Invasive High-grade Serous Carcinoma Research Articles

IGF-2 mediated hypoglycemia and the paradox of an apparently benign lesion: a case report & review of the literature

BackgroundNon-islet cell tumour hypoglycemia (NICTH) is rarely encountered in clinical practice. Insulin-like growth factor 2 (IGF2) is the most common cause of NICTH observed in the setting of mesenchymal and epithelial neoplasia. This is a paraneoplastic syndrome caused by IGF2 activation of the insulin receptor.Case presentationAn 80 year old female presented with a short history of recurrent episodes of confusion with laboratory confirmed hypoglycemia with a plasma glucose of 2.7 mmol/L on fasting which fulfilled Whipple’s triad. Diagnostic clues to the aetiology at presentation include the fasting pattern of hypoglycemia, hypokalaemia and the absence of weight gain. A 72 hour fast with results showed early hypoglycemia and suppression of serum insulin, c-peptide, and proinsulin. Serum insulin antibody was not detected. Subsequent measurement of the serum IGF2:IGF1 ratio was elevated at 22.3 and consistent with IGF-2 mediated hypoglycemia and imaging studies demonstrated a pelvic mass. Dietary intervention and oral prednisolone abated hypoglycemia prior to surgery. Ultimately, hypoglycemia resolved following operative intervention and steroid therapy was successfully withdrawn. Histopathology was remarkable for dual neoplastic processes with uterine solitary fibrous tumour (SFT) confirmed as the source of IGF2 hypersecretion on IGF-2 immunohistochemistry and a coincidental invasive high grade serous carcinoma involving the fimbria of the right fallopian tube.ConclusionThe paradox in this case is that the benign solitary fibrous tumour accounted for patient morbidity through secretion of IGF2 and without treatment, posed a mortality risk. This is despite the synchronous presence of a highly malignant fallopian tube neoplasm. This case reinforces the need for thorough clinical evaluation of hypoglycemia to allow prompt and definitive management.

Serous tubal intra-epithelial carcinoma: what do we really know at this point?

Serous tubal intra-epithelial carcinoma (STIC) is the earliest morphologically recognisable step in the development of invasive high-grade serous carcinoma of the fallopian tube. Lesions occurring prior to STIC within the carcinogenic sequence for the pathogenesis of invasive high-grade serous carcinoma include the p53 signature and secretory cell outgrowth (SCOUT). Variable histological criteria have been used for diagnosing STIC, but a combination of morphology and immunohistochemistry for p53/Ki-67 improves interobserver agreement. Half of all carcinomas identified in risk-reducing salpingo-oophorectomy specimens are in the form of STIC; however, STIC also may be incidentally found on occasion in specimens from women at low or average risk of ovarian/tubal/peritoneal carcinoma. TP53 mutation is the earliest known DNA sequence alteration in STIC and almost all invasive high-grade serous carcinomas of the ovary and peritoneum. Data on the clinical behaviour of STIC are limited. While the short-term follow-up in the prior literature suggests a low risk of malignant progression, a more recent meta-analysis indicates a 10-year risk of 28%. STIC probably should be best regarded as a lesion with uncertain malignant potential at present, and future molecular analysis will help to classify those with higher risk of dissemination. This review provides an update on the current knowledge of STIC and related issues.

Differential epithelial and stromal LGR5 expression in ovarian carcinogenesis

Lgr5 has been identified as a marker of the stem/progenitor cells in the murine ovary and oviduct by lineage tracing. However, little is known regarding LGR5 expression or its functional significance in human ovary tissues. Here, using RNA in situ hybridization and/or immunohistochemistry, we thoroughly investigated LGR5 expression in normal human ovaries, fallopian tubes and various ovarian tumors. We discovered that LGR5 expression is negligible in the human ovary surface epithelium, whereas ovarian stromal cells normally express low levels of LGR5. Remarkably, fallopian tube epithelium, inclusion cysts and serous cystadenomas with a Müllerian phenotype expressed high levels of LGR5, and LGR5 expression was restricted to PAX8+/FOXJ1− secretory cells of the tubal epithelium. Strong stromal LGR5 expression without epithelial LGR5 expression was consistently observed in the path from serous cystadenoma to serous borderline tumor to low grade serous carcinoma (LGSC). Unlike LGSC, high grade serous carcinoma (HGSC), clear cell carcinoma, endometrioid carcinomas displayed various epithelial-stromal LGR5 expression. Notably, high levels of LGR5 expression were observed in serous tubal intraepithelial carcinoma, which slightly declined in invasive HGSC. LGR5 expression was significantly associated with improved progression-free survival in HGSC patients. Moreover, in vitro assays demonstrated that LGR5 expression suppressed tumor proliferation and migratory capabilities. Taken together, these findings indicate a tumor-suppressive role for LGR5 in the progression of HGSC.

