The effect of ingestion of oral contraceptives (OCP) on cell proliferation and oestrogen (ER) and progesterone receptor (PR) expression of the epithelial cells of the normal human breast was compared with findings in controls not taking OCPs. Histologically normal breast tissue was removed during operation for fibroadenoma or reduction mammoplasty in 216 women whose mean age was 28.1 +/- 8.5 years (+/- SD range 14-53 years). During natural cycles the mean proportion of cells expressing ER was 3.94 +/- 3.71 (% mean +/- SD, range 0-20.8, n = 51), while of those expressing PR it was 12.1 +/- 7.1% (range 3.0-36.1, n = 47). There was a significant decline in ER during the menstrual cycle [p = 0.001 by multiple linear regression (MLR)], but there was no significant change in the proportion which expressed PR. The mean proportion of proliferating cells (LI) was 2.50 +/- 2.42 (range 0-11.5, n = 147). There was a significant increase of LI during the cycle (p = less than 0.001, MLR) and a significant inverse relationship between LI and ER (r = -0.29, p less than 0.01). Use of the OCP significantly reduced the number of cells which expressed ER and increased the LI earlier in the cycle. No effect of OCP use on the number of PR+ cells was detectable. We conclude that significant changes in the proportions of ER+ and proliferating cells occur during natural menstrual cycles. These changes are perturbed by ingestion of OCPs, so that there is greater suppression of ER and a longer period of high proliferation during the menstrual cycle. These results may explain the relationship between OCP use and the possible risk of breast cancer.

A proportion of extraskeletal myxoid chondrosarcomas (EMC) have been shown to have a characteristic translocation t(9;22)(q22;q12) involving the EWS gene at 22q12 and the CHN orphan nuclear receptor gene at 9q22. This translocation appears to be largely speci®c for EMC, but has not been detected in all such tumours. We report here a case of EMC with a t(9;17)(q22;q11.2) as the sole chromosome abnormality. We have determined that the translocation results in the fusion of the entire coding region of CHN to the N-terminal transactivation domain of RBP56/hTAF II 68. This is the ®rst report of a translocation involving RBP56/hTAF II 68, a protein with sequence homology to both EWS and TLS/FUS. The involvement of RBP56/hTAF II 68 may explain some unusual features of the tumour.Keywords: t(9;17)(q22;q11.2); RBP56/hTAF II 68; CHN; extraskeletal myxoid chrondrosarcoma Although recurrent chromosomal abnormalities are frequent in haematological malignancies, they are relatively uncommon in solid tumours. An exception to this is in the case of some sarcomas where a number of recurrent changes have been identi®ed. The best characterized chromosomal rearrangements occur in Ewing's and related tumours, which have translocations which fuse the N-terminal transactivation domain of the EWS gene to the DNA-binding domain of one of a number of transcription factors. All these gene fusions have the consequence that the non-transforming transcription factor is converted into a transforming protein with novel and potent transactivation properties endowed by the N-terminal portion of EWS (for review see Ladanyi, 1995). EWS is a member of a family of genes including TLS/FUS and RBP56/hTAF II 68, each encoding a protein which associates with components of the transcription machinery, with the latter two proteins being involved in elongation as well as initiation (Bertolotti et al., 1996(Bertolotti et al., , 1998. The C-terminal domains of EWS and hTAF II 68 have been shown to be essential for interaction with other TBP-associated factors (TAF II s) within the TFIID multiprotein complex (Bertolotti et al., 1998). As the C-terminal domain of EWS is missing in all the fusion proteins involving this gene characterized to date, the interaction with TFIID would be seriously compromised.The identi®ed fusion partners for EWS have been extended to include the entire coding region of either CHOP in myxoid liposarcomas (t(12;22)(q13;q12), Panagopoulos et al., 1996) or CHN in extraskeletal myxoid chondrosarcomas (t(9;22)(q22;q12), Labelle et al., 1995;Clark et al., 1996;Brody et al., 1997;Antonescu et al., 1998). Both these genes encode proteins which have DNA-binding domains. One other member of the EWS gene family, TLS/FUS, has also been implicated in human tumours by virtue of recurrent translocations. TLS/FUS-CHOP fusions has been identi®ed in a subset of myxoid liposarcomas (t(12;16)(q13;p11), Crozat et al., 1993;Rabbitts et al., 1993), and TLS/FUS-ERG fusions have been found in acute myeloid leukaemias (t(16;21)(p11;q22), Ichikawa et al., 19...

