Thomas L. McCurley

Nodal and extranodal lymphoproliferative disorders in sjogren's syndrome: A clinical and immunopathologic study

Sjogrens syndrome (SS) is frequently associated with both reactive and neoplastic lymphoproliferative disease. Over a 12-year period beginning in 1970, 21 of 138 patients with SS followed at two tertiary university medical centers had biopsies taken of enlarged lymph nodes (18) or extranodal lymphoid infiltrates (8). Many had immunologic studies performed on fresh tissue and all had paraffin-embedded tissue available for histochemical and immunoperoxidase studies. Eight of our patients had malignant lymphomas which were chiefly B cell neoplasms including two lymphoplasmacytic lymphomas and two follicular center cell lymphomas. The remaining 13 patients had either reactive adenitis (usually with follicular hyperplasia) or atypical lymphoid hyperplasia which failed to meet both histopathologic and immunopathologic criteria for malignancy. None of the nine patients with reactive hyperplasia has yet progressed to lymphoma, while one of four patients with atypical lymphoid hyperplasia progressed to overt lymphoma. Clinical features such as age, duration of disease, extent of lymphadenopathy, splenomegaly, or parotid swelling failed to identify those subsets of patients with lymphadenopathy at increased risk for lymphoma. Recognition of lymphoma in two patients was greatly facilitated by tissue immunologic studies demonstrating focal areas of monotypic B cell proliferation. In one patient in whom the histopathologic diagnosis was immunoblastic sarcoma of B cells, tumor cells were L26-negative and strongly UCHL1-positive suggesting T cell differentiation. In three patients with relatively homogeneous extranodal lymphoid infiltrates, B cell polyclonality on tissue immunoperoxidase studies, and the absence of cytologic atypia, precluded a diagnosis of malignant lymphoma; none of these three patients has progressed to overt lymphoma. Our results indicate that (1) patients with SS develop a variety of B cell lymphomas and other lymphoproliferative disorders, and (2) the nature of the lymphoproliferative disorder is best determined by multiparameter analysis including immunologic phenotyping.

Peripheral T-cell Lymphomas: Clinical Features and Prognostic Factors of 92 Cases Defined by the Revised European American Lymphoma Classification

The purpose of this study was to better define the clinical features and natural history of peripheral T-cell lymphomas (PTCL) entities included in the Revised European American lymphoma (REAL) classification. Cases of PTCL were retrieved from the records of the Department of Pathology and classified according to the REAL classification. In addition, cases of anaplastic large cell lymphoma (ALCL) were divided into classical, small cell, and primary cutaneous subtypes, and immunostaining for the anaplastic large-cell kinase (ALK) protein was performed on all cases of ALCL. Clinical features, response to therapy and survival were abstracted. Ninety-two cases of PTCL with adequate clinical information were retrieved. There were 40 cases of ALCL (30 classical, 7 small cell variant, 3 primary cutaneous), 28 PTCL, unspecified, 13 angioimmunoblastic T-cell lymphoma and 11 with other entities. The patients had a median age of 48 years with a range of 6-84 and had an estimated overall survival (OS) of 49% and progression-free survival (PFS) of 22% at 5 years. The International Prognostic Index (IPI) was a significant prognostic factor for both progression-free and OS. Histology was a significant predictor of PFS with anaplastic large cell having the best prognosis. ALK expression was not associated with an improved progression-free or overall-survival in patients with systemic T-cell ALCL. In conclusion, the REAL classification describes distinct PTCL entities. The IPI is the most important predictor of progression-free and OS in patients with PTCL. ALK expression may not provide prognostic information for systemic ALCL.

Fatal Polymyositis in D-Penicillamine-Treated Rheumatoid Arthritis

Thirteen reports of patients who developed polymyositis or dermatomyositis during treatment with D-penicillamine are reviewed and a fourteenth case is described. Twelve of the fourteen patients recovered after D-penicillamine was withdrawn; two patients died from cardiac involvement. Proximal muscle weakness was present in 13 patients and dermatomyositis in 4 patients. Dysphagia was the presenting symptom in 6 patients. Although D-penicillamine is useful in the management of rheumatoid arthritis, this drug should be used with caution and patients monitored closely for evidence of polymyositis or dermatomyositis.

Plasmacytic Differentiation in Parafollicular (Monocytoid) B-cell Lymphoma: A Study of 12 Cases

Parafollicular (or monocytoid) B-cell lymphoma (PBCL) is a recently described low grade lymphoma. The relationship of parafollicular B cells to other B lymphocytes is not known, but the authors observed plasmacytic differentiation in the initial case of PBCL. In this report 12 cases of PBCL were studied by light microscopy and immunophenotypic analysis, and plasmacytic differentiation was found in four cases. This plasmacytic differentiation and the anatomic relationship of the neoplastic cells to reactive follicular centers suggest a functional relationship between these cell types.

