Ann K. Folkins

Serous Carcinogenesis in the Fallopian Tube: A Descriptive Classification

Summary The fimbria is the most common site of early serous cancer (tubal intraepithelial carcinoma or STIC) in women with BRCA mutations (BRCA+). A candidate serous cancer precursor-the p53 signature-has been found in nonneoplastic secretory cells of the fimbria, suggesting serous carcinogenesis in the tube (SCAT). This study surveyed fallopian tubes from 3 populations to characterize the morphological and immunohistochemical correlates of SCAT. The SCAT sequence was defined by strong nuclear p53 staining and DNA damage (&ggr;-H2AX+) in secretory cells and subdivided morphologically by (1) degree of nuclear stratification, (2) proliferative index, and (3) degree of disorganized growth. Fallopian tubes from women without a current ovarian cancer, women with BRCA mutations, and women with a coexisting pelvic serous cancer were completely examined. p53 signatures exhibited cuboidal to pseudostratified, polarized p53+ epithelial segments with variable nuclear enlargement and a MiB1 index of 0% to 30%. Tubal intraepithelial carcinomas contained from single (uncommon) to multilayered, poorly polarized, uninterrupted neoplastic cell populations that completely displaced the normal mucosa; MiB1 index exceeded 45% and was usually more than 70%. An uncommon third category, p53-positive foci with features intermediate between p53 signatures and STICs, exhibited preserved epithelial polarity, pseudostratification, incomplete replacement of the adjacent normal ciliated cells, and a MiB1 index between 40% and 75%. Transitions from 1 category to another were documented. Combined with recent reports associating STICs with pelvic serous cancer, this continuum of epithelial change validates the SCAT sequence and the fimbrial secretory cell as the site of origin for many serous carcinomas.

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

Prolongation of ovarian epithelial cancer survival depends on early detection or improved responses to chemotherapy. Gains in either have been modest at best. Understanding the diverse pathogenesis of this disease is critical to early intervention or prevention. This review addresses six important variables, including (i) cell of origin, (ii) site of origin, (iii) initial genotoxic events, (iv) risks imposed by hereditary and other promoting conditions, (v) subsequent factors that promote different patterns of metastatic spread, and (vi) prospects for intervention. This review proposes two distinct pathways to pelvic epithelial cancer. The first initiates in ovarian surface epithelium (OSE), Mullerian inclusions or endometriosis in the ovary. The second arises from the endosalpinx and encompasses a subset of serous carcinomas. The serous carcinogenic sequence in the distal fallopian tube is described and contrasted with lower grade serous tumors based on tumour location, earliest genetic change and ability (or lack of) to undergo terminal (ciliated) differentiation. Ultimately, a clear understanding of tumour origin and the mechanism(s) leading to the earliest phases of the serous and endometrioid carcinogenic sequences may hold the greatest promise for designing prevention strategies and/or developing new therapies.

Precursors to pelvic serous carcinoma and their clinical implications

Pelvic serous carcinoma has traditionally been viewed as a rapidly evolving malignancy, due principally to its late stage at diagnosis and tendency for poor outcome, both in the endometrium and the upper genital tract. Recently, studies of women with BRCA1 or BRCA2 mutations (BRCA+) undergoing risk reducing salpingo-oophorectomy have highlighted the distal fallopian tube as a common (80%) site of tumor origin and additional studies of unselected women with pelvic serous carcinoma have demonstrated that serous tubal intraepithelial carcinoma may precede a significant percentage of these tumors. This review examines the serous carcinogenic spectrum in the fallopian tube, highlighting recent evidence that these tumors may follow a defined precursor that has been present for a prolonged interval. The data supporting a candidate precursor, the implications of these findings for early detection and prevention of pelvic serous carcinoma and the caveats, are discussed.