Immunohistochemical Expression Status of p53, CD44v9, and Ki-67 in a Series of Fallopian Tube Lesions of High-grade Serous Carcinoma.

Pelvic high-grade serous carcinoma (HGSC) has been postulated to arise via a stepwise accumulation of (epi)genetic alterations from normal epithelium to secretory cell outgrowth (SCOUT), p53 signature, and serous tubal intraepithelial carcinoma (STIC) to invasive HGSC. The aim of this study is to investigate alterations in p53 and CD44v9 expression and the status of Ki-67 labeling index in a series of fallopian tube lesions of HGSC patients. A total of 45 specimens were analyzed in 16 patients with HGSC, and their lesions were categorized as follows: morphologically normal fallopian tube epithelium (FTE, n=6 samples), SCOUT (n=5), p53 signature (n=4), dormant STIC (n=8), active STIC (n=6), and HGSC (n=16). Morphologic features and immunohistochemical expression patterns of the p53 protein, CD44v9 protein, and Ki-67 antigen were blindly evaluated by 2 pathologists. Increased nuclear p53 protein accumulation was observed in p53 signature, dormant STIC, active STIC and HGSC compared with normal FTE and SCOUT (P<0.001). Immunohistochemistry scores of CD44v9 protein expression were significantly higher in normal FTE, SCOUT, and p53 signature than in dormant STIC, active STIC, and HGSC (P<0.001). Both active STIC and HGSC had significantly higher Ki-67 labeling indices than normal FTE, SCOUT, p53 signature and dormant STIC (P<0.001). CD44v9 loss contributes to the stepwise progression of p53 signature to dormant STIC. In conclusion, p53 mutation followed by CD44v9 loss may be involved in the evolution of STIC, which may confer positive clonal selection with a growth and survival advantage.

Bulky peritoneal carcinosarcoma with tiny high-grade serous carcinoma of the fallopian tube: a case report.

Peritoneal carcinosarcoma is a highly aggressive and uncommon neoplasm that has carcinomatous and sarcomatous components; the malignancy rarely localizes to the omentum. We report a case of a bulky peritoneal carcinosarcoma with tiny high-grade serous carcinoma of the fallopian tube. A 60-year-old female with a huge pelvic mass (12cm in diameter) underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy for tumor debulking. Pathological findings showed minimally invasive high-grade serous carcinoma of the left fallopian tube and carcinosarcoma of the omentum. Similar p53 diffuse immunostaining in the omental carcinosarcoma and the tubal carcinoma provides evidence for a clonal relationship between the two neoplasias. This case suggests a small serous carcinoma, originating in the tubal mucosa, subsequently became implanted in the omentum and grew preferentially, converting to a carcinosarcoma at a remote site.

Results of a prospective phase II national study: Prophylactic radical fimbriectomy (NCT01608074), in women with a documented high risk of breast/ovarian cancer—Final pathological results and outcomes.