Intensified preparative regimens and autologous transplantation in refractory or relapsed intermediate grade non-Hodgkin's lymphoma

Between September 1986 and June 1998, 99 patients with relapsed or refractory IGL received intensified preparative therapy and underwent autologous transplantation at a single institution. Two intensified preparative regimens were used: cyclophosphamide, etoposide, total body irradiation (CY-VP-TBI) (n = 66) and cyclophosphamide, BCNU, etoposide (CBV) (n = 33). As clinical features and results were not different for the two preparative regimens, results were combined. For all patients undergoing autologous transplantation, 5-year actuarial overall survival (OS) was 34% ± 6%; 5-year event-free survival (EFS) was 26% ± 5%. For patients who responded to primary therapy, salvage therapy, or both, OS was 42% ± 7%; for non-responders to prior therapy, OS was 14% ± 7%, P < 0.025. OS was better among patients responding to salvage therapy (50% ± 9%), than among patients who had a complete response to initial therapy, but failed to respond or were untested/unevaluable with respect to salvage therapy (26% ± 10%; P < 0.025). On multivariate analysis, response to salvage therapy was associated with survival following autologous transplantation (P < 0.005). Treatment related mortality was 9% overall and only 6% after G-CSF and GM-CSF were introduced into routine clinical practice. High-intensity preparative therapy is highly effective, with acceptable treatment-related mortality, in patients with IGL who have responded to induction therapy, salvage therapy, or both. The best responses are observed in patients responding to salvage therapy. Randomized prospective studies will be needed to further define the role of intensified preparative regimens. Bone Marrow Transplantation (2000) 25, 257–262.

Detection of clonal immunoglobulin heavy chain gene rearrangements by polymerase chain reaction in scrapings from archival hematoxylin and eosin-stained histologic sections: implications for molecular genetic studies of focal pathologic lesions.

Using a simple scraping technique to obtain DN A directly from archival hematoxylin and eosin-stained slides, we successfully amplified clonal immunoglobulin heavy chain gene rearrangements (IGR) from lymphomatous infiltrates, as small as 1 mm2 The fragments amplified by the polymerase chain reaction (PCR) were identical in size to those from corresponding whole unstained sections freshly cut from the paraffin-embedded blocks. Using this technique, we detected clonal IGR from the scraping of a small lymphomatous nodule in the colon, although no amplified fragments were detected from the whole section. Furthermore, we demonstrated that two morphologically different areas in a case of B-cell lymphoma have identical amplified fragments. It is important that no amplified fragments were detected in scrapings from adjacent nonneoplastic areas. Although DNA recovered from scrapings was partially degraded, fragments as large as 725 base pairs were successfully amplified from a slide stored more than II years. This technique thus allows detection of clonal IGR in tissues focally involved by B-cell lymphoma and molecular genetic studies of focal pathologic lesions as an alternative to in; situ hybridization or in situ PCR. Finally, this technique can be applied to archival slides when tissue blocks are not available.

Leukocytoclastic Vasculitis and Multiple Myeloma

Excerpt To the editor: McMillen and colleagues (1) recently reported the case of a patient with leukocytoclastic vasculitis who subsequently was found to have an IgA-kappa myeloma. Their patient, a...

Pulmonary blastomycosis: Filamentous forms in an immunocompromised patient with fulminating respiratory failure

A 72-year-old woman with Sjögrens syndrome manifested acute fulminating respiratory failure and was treated with high-dose corticosteroids. Autopsy revealed overwhelming pulmonary infection by Blastomyces dermatitidis with no evidence of extrapulmonary dissemination. Hyphal forms, usually not observed in vivo, were noted in premortem sputum samples as well as in sections of lung obtained at autopsy. It is proposed that the immunocompromised state of the patient played a pathogenetic role in the fulminating clinical course as well as in the production of filamentous forms of B. dermatitidis.

Detection of Trypanosoma cruzi DNA within murine cardiac tissue sections by in situ polymerase chain reaction

The use of in situ techniques to detect DNA and RNA sequences has proven to be an invaluable technique with paraffin-embedded tissue. Advances in non-radioactive detection systems have further made these procedures shorter and safer. We report the detection of Trypanosoma cruzi, the causative agent of Chagas disease, via indirect and direct in situ polymerace chain reaction within paraffin-embedded murine cardiac tissue sections. The presence of three T. cruzi specific DNA sequences were evaluated: a 122 base pair (bp) sequence localized within the minicircle network, a 188 bp satellite nuclear repetitive sequence and a 177 bp sequence that codes for a flagellar protein. In situ hybridization alone was sensitive enough to detect all three T. cruzi specific DNA sequences.

Fatal Hemophagocytic Lymphohistiocytosis Associated with Epstein-Barr Virus Infection in a Patient with a Novel Mutation in the Signaling Lymphocytic Activation Molecule—Associated Protein

Individuals with X-linked lymphoproliferative disease are susceptible to severe Epstein-Barr virus (EBV) infections that are often fatal. Mutations in signaling lymphocytic activation molecule-associated protein (SAP) are associated with this illness. We describe a patient with a novel serine-to-proline mutation at aa 57 in SAP and compare the location of the altered amino acid with all known missense mutations in the SAP-encoding SH2D1A gene, including those of 4 additional individuals whose cases have not been described elsewhere. The patients genetic condition was discovered only after he exhibited an abnormal host response to primary EBV infection that resulted in hemophagocytic lymphohistiocytosis syndrome, which was complicated by marrow aplasia with terminal disseminated aspergillosis.