Risk Factors for a Serous Cancer Precursor (“p53 signature”) in Women with Inherited BRCA Mutations

OBJECTIVES Pelvic (ovarian) serous carcinomas frequently contain p53 mutations. Recently, a candidate serous cancer precursor (the p53 signature) with p53 mutations and other features in common with serous cancer has been discovered in distal fallopian tube mucosa. This study examined the relationship of putative ovarian cancer risk factors with the presence of p53 signatures in women with BRCA mutations (BRCA+). METHODS Fallopian tubes from 75 BRCA+ women were immunostained for p53 signatures and correlated with age at first childbirth, parity, oral contraceptive use, body mass index (BMI), and BRCA subtype (1 or 2). Statistical analysis was performed with the T-test or Chi-square analysis and logistic regression adjusting for age and parity. RESULTS Thirty-eight percent of the tubes contained p53 signatures, which were significantly associated with older age at first childbirth (mean 30.8 vs. 28.4 years; p=0.04) and lower parity (mean 1.4 vs. 2.2; p=0.01) in univariate analyses. The unadjusted odds ratios were 3.8 (p-trend=0.04) for first childbirth>/=30 years versus <30 and 0.2 (p-trend=0.01) for parity >/= 3 versus nulliparous women. After adjusting for age and parity, the trend for age at first childbirth became non-significant (adjusted odds ratio 3.5; p-trend=0.15), while that for parity remained significant (adjusted odds ratio 0.2; p-trend 0.02). CONCLUSIONS The p53 signature is significantly associated with lower parity and possibly higher age at first childbirth, further linking this entity to serous cancer via risk factors associated with ovulation. The p53 signature merits consideration as a surrogate marker for serous cancer risk.

Intercepting early pelvic serous carcinoma by routine pathological examination of the fimbria.

Recent evidence indicates that the distal fallopian tube is the principal site of early serous cancer in women with a hereditary risk for ovarian cancer. Moreover, the fimbria is involved by early cancer in a significant minority of pelvic serous carcinomas, irrespective of whether the patient has a hereditary BRCA1 or BRCA2 mutation. In addition, the distal tube has been identified occasionally as a site of concurrent endometrioid tumors in women with endometrial carcinoma. Although the risk of sporadic fimbrial tumors in otherwise healthy women without genetic risk is unknown, routine histological examination of the fimbria provides the opportunity to determine the risk of such an event. To illustrate this point, a case of a woman who underwent surgery for an ovarian fibroma is presented. The distal tube was submitted, and found to harbor a focus of serous tubal intraepithelial carcinoma (STIC) with a 2-mm invasive tumor. Incidentally discovered carcinomas underscore the potential risk, albeit low, of concurrent unsuspected malignancy in the distal fallopian tube and emphasize the importance of routine pathological examination of the fimbria in all salpingectomies. The rationale for this strategy, and its potential effect on early detection and in uncovering persons or families potentially at risk for ovarian cancer, is discussed.

Hereditary gynaecological malignancies: advances in screening and treatment

In the last two decades there have been significant advances in our understanding of female genital tract tumours. The discovery of BRCA1 and BRCA2 genes in ovarian cancer and the mismatch repair genes in endometrial carcinoma has revolutionized our approach to the diagnosis and screening of women for ovarian and uterine cancers. This review discusses the pathogenesis of these two hereditary syndromes in depth and explains how the molecular genetics is tailoring the manner in which these diseases are diagnosed and potentially treated. Other, less common hereditary conditions associated with gynaecological tract manifestations, such as Cowden syndrome, Peutz–Jeghers syndrome, Gorlin syndrome and hereditary leiomyomatosis and renal cell carcinoma, are also summarized briefly.

Evaluation of vascular space involvement in endometrial adenocarcinomas: laparoscopic vs abdominal hysterectomies

Recent reports have described ‘vascular pseudoinvasion’ in total laparoscopic hysterectomies with endometrial carcinoma. To better understand this phenomenon, we compared pathologic findings in these laparoscopic and total abdominal hysterectomies performed for uterine endometrioid adenocarcinoma. Reports from 58 robotically assisted laparoscopic and 39 abdominal hysterectomies with grade 1 or 2 endometrioid endometrial adenocarcinomas were reviewed for stage, depth of invasion, vascular space involvement, uterine weight, and lymph node metastases. In addition, attention was given to possible procedural artifacts, including vertical endomyometrial clefts, and inflammatory debris, benign endometrial glands, and disaggregated tumor cells in vascular spaces. All foci with vascular involvement were reviewed by three gynecologic pathologists. Nine of the 58 (16%) laparoscopic and 3 of the 39 (7%) abdominal hysterectomies contained vascular space involvement based on the original pathology reports (P-value=0.0833). No one histologic feature consistently distinguished laparoscopic from abdominal cases on blind review of the available cases. Disaggregated intravascular tumor cells were significantly associated with reported vascular involvement in both procedures (P-values<0.001 and 0.016), most of which were corroborated on review. Laparoscopic procedures tend to have a higher index of vascular involvement, which is associated with lower stage, fewer lymph node metastases, and less myometrial invasion; however, pathologists cannot consistently determine the procedure on histologic findings alone. Moreover, there is significant inter-observer variability in distinguishing true from artifactual vascular space involvement, even among pathologists at the same institution. The clinical significance of apparent true vascular space involvement seen adjacent to artifacts is unclear, as is the impact of laparoscopic hysterectomy on recurrence risk.