1594 Background: Risk-reducing salpingo-oophorectomy (RRSO) is the gold standard in surgical prophylaxis of pelvic high-grade serous carcinoma (HGSC) for women at risk of breast/ovarian cancer. Due to significant adverse effects of early oophorectomy, 20-30% of women delay or deny performing this operation. Recent data highlight the fallopian origin of most pelvic HGSC, especially its fimbrial part. Thus, we suggested a new two-step risk-reducing procedure: the radical fimbriectomy (RF) with delayed oophorectomy (DO) (Leblanc et al Gyn Oncol 2011), leading to the current RF/DO Phase 2 study. We present the definitive results on primary and secondary objectives of this trial. Methods: BRCA1/2 carriers or any women with a documented familial risk of breast/ovarian cancer were first counseled to perform a classical laparoscopic RRSO. If they denied, they were offered to enter the RF/DO study. All specimens were submitted to the SEE-FIM pathological protocol. Pathological data along with all intra- and 30-day and beyond post-operative adverse events were prospectively recorded. Follow-up consisted in an annual clinical breast and gynecological examination, with tumor markers and hormonal status assessment. Primary endpoint was the rate of pelvic serous carcinoma. Secondary endpoints were procedure morbidity, rates of tubal abnormalities, breast cancer, secondary oophorectomy. Results: From January 2012 to October 2014, 121 RF were performed: 120 by laparoscopy, 1 laparotomy (concurrent myomectomy). An occult neoplasia was found in 3 cases with 1 invasive HGSC. Intraoperative complications were two grade1 bleedings without transfusion with no grade ≥3 early post-operative or delayed complication. With a median follow-up of 5.3 years (0.2 -7.6), no patient developed any pelvic HGSC, 21 patients developed a breast cancer (3 de novo, 18 recurrences/contralateral.). 1 cancer-free BRCA1-mutated lady delivered safe twins, after an uneventful post-RF pregnancy obtained with assisted reproductive technology (ART). Overall, 29 women underwent DO (by choice: 12 or menopause: 17) resulting in grade 3b complication in 1 case, but no pathological abnormality. Conclusions: RF/DO appears as a safe, well tolerated and effective procedure in terms of occult neoplasia detection. A successful pregnancy with ART was possible after radical fimbriectomy. Longer follow-up and larger cohort are necessary to confirm its efficacy in terms of ovarian cancer prophylaxis. Clinical trial information: NCT01608074.

Morphologic features of fallopian tubal epithelium in pelvic high-grade serous carcinoma

Objective: To study the pathologic features of fallopian tubal epithelium in patients with pelvic high-grade serous carcinoma (HGSC), to investigate its role in pelvic serous carcinogenesis and to reclassify the primary site of HGSC based on recently proposed criteria. Methods: The fallopian tubes in 58 cases of pelvic HGSC (54 cases of ovarian primary, 3 cases of tubal primary, 1 case of peritoneum) and 25 cases of pelvic non-HGSC (5 cases of ovarian low-grade serous cancer, 9 cases of endometrioid cancer, and 11 cases of clear cell ovary carcinoma) were collected from June 2015 to December 2016, and serially examined under light microscope (SEE-FIM protocol). Immunostaining for p53 and Ki-67 was performed to evaluate the presence of p53 signature, serous tubal intraepithelial lesion (STIL), serous tubal intraepithelial carcinoma (STIC) and invasive carcinoma in these fallopian tubes. Meanwhile, primary site of HGSC based on the recently proposed diagnostic criteria were also reclassified. Results: Among the study group, the frequencies of p53 signature, STIL, STIC and invasive HGSC were 27.6% (16/58), 43.1% (25/58), 36.2% (21/58) and 67.2% (39/58), respectively, while in control group, the proportions were 24.0% (6/25), 0, 0 and 8.0% (2/25), respectively. The continuum of epithelial changes in the process of serous neoplasia including p53 signature, STIL, STIC and invasive carcinoma was identified in 8 cases of pelvic HGSC. The proportions of STIL, STIC and invasive carcinomas in HGSC group were higher than that in non-HGSC group (P<0.01). About 80.0% (20/25) of STIL and 85.7% (18/21) of STIC were present unilaterally. Diagnostically, the study group contained the 17 cases of ovarian HGSC, 40 cases of tubal HGSC, and 1 case of peritoneal HGSC after reclassification of the cancer primary. Conclusions: Continuous changes of tubal epithelium including p53 signature, STIL, STIC and invasive carcinomas are identified in patients with HGSC, supporting the current understanding that the fallopian tube is likely the cellular source of the majority HGSC. STIL and STIC may be specific to pelvic HGSC and may act as a target for future research on the early detection and prevention of this disease. The newly proposed diagnostic criteria for pelvic HGSC will lead us to more accurate classification of cancer primary sites. Correct classification of HGSC may have potential impacts for cancer prevention and improve our understanding of ovarian serous carcinogenesis.

Changes in the Extracellular Matrix Are Associated With the Development of Serous Tubal Intraepithelial Carcinoma Into High-Grade Serous Carcinoma.