The aims of this study in 227 premenopausal women were (a) to determine the mitotic index (MI), the thymidine labelling index (LI), and the apoptotic index (AI) within the epithelial cells of histologically 'normal' human breast biopsy material removed away from the site of either a fibroadenoma or a carcinoma; and (b) to relate differences in the kinetic indices of the 'normal' epithelium to the pathology in the same breast diagnosed as fibroadenoma alone (125 patients), fibroadenoma with accompanying mild fibrocystic change (79 patients), or carcinoma (23 patients). Ratios of the average indices (AI/MI, AI/LI, MI/LI) were also calculated to minimize uncertainties related to the total cell population counted, the denominator in the LI, MI, and AI. All indices and ratios of indices were corrected for age, averaged over the cycle, and expressed as log-transformed values for analysis. Significant (P less than 0.001) reductions in AI and in apoptosis relative to mitosis (reduced AI/MI) were found in 'normal' epithelium from breasts having fibrocystic change (AI = 0.17 +/- 0.02; AI/MI = 1.01 +/- 0.18) and carcinoma (AI = 0.19 +/- 0.04; AI/MI = 0.88 +/- 0.29), compared with breast with fibroadenoma alone (AI = 0.27 +/- 0.03; AI/MI = 1.29 +/- 0.39). In the absence of significant differences in MI and LI between the 'normal' tissue groups, this finding raises the possibility that reduced epithelial cell apoptosis might be causally associated with the development of fibrocystic change and with an increased risk of development of carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Two cases of malignant melanoma are reported in adults exhibiting rhabdomyoblastic differentiation to alert pathologists to this rare variant of malignant melanoma. One of the cases presented as a metastasis in a submandibular lymph node, and the other was a primary skin melanoma. There are only a few published reports on melanocytic tumors with rhabdomyoblastic differentiation, mainly occurring in giant congenital nevi. Both cases reported here were confirmed by immunohistochemistry. Both cases were also studied by electron microscopy, and one showed distinctive ultrastructural features of striated muscle.

Since the introduction of spiral CT scanners, smaller lesions are being seen at the time of preoperative staging. Our study concludes that only a small proportion of indeterminate lung lesions did develop into definite metastases and those that did had node positive disease. Indeterminate lung lesions are not a reason to delay surgery for colorectal cancer.

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Gene mutation status assessment of tumors has become standard practice in diagnostic pathology. This is done using samples comprising tumor cells but also non-tumor cells, which may dramatically dilute the proportion of tumor DNA and induce false negative results. Increasing sensitivity of molecular tests presently allows detection of a targeted mutation in a sample with a small percentage of tumor cells, but assessment of tumor cellularity remains essential to adequately interpret the results of molecular tests. Comprehensive tumor cell counting would provide the most reliable approach but is time consuming, and therefore rough global estimations are used, the reliability of which has been questioned in view of their potential clinical impact. The French association for quality assurance in pathology (AFAQAP) conducted two external quality assurance schemes, partly in partnership with the French group of oncology cytogenomics (GFCO). The purpose of the schemes was to (1) evaluate how tumor cellularity is assessed on tissue samples, (2) identify reasons for discrepancies, and (3) provide recommendations for standardization and improvement. Tumor cell percentages in tissue samples of lung and colon cancer were estimated by 40-50 participants, on 10 H&E virtual slides and 20 H&E conventional slides. The average difference between lowest and highest estimated percentage was 66. This was largely due to inadequate definition of cellularity, reflecting confusion between the percentage of tumor cells and the percentage of the area occupied by tumor in the assessed region. The widest range of interobserver variation was observed for samples with dense or scattered lymphocytic infiltrates or with mucinous stroma. Estimations were more accurate in cases with a low percentage of tumor cells. Macrodissection of the most homogeneous area in the tissue reduced inter-laboratory variation. We developed a rating system indicating potential clinical impact of a discrepancy. Fewer discrepancies were clinically relevant since the study was conducted. Although semi-quantitative estimations remain somewhat subjective, their reliability improves when tumor cellularity is adequately defined and heterogeneous tissue samples are macrodissected for molecular analysis.

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