Incidental Serous Tubal Intraepithelial Carcinoma Finding in a Nepalese Patient Undergoing Opportunistic Salpingectomy and the Discovery of a BRCA1 Pathogenic Variant

Abstract

Background

Serous tubal intraepithelial carcinoma (STIC) lesions are the precursor to high grade serous ovarian carcinomas (HGSC) which have the highest mortality rate among gynecologic malignancies. Among women diagnosed with HGSC, 20% are found to be secondary to hereditary causes with the majority being associated with germline pathogenic variants (PVs) in BRCA1 and BRCA2 genes. Patients with a PV are high risk for developing HGSC, so it is recommended that they undergo risk reducing salpingo-oophorectomies in their 30s-40s. Opportunistic salpingectomy is the only ovarian cancer prevention method available for average risk patients. While STIC lesions are rare in average risk women, studies quote incidental STIC lesion findings in 1–7% of patients undergoing opportunistic salpingectomy.

Case

A 38-year-old woman (gravida 2, para 2) of Nepalese ethnicity had an incidental finding of a STIC lesion at the time of opportunistic salpingectomy for permanent sterilization at cesarean delivery. The STIC lesion was found using representative sampling of the fallopian tubes since the patient was considered average risk for ovarian cancer. This method is much less sensitive than SEE-FIM protocol which is used with known high-risk women. This ultimately led to discovery of a BRCA1 mutation in the patient.

Conclusion

SEE-FIM protocol is used to identify STIC lesions, but it is not routinely used on average risk patients’ fallopian tubes. Using SEE-FIM protocol would lead to less missed STICs, but it is unclear how much extra cost and effort would be required to implement this. There are knowledge gaps when it comes to understudied populations and hereditary breast and ovarian cancer (HBOC) gene prevalence. Studies show that current BRCA prediction models underestimate HBOC gene prevalence in Asian populations. Diagnosing STICs in understudied populations could lead to the discovery of an HBOC PV which the patient may not have discovered until after a cancer diagnosis. Identification of a STIC in an average risk patient should lead to a referral for genetic counseling and screening.

Precis

An incidental serous tubal intraepithelial carcinoma in a Nepalese woman undergoing opportunistic salpingectomy at the time of cesarean delivery led to the discovery of a BRCA1 pathogenic variant.

Introduction

Epithelial ovarian cancer (EOC) has the highest mortality rate among gynecologic malignancies. Although survival rates have improved over the last 40 years, in women with advanced-stage disease at diagnosis, the 5-year survival rate remains less than 50% in high income countries [1]. The majority (75%) of newly diagnosed EOCs are high-grade serous carcinomas (HGSC) [2]. Among women diagnosed with HGSC, 20% are found to be secondary to hereditary causes with the majority being associated with germline pathogenic variants (PVs) in BRCA1 and BRCA2 genes [1]. Given the dramatically increased lifetime risk of EOC associated with BRCA1 or BRCA2 PVs, women without cancer with these gene PVs are recommended to undergo risk reducing salpingo-oophorectomy (RRSO) between the ages of 35–40 and 40–45, respectively [2].