The identification of a marker for early progression of preinvasive lesions into invasive pelvic high-grade serous carcinoma (HGSC) may provide novel handles for innovative screening and prevention strategies. The interplay between cancer cells and the extracellular matrix (ECM) is one of the main principles in cancer development and growth, but has been largely neglected in preinvasive lesions. This is the first study addressing the involvement of the ECM in the "step-by-step" transition of normal fallopian tube epithelium into preinvasive lesions, and eventually the progression of preinvasive lesions into invasive HGSC. The expression of highly sulfated chondroitin sulfate (CS-E), a characteristic glycosaminoglycan of the cancer-associated ECM, was assessed by immunohistochemistry in a large cohort of precursor lesions of the full spectrum of HGSC development, including 97 serous tubal intraepithelial carcinomas (STICs), 27 serous tubal intraepithelial lesions, and 24 p53 signatures. In addition, the immunological reactivity in the microenvironment was evaluated. Increased stromal expression of highly sulfated CS-E was observed in 3.7%, 57.7%, and 90.6% of serous tubal intraepithelial lesions, STICs, and invasive HGSCs, respectively (P < 0.001). No or limited expression was found in p53 signatures and normal tubal epithelium (compared with STIC, P < 0.001). A gradual increase in the amount of CS-E expression between STIC and paired HGSC was demonstrated. Intense stromal CS-E expression in STIC was significantly associated with an immune infiltrate (P < 0.001). Our study showed that increased stromal CS-E expression is related to the degree of the tubal epithelium abnormality. Specific alterations in the ECM (ie, CS-E expression) occur early in pelvic HGSC development and may represent a novel biomarker of early cancer progression, useful for the identification of novel clinical strategies.

Outcomes of Incidental Fallopian Tube High-Grade Serous Carcinoma and Serous Tubal Intraepithelial Carcinoma in Women at Low Risk of Hereditary Breast and Ovarian Cancer.

The natural history and optimal management of serous tubal intraepithelial carcinoma (STIC), regardless of BRCA status, is unknown. We report the follow-up findings of a series of incidental fallopian tube high-grade serous carcinomas (HGSCs) and STICs identified in women at low risk for hereditary breast and ovarian cancer (HBOC), undergoing surgery for other indications. Cases of incidental STIC and HGSC were identified from 2008. Patients with known BRCA1 or BRCA2 mutations, or a family history of ovarian or breast cancer before the diagnosis of STIC or HGSC were excluded. A retrospective chart review was conducted to obtain clinical data. Eighteen cases were identified with a median follow-up of 25 months (range, 4-88 months). Twelve of 18 patients had a diagnosis of STIC with no associated invasive HGSC and 6 had STIC associated with other invasive malignancies. Completion staging surgery was performed on 7 of the 18 patients, including 5 of 12 in which there was STIC only identified on primary surgery; 3 cases were upstaged from STIC only to HGSC based on the staging surgery. Recurrence of HGSC occurred in 2 of the 18 patients. BRCA testing was performed on 3 patients, 1 of whom tested positive for a pathogenic BRCA1 mutation. Our study suggests that completion staging surgery for incidental STICs in non-BRCA patients may be considered. These patients should be offered hereditary testing. The Pelvic-Ovarian cancer INTerception (POINT) Project is an international registry set up to add to our understanding of STICs.

Stathmin 1 and p16INK4A are sensitive adjunct biomarkers for serous tubal intraepithelial carcinoma

ObjectiveTo credential Stathmin 1 (STMN1) and p16INK4A (p16) as adjunct markers for the diagnosis of serous tubal intraepithelial carcinoma (STIC), and to compare STMN1 and p16 expression in p53-positive and p53-negative STIC and invasive high-grade serous carcinoma (HGSC). MethodsImmunohistochemistry (IHC) was used to examine STMN1 and p16 expression in fallopian tube specimens (n=31) containing p53-positive and p53-negative STICs, invasive HGSCs, and morphologically normal FTE (fallopian tube epithelium). STMN1 and p16 expression was scored semiquantitatively by four individuals. The semiquantitative scores were dichotomized, and reported as positive or negative. Pooled siRNA was used to knockdown p53 in a panel of cell lines derived from immortalized FTE and HGSC. ResultsSTMN1 and p16 were expressed in the majority of p53-positive and p53-negative STICs and concomitant invasive HGSCs, but only scattered positive cells were present in morphologically normal FTE. Both proteins were expressed consistently across multiple STICs from the same patient and in concomitant invasive HGSC. Knockdown of p53 in immortalized FTE cells and in four HGSC-derived cell lines expressing different missense p53 mutations did not affect STMN1 protein levels. ConclusionsThis study demonstrates that STMN1 and p16 are sensitive and specific adjunct biomarkers that, when used with p53 and Ki-67, improve the diagnostic accuracy of STIC. The addition of STMN1 and p16 helps to compensate for practical limitations of p53 and Ki-67 that complicate the diagnosis in up to one third of STICs.