Epidemiologic correlates of ovarian cortical inclusion cysts (CICs) support a dual precursor pathway to pelvic epithelial cancer.

OBJECTIVE Many ovarian carcinomas are presumed to arise within ovarian cortical inclusion cysts (CICs). This study examined the frequency of ovarian CICs in relation to epidemiologic risk factors in women with BRCA1 and BRCA2 (BRCA+) mutations. METHODS BRCA+ women who underwent risk-reducing bilateral salpingo-oophorectomy were studied (n=74). Fifteen demographic variables (e.g., age at time of surgery, age at first birth, age at menopause, body mass index (BMI), gravidity) from a review of the medical records and three pathologic variables (cystic and atretic follicles, corpora lutea) were recorded. Statistical associations were made using T-test or Chi Square analysis and logistic regression analysis for p-trend. RESULTS Women whose ovaries contained 7 for more CICs were older at first birth (p=0.034), surgery (p=0.059), menopause (p=0.046) and had a higher BMI (p=0.034) than those with <7 CICs. Regression analysis revealed a significant association between CICs and increasing BMI (p=0.01). CONCLUSIONS CICs correlate with greater body mass index, similar to low-grade serous and endometrioid tumors and in contrast to high-grade serous carcinoma and its putative precursor in the fallopian tube. A model is presented for ovarian and tubal pathways to pelvic cancer that are linked to different microscopic precursors with distinct epidemiologic correlates.

The impact of tissue block sampling on the detection of p53 signatures in fallopian tubes from women with BRCA 1 or 2 mutations (BRCA+) and controls

The tubal p53 signature is a putative precursor to pelvic serous carcinoma, but its frequencies in women with inherited mutations in the BRCA1 or BRCA2 genes (BRCA+) and controls has been controversial. An initial section and two levels (100–200 μm) from every block in BRCA+ (24) and control tubes (40) were stained for p53. The frequency of p53 signatures was computed between the populations and across the three levels from each block, and analyzed by Fisher exact test. A total of 17 (71%) BRCA+ and 20 (50%) control tubes were p53 signature positive (P=0.12); 21 and 16% of all tissue blocks sectioned harbored signatures (P=0.29), and 76 and 67% were found in the fimbria. In 49 and 32% of p53 signature positive cases in the two groups, the p53 signatures were not discovered until the second or third round of sectioning. In all, 38 and 40% of BRCA+ and control subjects harbored p53 signatures in more than one focus in a single block. In one case (BRCA+), a highly atypical proliferation was identified in one serial section. The p53 signatures are more common than previously reported and the frequency of detection increases as a function of sectioning through the tissue block, both in absolute frequency and in numbers of p53 signatures detected in a given block. There is a trend for a higher absolute frequency of p53 signatures (71 vs 50%; P=0.12) in BRCA+ subjects, but this is not reflected in a greater average number of p53 signatures or positive blocks per case. This study underscores the importance of systematic immunohistochemical examination of fallopian tubes when conducting epidemiological studies that compare the frequency of p53 signatures in different populations. Attention to this detail is critical when exploring risk factors germane to early serous carcinogenesis.

Cost and turn-around time display decreases inpatient ordering of reference laboratory tests: a time series

Objective Reference tests, also known as send-out tests, are commonly ordered laboratory tests with variable costs and turn-around times. We aim to examine the effects of displaying reference laboratory costs and turn-around times during computerised physician order entry (CPOE) on inpatient physician ordering behaviour. Design We conducted a prospective observational study at a tertiary care hospital involving inpatient attending physicians and residents. Physician ordering behaviour was prospectively observed between September 2010 and December 2012. An intervention was implemented to display cost and turn-around time for reference tests within our CPOE. We examined changes in the mean number of monthly physician orders per inpatient day at risk, the mean cost per order, and the average turn-around time per order. Results After our intervention, the mean number of monthly physician orders per inpatient day at risk decreased by 26% (51 vs 38, p<0.0001) with a decrease in mean cost per order (US