Jurgen M.J. Piek

Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer

The aim of this study was to investigate the occurrence of (pre)neoplastic lesions in overtly normal Fallopian tubes from women predisposed to developing ovarian carcinoma. The presence of (pre)neoplastic lesions was scored in histological specimens from 12 women with a genetically determined predisposition for ovarian cancer, of whom seven tested positive for a germline BRCA1 mutation. A control group included 13 women. Immunohistochemistry was used to determine the expression of p21, p27, p53, cyclin A, cyclin D1, bcl‐2, Ki67, HER‐2/neu, and the oestrogen and progesterone receptors. Loss of heterozygosity (LOH) analysis on the BRCA1 locus was also assessed on dysplastic tissue by PCR studies. Of the 12 women with a predisposition for ovarian cancer, six showed dysplasia, including one case of severe dysplasia. Five harboured hyperplastic lesions and in one woman no histological aberrations were found in the Fallopian tube. No hyperplastic, dysplastic or neoplastic lesions were detected in the Fallopian tubes of control subjects. In the cases studied, morphologically normal tubal epithelium contained a higher proportion of Ki67‐expressing cells (p=0.005) and lower fractions of cells expressing p21 (p<0.0001) and p27 (p=0.006) than in the control group. Even higher fractions of proliferating cells were found in dysplastic areas (p=0.07) and accumulation of p53 was observed in the severely dysplastic lesion. Expression patterns of other proteins studied, including the hormone receptors, were similar in cases and controls. One subject, a germline BRCA1 mutation carrier, showed loss of the wild‐type BRCA1 allele in the severely dysplastic lesion. In conclusion, the Fallopian tubes of women predisposed to developing ovarian cancer frequently harbour dysplastic changes, accompanied by changes in cell‐cycle and apoptosis‐related proteins, indicating an increased risk of developing tubal cancer. Copyright

Genome-wide-array-based comparative genomic hybridization reveals genetic homogeneity and frequent copy number increases encompassing CCNE1 in Fallopian tube carcinoma

Fallopian tube carcinoma (FTC) is a rare, poorly studied and aggressive cancer, associated with poor survival. Since tumorigenesis is related to the acquisition of genetic changes, we used genome-wide array comparative genomic hybridization to analyse copy number aberrations occurring in FTC in order to obtain a better understanding of FTC carcinogenesis and to identify prognostic events and targets for therapy. We used arrays of 2464 genomic clones, providing ∼1.4 Mb resolution across the genome to map genomic DNA copy number aberrations quantitatively from 14 FTC onto the human genome sequence. All tumors showed a high frequency of copy number aberrations with recurrent gains on 3q, 6p, 7q, 8q, 12p, 17q, 19 and 20q, and losses involving chromosomes 4, 5q, 8p, 16q, 17p, 18q and X. Recurrent regions of amplification included 1p34, 8p11–q11, 8q24, 12p, 17p13, 17q12–q21, 19p13, 19q12–q13 and 19q13. Candidate, known oncogenes mapping to these amplicons included CMYC (8q24), CCNE1 (19q12–q21) and AKT2 (19q13), whereas PIK3CA and KRAS, previously suggested to be candidate driver genes for amplification, mapped outside copy number maxima on 3q and 12p, respectively. The FTC were remarkably homogeneous, with some recurrent aberrations occurring in more than 70% of samples, which suggests a stereotyped pattern of tumor evolution.

Low prevalence of (pre) malignant lesions in the breast and high prevalence in the ovary and Fallopian tube in women at hereditary high risk of breast and ovarian cancer.