Ovarian high-grade serous carcinoma with a noninvasive growth pattern simulating a serous borderline tumor.

Ovarian serous borderline tumors (SBTs) being a precursor of low-grade serous carcinomas are morphologically characterized by noninvasive growth and low-grade cytology. On the other hand, many pathologists regard cytologically high-grade, noninvasive (HG-noninv) ovarian serous tumors resembling SBTs in low magnification as conventional high-grade serous carcinomas (HGSCs) by personal experiences. Nonetheless, there are no established molecular characteristic of such tumors. In this study, therefore, we attempted to provide the molecular evidence. We selected 37 ovarian serous tumors that exhibited a cytologically HG-noninv growth pattern, including 36 tumors that coexisted with conventional invasive HGSC components (HG-inv) and a single tumor exclusively composed of pure HG-noninv. Histologically, all HG-noninv showed many mitotic figures, and serous tubal intraepithelial carcinomas were identified in 3 tumors with HG-noninv. Immunohistochemically, most HG-noninv showed aberrant p53 expression, frequent IMP3 positivity, p16 overexpression, a high MIB-1 labeling index, and infrequent PAX2. By molecular analysis, the pure HG-noninv and 13 HGSCs with HG-noninv showed TP53 mutations, but KRAS/BRAF mutations were not detected in any of them. In 1 tumor, we detected an identical TP53 mutation in both HG-noninv and HG-inv components by using laser capture microdissection. These immunohistochemical and molecular features of HG-noninv were similar to those of conventional invasive HGSCs but different from those of SBTs. In conclusion, our results showed that a cytologically HG-noninv growth pattern simulating an SBT is a morphological spectrum of HGSC, but not a true SBT.

Incidental serous tubal intraepithelial carcinoma and early invasive serous carcinoma in the nonprophylactic setting: analysis of a case series.

A precursor for invasive ovarian/pelvic high-grade serous carcinoma, termed serous tubal intraepithelial carcinoma (STIC), has been identified and characterized through careful analysis of the fallopian tubes in both prophylactic salpingo-oophorectomy specimens obtained from women with either a family history of breast and/or ovarian cancer or germline mutations of BRCA1 and BRCA2 and in cases of pelvic high-grade serous carcinoma. Data on incidental STICs and clinically occult microscopic invasive high-grade serous carcinomas are limited. We analyzed the clinicopathologic features of 22 cases, including 15 pure STICs and 7 STICs associated with microscopic invasive high-grade serous carcinomas, identified incidentally in fallopian tubes removed for nonprophylactic indications. Patient age ranged from 39 to 79 years (mean: 62.7; median: 61), with only 1 patient under the age of 50. No patients were known to carry BRCA1 or BRCA2 mutations. Of the 12 pure STICs for which the location in the fallopian tube could be established, 9 were in the fimbriated portion, 1 was at the junction of the fimbria and infundibulum, and 2 were in the nonfimbriated tube. Of the 7 STICs with associated invasive high-grade serous carcinoma, 3 were located in the fimbriated portion, 2 were at the junction of the fimbria and infundibulum, and 2 were in the nonfimbriated tube. The invasive components were in the fallopian tube in 6 cases, 4 in subepithelial stroma of tubal mucosa, and 2 as an intramucosal (exophytic) luminal lesion without invasion of underlying subepithelial stroma (size range: 1 to 4 mm). The remaining case had a microscopic focus of high-grade serous carcinoma within the ipsilateral ovary (1.3 mm cortical focus) identified only on deeper sections, without an associated invasive component in the fallopian tube. The preferential finding of atypical epithelium with the cytologic features of high-grade serous carcinoma, namely STIC, in the fallopian tubes rather than the ovaries as an incidental (clinically occult) microscopic lesion in the absence of widespread pelvic carcinoma provides further evidence that STIC is the earliest form of pelvic high-grade serous carcinoma and that the fallopian tube is the site of origin. This study demonstrates the potential for complete examination of the fallopian tubes and ovaries to identify STICs and early invasive serous carcinomas that might be more amenable to the earliest intervention and potential cure.

