Reynolds, Carol

OBJECTIVE—To demonstrate the strong association of diabetic mastopathy or sclerosing lymphocytic lobulitis with type 1 diabetes mellitus by studying appropriate control groups and to describe risk factors and natural history of the disorder. RESEARCH DESIGN AND METHODS—This was a retrospective cross-sectional study of four groups of patients conducted at a setting tertiary care medical center. We examined benign breast biopsies (investigator masked to identity) from age-matched patients with types 1 and 2 diabetes, autoimmune thyroid disease, or none of the above disorders for sclerosing lymphocytic lobulitis. Several risk factors proposed for the disorder (age at diagnosis of benign breast disease, duration of diabetes, age at onset of diabetes, prevalence of retinopathy, neuropathy, nephropathy and cheiroarthropathy, glycemic control, parity, oral contraceptive use, menopausal status, or number of breast biopsies) were evaluated, and patients were contacted to describe the natural history of the disorder. RESULTS—Sclerosing lymphocytic lobulitis was identified in 69.7% of the subjects with type 1 diabetes and 1.8% of those with autoimmune thyroid disease diagnosed with benign breast disease at surgery. It did not occur in patients with type 2 diabetes with or without insulin treatment or in control subjects. Only retinopathy and peripheral neuropathy were associated with sclerosing lymphocytic lobulitis. Breast carcinoma or lymphoma did not occur subsequently in any type 1 diabetes patient with or without sclerosing lymphocytic lobulitis. CONCLUSIONS—Sclerosing lymphocytic lobulitis is strongly associated with type 1 diabetes. Retinopathy and neuropathy are associated with the disorder. The risk of malignancy is not increased.

Abstract Purpose: In the adjuvant treatment of estrogen receptor (ER)–positive breast cancer, additional markers are needed to identify women at high risk for recurrence. Experimental Design: We examined the association between the ratio of the homeobox 13 (HOXB13) to interleukin-17B receptor (IL-17BR) expression and the clinical outcomes of relapse and survival in women with ER-positive breast cancer enrolled onto a North Central Cancer Treatment Group adjuvant tamoxifen trial (NCCTG 89-30-52). Results: Tumor blocks were obtained from 211 of 256 eligible patients, and quantitative reverse transcription-PCR profiles for HOXB13 and IL-17BR were obtained from 206 patients. The cut point for the two-gene log 2(expression ratio) that best discriminated clinical outcome (recurrence and survival) was selected and identified women with significantly worse relapse-free survival (RFS), disease-free survival (DFS), and overall survival (OS), independent of standard prognostic markers. The cut point differed as a function of nodal status [node negative (59th percentile) versus node positive (90th percentile)]. In the node-positive cohort (n = 86), the HOXB13/IL-17BR ratio was not associated with relapse or survival. In contrast, in the node-negative cohort (n = 130), a high HOXB13/IL-17BR ratio was associated with significantly worse RFS [hazard ratio (HR), 1.98; P = 0.031], DFS (HR, 2.03; P = 0.015), and OS (HR, 2.4; P = 0.014), independent of standard prognostic markers. Conclusion: A high HOXB13/IL-17BR expression ratio is associated with increased relapse and death in patients with resected node-negative, ER-positive breast cancer treated with tamoxifen and may identify patients in whom alternative therapies should be studied.

Purpose Polymorphisms in tamoxifen metabolizing genes affect the plasma concentration of tamoxifen metabolites, but their effect on clinical outcome is unknown. Methods We determined cytochrome P450 (CYP)2D6 (*4 and *6) and CYP3A5 (*3) genotype from paraffin-embedded tumor samples and buccal cells (living patients) in tamoxifen-treated women enrolled onto a North Central Cancer Treatment Group adjuvant breast cancer trial. The relationship between genotype and disease outcome was determined using the log-rank test and Cox proportional hazards modeling. Results Paraffin blocks were obtained from 223 of 256 eligible patients, and buccal cells were obtained from 17 living women. CYP2D6 (*4 and *6) and CYP3A5 (*3) genotypes were determined from 190, 194, and 205 patient samples and in 17 living women. The concordance rate between buccal and tumor genotype was 100%. Women with the CYP2D6 *4/*4 genotype had worse relapse-free time (RF-time; P = .023) and disease-free survival (DFS; P = .012), but not overall survival (P = .169) and did not experience moderate to severe hot flashes relative to women heterozygous or homozygous for the wild-type allele. In the multivariate analysis, women with the CYP2D6 *4/*4 genotype still tended to have worse RFS (hazard ratio [HR], 1.85; P = .176) and DFS (HR, 1.86; P = .089). The CYP3A5*3 variant was not associated with any of these clinical outcomes. Conclusion In tamoxifen-treated patients, women with the CYP2D6 *4/*4 genotype tend to have a higher risk of disease relapse and a lower incidence of hot flashes, which is consistent with our previous observation that CYP2D6 is responsible for the metabolic activation of tamoxifen to endoxifen.

Abstract OBJECTIVE AND IMPORTANCE: Optic nerve choristoma is a rare lesion composed of adipose tissue and smooth muscle involving the optic nerve. Few cases have been reported. CLINICAL PRESENTATION: A 20-year-old woman presented with a history of slowly progressive visual loss in the left eye. On T1-weighted magnetic resonance imaging studies, after frequency-selective fat saturation, an optic nerve mass was detected at the level of the optic canal with signal characteristics suggesting the diagnosis of optic nerve lipoma. INTERVENTION: At left frontotemporal craniotomy, the intracranial optic nerve appeared thin and atrophic proximally and was covered by abundant adipose tissue distally. Because no cleavage plane could be identified between the fatty lesion and the optic nerve, which appeared splayed within the adipose tissue, the nerve was resected after an intraoperative biopsy. The presence of two heterotopic mesodermal elements, a rim of adipose tissue admixed with bundles of mature smooth muscle, extending into the nerve septa, warranted a diagnosis of optic nerve choristoma. CONCLUSION: Optic nerve choristoma is an uncommon optic nerve lesion. Even if imaging studies are highly suggestive of the diagnosis, pathological confirmation is required because of the high adipose tissue content in the majority of cases. The lesion, most likely malformative and nonneoplastic in nature, can be the cause of progressive visual loss.

Earlier studies of invasive breast tumors have shown that 60–80% are aneuploid and ≈80% exhibit amplified centrosomes. In this study, we investigated the relationship of centrosome amplification with aneuploidy, chromosomal instability, p53 mutation, and loss of differentiation in human breast tumors. Twenty invasive breast tumors and seven normal breast tissues were analyzed by fluorescence in situ hybridization with centromeric probes to chromosomes 3, 7, and 17. We analyzed these tumors for both aneuploidy and unstable karyotypes as determined by chromosomal instability. The results were then tested for correlation with three measures of centrosome amplification: centrosome size, centrosome number, and centrosome microtubule nucleation capacity. Centrosome size and centrosome number both showed a positive, significant, linear correlation with aneuploidy and chromosomal instability. Microtubule nucleation capacity showed no such correlation, but did correlate significantly with loss of tissue differentiation. Centrosome amplification was detected in in situ ductal carcinomas, suggesting that centrosome amplification is an early event in these lesions. Centrosome amplification and chromosomal instability occurred independently of p53 mutation, whereas p53 mutation was associated with a significant increase in centrosome microtubule nucleation capacity. Together, these results demonstrate that independent aspects of centrosome amplification correlate with chromosomal instability and loss of tissue differentiation and may be involved in tumor development and progression. These results further suggest that aspects of centrosome amplification may have clinical diagnostic and/or prognostic value and that the centrosome may be a potential target for cancer therapy.