To analyse the prevalence of (pre) malignant lesions occurring in breast and adnexal tissue at prophylactic surgery in women at hereditary high risk of breast and/or ovarian cancers. Tissue was obtained from 85 women who underwent prophylactic bilateral salpingo‐oophorectomy (pBSO) and from 59 women who underwent prophylactic mastectomy (pM). Control tissue samples were obtained from women undergoing breast reduction surgery (N = 99) or adnexal surgery for benign reasons (N = 72). In women with a BRCA1/2 mutation, the prevalence of a (pre) malignant adnexal lesion was 50% (95% CI 26–74) if older than 40 years and 14% (95% CI 0–58) if younger. The prevalences of (pre) malignant breast lesions in women older than 40 years, with and without a BRCA1/2 mutation, were 0% (95% CI 0–16) and 47% (95% CI 21–73), respectively. No association was found between (pre) malignant lesions in breast and adnexal tissue occurring in 28 women who underwent surgery on both organs (R = 0.155, p = 0.432), but the prevalence of lesions was significantly higher in adnexal tissue than in the breast (p = 0.023). Compared to controls, women at hereditary high risk had a higher chance of (pre) malignant lesions in the breast and an even higher chance of such lesions in the adnexal tissue. There was no indication for concomitant presence of such lesions in both organs at the time of prophylactic surgery. The high frequency of (pre) malignant lesions in the adnexal tissue stresses further the importance of pBSO from the age of 40 onwards in women at hereditary high risk.

Cell cycle-related proteins p21 and bcl-2: markers of differentiation in the human fallopian tube.

lase (NSE, BBS/NC/Vi-H-14, Dako) and chromogranin A (monoclonal, Dako). The diagnosis was pericardial rhabdomyomatous spindle cell thymoma with mucinous cystic degeneration. The patient was disease-free during 28-month follow-up. Immunohistochemically, these myoid cells express muscle markers such as desmin, myoglobin, actin. Their histogenesis is still unclear. The myoid cells may play a role in triggering the autoimmune reactions. The mucinous cysts were explained as degenerate in Hassalls corpuscles. The presence of mucous substance in our case was similar to the observation of Murakami et al. They showed the presence of a mucous substance on the surface of myoid cells. We think that the myoid cell clusters with at least 20±30 cells degenerate due to an unknown, probably vascular, reason. Finally, cystic spaces with mucous substance remain. In the differential diagnosis, mediastinal rhabdomyoma and solitary ®brous tumour (SFT) should primarily be considered. Mediastinal rhabdomyoma, whose origin is probably from the myoid cells of the thymus, does not include an epithelial spindle cell component with cytokeratin expression. Histological features of the SFT may be similar to thymoma with a predominantly spindle cell pattern. However, the characteristic rosette formations, mucous cysts and myoid cells were not seen. Spindle cells in SFT show immunohistochemical reactivity to vimentin and CD34, but not to cytokeratins. The myoid cells are only immunoreactive for vimentin in thymoma. Finally, this unusual presentation site of ectopic thymoma should be considered in the differential diagnosis of problematic pericardial lesions.

HER-2/neu and p27Kip1 in progression of Fallopian tube carcinoma: an immunohistochemical and array comparative genomic hybridization study

Aims:  To determine expression of p53, HER‐2/neu and p27Kip1 in serous Fallopian tube carcinoma (FTC) in relation to stage and grade, and to investigate DNA copy number changes of HER‐2 and P27KIP1 as a potential mechanism of altered expression status.

Tubal and ovarian pathways to pelvic epithelial cancer: a pathological perspective

Sir: I read with interest the excellent paper by Diebold et al. on the entity we have described as sclerosing angiomatoid nodular transformation of the spleen (SANT) and their intriguing thoughts about a possible relationship with splenic inflammatory pseudotumour. In that article, the authors make a priority claim to the description of this entity under the term ‘splenic exuberant granulation tissue (SEGT) resulting in localized nodular transformation of the red pulp’. Specifically, they state that at one point they ‘decided’ to publish their seven initial cases. They further state that they had previously used that term to describe the entity. The perplexing aspect about this claim is that there is no reference at all to the paper in question. Where and when did they publish their work?

Women harboring BRCA1/2 germline mutations are at risk for breast and female adnexal carcinoma.