Incidental nonuterine high-grade serous carcinomas arise in the fallopian tube in most cases: further evidence for the tubal origin of high-grade serous carcinomas.

Most nonuterine high-grade serous carcinomas (HGSCs) in women with hereditary breast and ovarian cancer syndrome, due to germline BRCA1/2 mutation, arise in the fimbria of the fallopian tube. However, the site of origin of sporadic HGSC, which is usually widely disseminated at presentation, is not well established. We sought to characterize cases of HGSC discovered incidentally in patients not known to be at high risk, in order to determine the site distribution and possible origin of sporadic HGSC. Incidental microscopic, non-mass-forming cases of serous tubal intraepithelial carcinoma or HGSC in salpingo-oophorectomy specimens in which the tubes and ovaries had been extensively examined were identified. No patients were known or suspected BRCA1/2 mutation carriers. Twenty-one cases were identified (mean age: 57 y). Surgery was for benign disease (n=15), uterine endometrioid adenocarcinoma or atypical hyperplasia (n=3), bladder carcinoma (n=1), or ovarian serous borderline tumor (n=2). In 16 of 21 cases, the lesion was confined to the fallopian tube (unilateral in 14 cases, bilateral in 2). There was serous tubal intraepithelial carcinoma in all cases and invasive HGSC into the underlying lamina propria in 8 of these 16 cases; the invasive focus measured 1.3 cm or less in every case. In the remaining 5 cases, there was fallopian tube mucosal and ovarian involvement; in 2 of these cases, there was also microscopic peritoneal involvement. Sporadic cases of nonuterine HGSC arise in the fallopian tube fimbria in a large majority of cases, providing further evidence for the tubal origin of these neoplasms.

A genetically engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high‐grade serous carcinoma development

Recent evidence suggests that ovarian high-grade serous carcinoma (HGSC) originates from the epithelium of the fallopian tube. However, most mouse models are based on the previous prevailing view that ovarian cancer develops from the transformation of the ovarian surface epithelium. Here, we report the extensive histological and molecular characterization of the mogp-TAg transgenic mouse, which expresses the SV40 large T-antigen (TAg) under the control of the mouse müllerian-specific Ovgp-1 promoter. Histological analysis of the fallopian tubes of mogp-TAg mice identified a variety of neoplastic lesions analogous to those described as precursors to ovarian HGSC. We identified areas of normal-appearing p53-positive epithelium that are similar to 'p53 signatures' in the human fallopian tube. More advanced proliferative lesions with nuclear atypia and epithelial stratification were also identified that were morphologically and immunohistochemically reminiscent of human serous tubal intraepithelial carcinoma (STIC), a potential precursor of ovarian HGSC. Beside these non-invasive precursor lesions, we also identified invasive adenocarcinoma in the ovaries of 56% of the mice. Microarray analysis revealed several genes differentially expressed between the fallopian tube of mogp-TAg and wild-type (WT) C57BL/6. One of these genes, Top2a, which encodes topoisomerase IIα, was shown by immunohistochemistry to be concurrently expressed with elevated p53 and was specifically elevated in mouse STICs but not in the surrounding tissues. TOP2A protein was also found elevated in human STICs, low-grade and high-grade serous carcinoma. The mouse model reported here displays a progression from normal tubal epithelium to invasive HGSC in the ovary, and therefore closely simulates the current emerging model of human ovarian HGSC pathogenesis. This mouse therefore has the potential to be a very useful new model for elucidating the mechanisms of serous ovarian tumourigenesis, as well as for developing novel approaches for the prevention, diagnosis and therapy of this disease.

