Aromatase activity is absent in normal endometrium. In contrast, aromatase is expressed aberrantly in endometriosis, which gives rise to strikingly high levels of aromatase activity in this tissue. Both aromatase expression and activity are stimulated by PGE2. This results in local production of estrogen, which induces PGE2 formation and establishes a positive feedback cycle. Another abnormality in endometriosis, that is, deficient 17beta-HSD type 2 expression, impairs the inactivation of estradiol to estrone. These molecular aberrations collectively favor accumulation of increasing quantities of estradiol and PGE2 in endometriosis. The clinical relevance of these findings was exemplified by the successful treatment of an unusually aggressive case of postmenopausal endometriosis using an aromatase inhibitor.
The biologic relationship between small B-cell lymphoma and histiocytic sarcoma (HS) when occurring in the same patient remains unclear, though recent data suggest a possible 'transdifferentiation' from follicular lymphoma (FL) to HS. We investigated the clonal relationship in two cases of small B-cell lymphoma with subsequent HS. Case 1: A 62-year-old female with splenic marginal zone lymphoma (SMZL) developed HS in a groin lymph node 1 year after the primary diagnosis. PCR/sequence analysis of the IGH gene showed a monoclonal rearrangement carrying an identical nucleotide sequence of PCR products from the spleen with SMZL and the lymph node with HS. Case 2: A 61-year-old female with a remote history of FL developed supraclavicular lymphadenopathy, which was confirmed to be HS. PCR analysis of the HS detected a monoclonal rearrangement of the IGH gene and FISH analysis revealed IGH/BCL2 fusion, a genetic hallmark for FL. The transformed HSs showed partial retention of their prior B-cell lymphomas' signatures, including expression of OCT2 in both cases and expression of BCL6 and enhanced expression of BCL2 in case 2. Both HSs demonstrated hypermutated IGH variable regions, arguing against a common progenitor mechanism of the transformation process. The data suggest a common clonal origin of B-cell lymphoma and subsequent HS occurring in the same patient, indicating that 'transdifferentiation' occurs in other small B-cell lymphomas, in addition to the previously reported FL or B-cell lymphoma with IGH/BCL2.
Heterozygous inversions in chromosome 15q21.2-3, which caused the coding region of the aromatase gene to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, resulted in severe estrogen excess owing to the overexpression of aromatase in many tissues.
We report 10 cases of donor cell leukemia (DCL). All cases except the case of chronic lymphocytic leukemia had anemia, neutropenia, and/or thrombocytopenia when DCL was diagnosed. Eight cases with sex-mismatched hematopoietic stem cell transplant (HCT) showed donor gonosomal complements, suggesting DCL. Clonal cytogenetic abnormalities were detected in 8 cases: 6 were monosomy 7/del(7q). In all 10 cases, engraftment studies confirmed donor cell origin. Retrospective fluorescence in situ hybridization in archived donor cells in 4 cases showed a low level of abnormalities in 2. Of 7 patients with clinical follow-up of 5 months or more, 1 (with acute myeloid leukemia) died of disease; 6 are alive, including 1 with myelodysplastic syndrome with spontaneous remission. Similar to reported cases, we found disproportional sex-mismatched HCTs, suggesting probable underdetection of DCL in sex-matched HCTs. The latency between HCT and DCL ranged from 1 to 193 months (median, 24 months), in keeping with the literature. Analyzing our cases, pooled with reported cases, with survival models showed much shorter latency for malignancy as primary disease, for T-cell large granular lymphocyte leukemia as type of DCL, and for umbilical cord blood as stem cell source.
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