To the Editor: We read with interest the review article by Dr. Colgan (1) in which he discusses the proposed amendments in the International Federation of Gynecology and Obstetrics staging of fallopian tube carcinoma (FTC), with which we are in agreement. As we and several others have shown that FTC is part of the BRCA-related cancer spectrum (1,2), we also advocate that FTC should be included in the nomenclature for BRCA-related tumors by the use of the term “female adnexal tumor” to refer to both ovarian and tubal carcinomas. Regarding the natural history of in situ FTC, we showed in 2001 that prophylactically removed fallopian tubes from women at hereditary high risk for the development of adnexal carcinomas frequently contain preneoplastic lesions (3). In these lesions, the levels of cell cycle regulatory proteins p21/WAF and p27 are frequently down-regulated, whereas the proliferation marker Ki67 is commonly up-regulated when compared with normal tubal epithelium from women not at hereditary high risk for breast and adnexal tumors. Furthermore, we detected loss of the wild-type BRCA1 allele in a tubal carcinoma in situ in a prophylactic bilateral salpingo-oophorectomy specimen from a woman harboring a germline BRCA1 mutation. In this lesion p53 overexpression was observed, possibly indicating loss of normal p53 function as well. Thus, the natural history of dysplastic lesions in women at hereditary high risk for breast and female adnexal carcinomas may include changes in the expression of the cell-cycle proteins p21 and p27 and possibly others, changes that may precede loss of normal BRCA1 and p53 function. Further research will be needed to substantiate these findings.

Genomic aberrations relate early and advanced stage ovarian cancer

BackgroundBecause of the distinct clinical presentation of early and advanced stage ovarian cancer, we aim to clarify whether these disease entities are solely separated by time of diagnosis or whether they arise from distinct molecular events.MethodsSixteen early and sixteen advanced stage ovarian carcinomas, matched for histological subtype and differentiation grade, were included. Genomic aberrations were compared for each early and advanced stage ovarian cancer by array comparative genomic hybridization. To study how the aberrations correlate to the clinical characteristics of the tumors we clustered tumors based on the genomic aberrations.ResultsThe genomic aberration patterns in advanced stage cancer equalled those in early stage, but were more frequent in advanced stage (p = 0.012). Unsupervised clustering based on genomic aberrations yielded two clusters that significantly discriminated early from advanced stage (p = 0.001), and that did differ significantly in survival (p = 0.002). These clusters however did give a more accurate prognosis than histological subtype or differentiation grade.ConclusionThis study indicates that advanced stage ovarian cancer either progresses from early stage or from a common precursor lesion but that they do not arise from distinct carcinogenic molecular events. Furthermore, we show that array comparative genomic hybridization has the potential to identify clinically distinct patients.

Opportunistic salpingectomy in women undergoing hysterectomy: Results from the HYSTUB randomised controlled trial

OBJECTIVE To evaluate whether opportunistic salpingectomy in premenopausal women undergoing hysterectomy for benign indications is both hormonally and surgically safe, compared with hysterectomy without salpingectomy. STUDY DESIGN In this multicentre randomised controlled trial, women were randomised to undergo either hysterectomy with opportunistic bilateral salpingectomy (intervention group) or standard hysterectomy with preservation of the Fallopian tubes (control group). MAIN OUTCOME MEASURES The primary outcome was the difference in serum anti-Müllerian hormone concentration (ΔAMH), measured pre-surgery and 6 months post-surgery. Secondary outcomes were surgical outcomes and duration of hospital stay. The sample size was powered at 50 participants per group (n=100) to compare ΔAMH after hysterectomy with salpingectomy to ΔAMH after standard hysterectomy. RESULTS Between March 2013 and December 2016, 104 women, aged 30-55 years, were randomly allocated to hysterectomy with opportunistic bilateral salpingectomy (n=52) or standard hysterectomy (n=52). The baseline characteristics did not differ between the two groups. The median ΔAMH was -0.14pmol/L (IQR -1.47-0.95) in the intervention group and 0.00pmol/L (IQR -1.05-0.80) in the control group (p=0.49). The addition of salpingectomy did not impair surgical results and it did not affect duration of hospital stay. CONCLUSION Addition of opportunistic bilateral salpingectomy during hysterectomy did not result in a larger effect on ovarian reserve when compared with hysterectomy alone, neither did it affect surgical outcomes. Therefore, opportunistic salpingectomy seems to be a safe procedure in premenopausal women undergoing hysterectomy for benign gynaecological conditions.

Peritoneal Carcinomatosis After Risk-Reducing Surgery in BRCA1/2 Mutation Carriers

Risk‐reducing salpingo‐oophorectomy (RRSO) is recommended for BRCA1/2 mutation carriers because of their increased risk of ovarian carcinoma. Despite RRSO, metachronous peritoneal carcinomatosis occasionally is diagnosed.