Immunophenotypic comparison of CK7 and CK5 in normal and neoplastic fallopian tube mucosa

In the lower genital tract, CK7 is most strongly expressed in the cervical squamocolumnar junction and surface endometrial lining suggesting a link to progenitor cells; CK5 is typically expressed in basal and reserve cells and related proliferations. Both are expressed in the mesothelium. We studied 38 benign and neoplastic tissue sections from 18 high grade serous carcinomas (HGSCs) and clonogenic cell cultures from adult and fetal fallopian tube. CK7+ cells in vitro behaved as progenitor cells, becoming CK7- upon ciliated or basal (CK5+) differentiation. In normal tube, CK7+ was most intense in the apices and sides of the plicae and occasionally diffuse in atrophic epithelium. In intramucosal (STICs) and invasive HGSCs, CK7+ was typically non-uniform and strongest on the luminal borders, while CK5 staining was usually less intense albeit occasionally strong. These findings support a model where progenitor CK7+ cells give rise to CK5+ in both benign and malignant tubal epithelium. In this model, the apical localization of CK7+ suggests that progenitor-type cells in this setting might actually be luminal rather than basal. Given the unique location of CK7+ to CK5+ transitions in the fimbria, the possibility of a novel tumorigenic pathway near the Mullerian-mesothelial junction bears further study.

Clinically Occult Tubal and Ovarian High-grade Serous Carcinomas Presenting in Uterine Samples

We report the clinicopathologic and immunohistochemical features in 8 patients with tubal or ovarian high-grade serous carcinoma that was present in uterine samples, in which there was the potential for clinical and morphologic misinterpretation as a primary uterine lesion before hysterectomy/bilateral salpingo-oophorectomy. Patients ranged in age from 45 to 70 yr (mean, 57 yr). The initial presentation was variable, ranging from incidental findings on routine Pap smears to pleural effusion. During the preoperative clinical investigation, 7 of 8 patients did not have evidence of an adnexal tumor based on physical examination and radiologic imaging, and serum CA-125 levels were normal to low in 4 of 5 patients. Six patients required multiple rounds of uterine samples, and the preoperative uterine specimens that contained lesional tissue and were available for rereview in all 8 patients included endometrial biopsies/curettages (n=6), endocervical curettages (n=3), Pap smears (n=2), and a hysteroscopic myomectomy specimen (n=1). The amount of carcinoma in these specimens was typically scanty. The lesions in most cases were characterized by detached and minute epithelial clusters, small papillae, and/or individual cells. The constituent glandular cells exhibited notable atypia. Psammoma bodies were identified in only 2 cases. Immunostains for WT-1 were positive in 3 of 4 preoperative specimens. All patients ultimately underwent a hysterectomy/bilateral salpingo-oophorectomy, which revealed an invasive high-grade serous carcinoma of tubal (n=6) or ovarian (n=2) origin. The mean/median tumor size was 3.2/1.7 cm. Transtubal spread was considered the most likely mechanism resulting in tubal/ovarian carcinoma being found in the preoperative uterine samples. These findings highlight the deceptive clinical features of some tubal/ovarian high-grade serous carcinomas, and demonstrate that small and clinically undetectable adnexal high-grade serous carcinomas can initially present in uterine biopsies/curettages. To guide clinical evaluation more accurately and prevent histologic misdiagnosis/misclassification, a possible adnexal origin should be considered in the differential diagnosis of small, detached, and markedly atypical glandular fragments in endometrial or cervical specimens, and immunohistochemical staining for WT-1 is recommended in this setting.

Expression of BRAF V600E Mutant Protein in Epithelial Ovarian Tumors

Genetic analyses have identified BRAF V600E mutations in a subset of ovarian carcinomas. The aim of this study was to investigate the expression of BRAF V600E aberrant protein using a novel mutation-specific antibody in epithelial ovarian tumors. We immunohistochemically analyzed expression of V600E-mutant BRAF protein in archival formalin-fixed, paraffin-embedded tissue specimens of 142 epithelial ovarian tumors [98 invasive carcinomas and 44 tumors of low malignant potential (LMP)] using monoclonal antibody VE1. BRAF mutation status was validated in all immunopositive cases and in 6 immunonegative control cases by gene sequencing. We found anti-BRAF V600E immunolabeling in 4 serous carcinomas and 5 serous LMP. Presence of a BRAF V600E mutation was confirmed by sequencing analysis in 6 of the 9 cases (3 LMP tumors, 3 low-grade carcinomas). In 2 partially VE1-positive tumors deriving from 1 patient (1 LMP and 1 contralateral invasive high-grade serous carcinoma), genetic analysis repeatedly resulted in BRAF wild-type, arguing for false-positive immunostaining results. One immunopositive case was repeatedly inconclusive in genetic analysis. In all 6 genetically confirmed cases, BRAF V600E mutant protein expression was homogenous throughout the tumor tissue. We found BRAF V600E mutations in 13% (4/31) of serous LMP and 5% (3/62) of invasive serous carcinomas. No BRAF V600E mutations were detected in nonserous epithelial ovarian tumors. For reliable assessment of the BRAF V600E status in ovarian epithelial tumor samples, an integrated approach using immunohistochemistry and genetic analysis seems advisable, as both methods lead to incorrect results in some cases.

