular weights of 150, 180, 230, and 285 kd in the dermal extract. In contrast to paraneoplastic pemphigus, the intercellular antibodies did not react to mammalian bladder. The intercellular antibodies were of the IgM class and were associated with the paraprotein produced by the malignant B cells. CONCLUSIONS--We believe that this condition represents a novel bullous disease, which we refer to as paraneoplastic mixed bullous disease. This condition illustrates that distinct bullous diseases are associated with paraneoplastic syndromes and that at least one possible mechanism for such eruptions is the production of anti-skin antibodies by malignant B cells

Immunophenotypic evaluations of the bone marrow (BM) are reported on 69 aspirates from 58 patients who had non-Hodgkin's lymphoma or chronic lymphocytic leukemia involving the BM. Using flow cytometry and immunofluorescence microscopy on density gradient isolated BM mononuclear cells, the neoplasm could be identified and characterized in 59 aspirates (86%) from 49 patients (84%). Using International Working Formulation guidelines the neoplasms were classified on the basis of prior or subsequent histopathology of lymph node, spleen, skin, or other soft tissue site, or by evaluation of peripheral blood in chronic lymphocytic leukemia. In nine cases the lymphoma could not be completely classified according to International Working Formulation guidelines because only BM was available for evaluation. The neoplasm in the BM was identified and characterized immunophenotypically in all 29 cases of chronic lymphocytic leukemia/well-differentiated lymphocytic lymphoma (WDLL) (100%), in 11 of 12 cases of low-grade lymphoma other than WDLL (92%), in 11 of 15 cases of intermediate-grade lymphoma (73%), and in two of four cases of high-grade lymphoma (50%). Six of the nine cases not classified by International Working Formulation guidelines could be characterized immunophenotypically. In 10 cases immunophenotypic studies revealed negative findings, although the concurrent core biopsy specimens were positive. In two cases immunophenotypic studies with positive findings accompanied a negative core biopsy specimen. A panel of immunohistochemical reagents reactive with fixative/paraffin-resistant antigens was used for a retrospective evaluation of the 69 core biopsy specimens. When compared with the immunophenotypic data obtained from the marrow aspirates these results proved to be only moderately reliable in B-lineage neoplasms and unreliable in T-cell neoplasms. Thus, immunophenotyping of aspirated marrow by flow cytometry was found to be the most reliable method for determining the antigenic profiles of BM-based lymphomas

The presence of a monoclonal paraprotein in the serum or urine raises the possibility of myeloma or lymphoma/leukemia. Yet, in a significant proportion of individuals with serum paraproteins, particularly those with low levels of paraprotein, clinical and routine bone marrow evaluation is not diagnostic of an underlying neoplasm. The purpose of this study was to define the pathologic basis for macroglobulinemia in patients whose routine bone marrow biopsies were not diagnostic of a lymphoplasmacytic neoplasm. We used immunofluorescence microscopy and flow cytometry of cell suspensions prepared from aspirated marrow, as well as immunohistochemistry of core biopsies, to perform immunopathologic evaluations of the bone marrow from 16 such patients. Seven individuals without a monoclonal serum paraprotein, who were similarly studied, served as controls. Our data indicate that 13 of the 16 patients with monoclonal serum IgM paraproteins whose routine bone marrow biopsies were normal or showed nondiagnostic changes morphologically had a dispersed monotypic B lineage population of concordant immunoglobulin heavy and light chain type in the bone marrow. The immunophenotype of these cells spanned the range from mature B cell to plasmacytoid B cell to plasma cell. In four of these 13 patients a diagnosis of lymphoplasmacytic lymphoma could be made on the basis of greater than or equal to 20% monoclonal B lineage cells among bone marrow mononuclear cells