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Patients with the nevoid basal cell carcinoma syndrome (NBCCS) are at increased risk for medulloblastomas as well as for basal cell carcinomas. The gene for NBCCS has been mapped to chromosome 9q22.3-q31 by linkage analysis, and loss of heterozygosity (LOH) in this region has been demonstrated in approximately one-half of sporadic basal cell carcinomas. In the present study, LOH for chromosome 9q22.3-q31 microsatellite markers was investigated in medulloblastomas occurring among children with NBCCS and in sporadic medulloblastomas. Histologically, all 3 NBCCS medulloblastomas were noted to have a desmoplastic phenotype, and LOH was detected in both of the 2 cases for which microsatellite markers were heterozygous in normal tissues. LOH was also detected in a subset of sporadic medulloblastomas, each of which were found to display the desmoplastic phenotype. In all, 3 of the 6 sporadic desmoplastic tumors showed LOH, whereas LOH was not seen in any of the 11 sporadic, non-desmoplastic medulloblastomas studied. Additionally, desmoplastic tumors lacking detectable LOH each showed histological features of so-called cerebellar neuroblastoma, a subgroup of desmoplastic medulloblastoma with extensive neuroblastomatous differentiation. The data are consistent with a role for inactivation of a tumor suppressor gene at chromosome 9q in the development of medulloblastomas in patients with NBCCS and of sporadic medulloblastomas characterized by a desmoplastic phenotype similar to that found in patients with NBCCS. Restriction of chromosome 9q loss to non-neuroblastomatous desmoplastic tumors suggests that this variant of medulloblastoma maybe pathogenetically distinct from tumors having other histological phenotypes.

Follicular lymphoma shows a wide geographic variation in incidence, occurring more frequently in the U.S. than in Japan. A translocation involving the bcl-2 gene on chromosome 18 and the immunoglobulin heavy chain gene on chromosome 14 is frequently found in follicular lymphomas and is believed to play a critical role in the pathogenesis of these tumors. Recently, bcl-2/IgH rearrangements have been detected in reactive lymphoid tissue obtained from European patients, indicating that such rearrangements occur at some low but measurable background rate. In non-malignant tissues, the polymerase chain reaction was used to study the frequency of bcl-2/IgH rearrangements in reactive lymphoid tissue obtained from American and Japanese patients to find out whether geographic variation in the incidence of follicular lymphoma was caused by differences in sporadic occurrence of the t(14;18). We found such rearrangements in 5 of 15 American hyperplastic tonsils and lymph nodes and 5 of 10 Japanese tonsils, an incidence close to that previously seen in European patients. These data suggest that the background incidence of such rearrangements is similar in all populations, regardless of the incidence of follicular lymphoma.

A method is described that allows the quantitation of T-cell DNA within a tissue biopsy specimen. This method is based on the densitometric evaluation of the multiband pattern of TCR-gamma gene rearrangements detectable in Southern blot analyses of polyclonal T-cell DNA digested with HindIII. These rearrangements can be detected down to a limit of approximately 5% T-cell DNA. The information derived from this type of analysis can be used to roughly assess the total T-cell content of lesional tissue specimens expressed as a percentage of total tissue DNA, and can be correlated with the pattern of T-cell infiltration visualized by immunohistology. This assessment can be used also to determine the threshold, expressed as a percentage of total lesional T-cell DNA instead of total tissue DNA, required for the detection of a monoclonal T-cell population by Southern blot analysis. These quantitative relationships may prove useful for studying cutaneous T-cell lymphoma and associated precursor conditions.

Ten cases of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) and AILD-like lymphoma were studied by immunophenotypic and immunogenotypic analysis. All specimens were found to have a predominance of T cells by immunophenotypic analysis. DNA hybridization analyses showed three of five specimens of AILD and five of six specimens of AILD-like lymphoma to contain clonal rearrangements of the beta T-cell receptor gene. No rearrangements of the heavy or light chain immunoglobulin genes were seen in any case. A single case showed a progression of AILD with a germ-line pattern of beta T-cell receptor DNA to AILD-like lymphoma with detectable clonal rearrangements for beta T-cell receptor DNA. These results suggest that many, but not all, cases diagnosed histologically as AILD or AILD-like lymphoma contain a clonal proliferation of T-lymphocytes.