Fallopian tube precursors of ovarian low‐ and high‐grade serous neoplasms

Traditionally, it was thought that ovarian high-grade serous carcinoma arises from the ovarian surface epithelium and epithelial inclusion glands and that the pathogenesis is de novo; nonetheless, a convincing precursor in the ovary or peritoneum has not been identified to date. During the last few years, however, there has been a dramatic shift in thinking, and a candidate precursor is now recognized in the fallopian tube, especially within the fimbriated end - serous tubal intra-epithelial carcinoma (STIC). Accordingly, STIC is probably the earliest histologically recognizable lesion in the pathogenesis of high-grade serous carcinoma, but steps in this pathway which precede STIC have also been proposed. With subsequent progression, STIC implants onto the ovary and then develops into an invasive high-grade serous carcinoma with rapid tumour growth. For invasive low-grade serous carcinoma, it is well-established that its pathogenesis begins with serous cystadenoma/adenofibroma, which develops sequentially into atypical proliferative serous tumour (typical serous borderline tumour), non-invasive micropapillary (low-grade) serous carcinoma (micropapillary serous borderline tumour) and then invasive low-grade serous carcinoma in a relatively slow stepwise process. It is presumed that cystadenoma/adenofibroma arises from epithelial inclusion glands in the ovary, but recent evidence suggests that epithelial inclusion glands originate in the fallopian tube. Alternatively, it has been proposed that the other early precursors in the low-grade pathway, including serous borderline tumours, non-invasive implants and endosalpingiosis, may also arise directly from tubal mucosa. Therefore, the precursor of most ovarian high-grade serous carcinomas originates in the fallopian tube, and that for low-grade serous tumours may also be derived from the tube. This review paper provides an overview of the fallopian tube's potential role in the pathogenesis of both types of serous neoplasms of the ovary.

Different proportions of aneusomic cells in ovarian inclusion cysts associated with serous borderline tumours and serous high‐grade carcinomas support different pathogenetic pathways

Ovarian serous tumours may arise from the ovarian surface epithelium or from ovarian cortical epithelial inclusion cysts. However, little is known about the pathogenetic mechanisms involved in the progression from ovarian surface epithelium or inclusion cysts to neoplastic disease. In the present study, chromosomal aberrations typical of ovarian serous tumours were studied in ovarian surface epithelium and inclusion cysts. Ten ovaries with inclusion cysts obtained from patients without a gynaecological tumour, as well as 15 serous borderline tumours and 16 invasive high-grade serous carcinomas with inclusion cysts either in the ipsi- or in the contralateral ovary, were investigated by fluorescence in situ hybridization (FISH) using centromere enumeration probes directed against chromosomes 1, 6, 7, and X. The proportions of aneusomic cells were assessed. Trisomies 1 and 7 and monosomies 6 and X were present in the surface epithelium, inclusion cysts, and tumours, providing evidence for a link between the surface epithelium, and inclusion cysts, and serous neoplasia. Inclusion cysts generally harboured more aneusomic cells than the associated surface epithelium, suggesting an influence of the ovarian stroma on the development of chromosomal instability. Moreover, inclusion cysts associated with borderline tumours displayed a higher proportion of aneusomic cells than inclusion cysts associated with invasive high-grade carcinoma and than inclusion cysts in ovaries without neoplastic disease. These results suggest a genetic field defect of the inclusion cyst epithelium in serous borderline tumours. Invasive high-grade serous carcinomas, by contrast, may arise from single cell clones subject to a different set of genetic events.