Tissue specimens from 21 cases of Hodgkin's disease were examined for the presence of Epstein-Barr virus (EBV) and cytomegalovirus DNA by molecular hybridization techniques. EBV DNA was detected in 4 cases, including 2 of 8 cases which had been previously shown to contain clonal immunoglobulin gene rearrangements. Two of the cases containing EBV DNA were of the nodular sclerosing type and had received prior therapy; the other 2 were classified as mixed cellularity Hodgkin's disease and had not received therapy before the biopsy tissue was obtained. Analyses of the terminal portions of EBV genomes indicated a monoclonal or oligoclonal proliferation of EBV-infected cells in the tissues studied. In contrast, none of the 21 cases had detectable cytomegalovirus DNA sequences. The identification of EBV DNA may reflect the proliferation of lymphoblastoid cells due to the reduced immune competence frequently noted in Hodgkin's disease or may indicate the presence of EBV genomes within Reed-Sternberg cells.

Cutaneous lymphoid hyperplasia (CLH) is a disorder characterized by the development of one or more skin lesions containing dense lymphoid infiltrates that exhibit the histopathologic features of a benign, reactive process. Nevertheless, some cases have been associated with the subsequent development of clinically overt lymphomas. This suggests that monoclonal populations may exist in some cases of CLH and that these cases may represent a subset more likely to evolve into lymphoma. To determine if such a subset of CLH can be distinguished, Southern blot analysis of DNA was used to study the immunogenotypic features of lesions from 14 patients with clinical, histopathologic, and immunopathologic findings characteristic of CLH. Five cases exhibited detectable clonal rearrangements of immunoglobulin genes. Furthermore, one of these five cases evolved into overt diffuse large cell lymphoma of B cell lineage during a 2-year follow-up of recurrent disease at the original cutaneous site. The immunoglobulin gene rearrangements of this lymphoma were identical to those of the prior CLH lesion. There was no evidence of detectable t(14;18) chromosomal translocations or clonal rearrangements of the beta gene of the T cell receptor in any case. It was concluded that CLH can be divided into two subsets based on the presence or absence of a clonal B cell population, and that overt lymphoma can arise from the former subset and contain the same B cell clone identified in the pre-existent CLH lesion.

Patients with the skin disorder pityriasis lichenoides et varioliformis acuta (PLEVA) develop recurrent, self-healing papulonecrotic lesions that contain infiltrates of cytologically and antigenically normal T lymphocytes. DNA extracted from the lesions of 3 patients with PLEVA was analyzed for rearrangement of beta-T-cell receptor genes for the purpose of assessing the clonality of T lymphocytes within the tissues of this disease. Lesions from all 3 cases showed clonal gene rearrangements. In each of 2 cases from which two separate lesions were biopsied, identical rearrangements were found in specimens from both sites. DNA from a variety of inflammatory lesions obtained from patients with other types of skin diseases failed to show detectable rearrangements of beta-T-cell receptor genes. These results suggest that PLEVA represents a T-cell lymphoproliferative process, rather than an inflammatory disorder, as had been previously thought.

The authors describe a set of seven peripheral T-cell lymphomas that lack detectable rearrangements of T-cell receptor (TCR) genes. All cases showed antigenic profiles consistent with T-cell lymphoma, including expression of Leu-5 (CD2) antigen. However, few other T-lineage markers were found, and none of the cases tested (6 of 7) bound antibody recognizing the constant region of the beta TCR protein. Each case showed exclusively germline configurations of DNA for the beta TCR genes in Southern blot analyses with the use of several different combinations of restriction enzymes and DNA hybridization probes. One case contained clonal rearrangements of the gamma TCR gene and of the immunoglobulin heavy chain gene. Our results suggest that certain cases of peripheral T-cell lymphoma may lack rearrangements of TCR genes--particularly those cases expressing restricted numbers of T-lineage antigens. In view of these findings, failure to detect rearrangements of TCR genes by Southern blot analyses is not necessarily inconsistent with malignant lymphocytic proliferations in T-lineage neoplasia.

The authors have analyzed the DNA of immunoglobulin and T-cell receptor genes in a series of 6 malignancies which were judged to be of histiocytic derivation on the basis of morphologic criteria. They found that 4 of these cases showed rearrangements of the beta T-cell receptor genes in spite of the lack of any specific immunohistochemical markers for B or T cells. One case showed rearrangements of both heavy and light chain immunoglobulin genes and probably represents either a sinusoidal large cell lymphoma or a B-cell lymphoma with activation of histiocytes simulating malignant histiocytosis. A single case lacked both immunoglobulin and T-cell receptor rearrangements consistent with immunologic analyses that suggested its origin from an interdigitating reticulum cell. The result of this study in conjunction with the authors' previous immunologic observations suggests that many presumed histiocytic malignancies actually represent T-cell lymphomas. Alternatively, beta T-cell receptor rearrangement may be a common feature of tumors that show monocyte/histiocytic differentiation.