As more patients with BRCA PVs underwent RRSO, it was discovered that many had serous tubal intraepithelial carcinoma (STIC) lesions [3]. This led to the hypothesis that most HGSCs do not come from the ovary but from the fallopian tube [3]. STICs are the precursor lesions to HGSC and over 90% of STIC lesions are found in the fimbriated end of the fallopian tubes [4]. Given this discovery, among average risk women, one ovarian cancer reduction strategy that has been widely adopted and is supported by American College of Obstetricians and Gynecologists is opportunistic salpingectomy, which has quickly become widely accepted at the time of benign hysterectomy and as the preferred method for elective permanent tubal sterilization [5]. While STIC lesions are found in 70% of specimens when there is a concurrent invasive cancer and in 2–8% of specimens when invasive cancer is absent at the time of RRSO in patients with PVs in BRCA1 and BRCA2, incidental STIC diagnoses at the time of opportunistic salpingectomy for average risk women do occur [6]. A meta-analysis describing pathology findings in the setting of opportunistic salpingectomy demonstrated that somewhere between 1–7% of women who undergo opportunistic salpingectomy have an incidental STIC lesion identified [7]. A systematic review by Patrono et al found that 4.5% of BRCA PV carriers who had a STIC at the time of RRSO went on to develop a primary peritoneal carcinoma [8]. The clinical management in the setting of an isolated STIC lesion remains unclear beyond determining whether a concomitant HGSC exists. Furthermore, the actual incidence of STIC lesions within opportunistically removed fallopian tubes is unknown as the fallopian tubes may not be microscopically examined in the same fashion for an average risk person as they are among people known to be BRCA1 or BRCA2 PV carriers. Here we present a 38-year-old Nepalese woman ultimately diagnosed with a BRCA1 PV following the finding of a STIC lesion after undergoing an opportunistic salpingectomy performed for elective permanent sterilization at the time of cesarean delivery.

Case

A 38-year-old woman (gravida 2, para 2) of Nepalese ethnicity was referred after an incidental finding of a STIC lesion. At the time of her second delivery via repeat cesarean delivery, she underwent bilateral opportunistic salpingectomy for elective permanent sterilization. The pathologist that evaluated her fallopian tubes identified a unilateral STIC lesion that was 1 mm in size. The patient’s medical history was unremarkable and there was no family history of breast or ovarian cancers.

Upon clinical referral for further management in the setting of a STIC, pathological review of her fallopian tube slides by a gynecologic pathologist confirmed the diagnosis of a STIC lesion. Imaging, including a CT of the chest, abdomen, and pelvis and a CA-125 level were completed. Her imaging was unremarkable and her CA-125 was 6.6 U/mL. Genetic counseling and subsequent germline genetic testing were recommended. At her genetic counseling appointment, a thorough family history was taken (Figure 1). The patient’s pedigree included the patient’s two sons, one brother, and her parents that had no reported cancers. There was a limited paternal family structure as her father is an only child. Also, of note there were limited first degree female relatives. The patient elected to pursue the Common Hereditary Cancers panel through Invitae Genetics Laboratory. This genetic panel includes 47 genes shown to be associated with hereditary cancers. The patient was found to carry a deleterious loss-of-function BRCA1 PV, specifically c.2214dup (p. Lys739*). The patient’s parents both subsequently underwent genetic testing with the same Invitae panel, and her father was positive for the BRCA1 PV.

Figure 1.

Patient’s family pedigree

Given the STIC lesion and new diagnosis of BRCA1 PV, bilateral oophorectomy was recommended. In addition, the patient was counseled on the potential increase in risk of serous endometrial carcinomas in the setting of BRCA1 PVs [9]. The patient was referred for a consultation with the breast clinic due to her increased risk of breast cancer. At that time, the patient was breast feeding. It was recommended that the patient have a screening mammogram, clinical breast exam, an MRI in six months’ time, and surgical consultation for prophylactic mastectomy at least 3 months after completion of breastfeeding. The screening mammogram and breast exam were normal.

Ultimately, the patient elected to undergo a laparoscopic-assisted vaginal hysterectomy, bilateral oophorectomy, and omentectomy. The final pathology was benign and pelvic washing cytology was negative for abnormality. Since surgery, she has been followed by her local gynecologist for 27 months with pelvic exams and CA125 levels every 3 months with normal exam findings and CA125 levels ranging from 5 – 11 U/mL. Her surveillance plan includes continuing exams and CA-125 levels every 3 months for 2 years from the diagnosis of her STIC lesion and after that, every 6 months until she is 5 years out from the STIC diagnosis. The patient also chose to undergo a prophylactic bilateral mastectomy 35 months after the BRCA1 testing and final pathology was also benign.

Discussion

STIC lesions are most often described as microscopic foci <1 mm which makes them challenging to identify without complete microscopic evaluation of the fallopian tube [6]. In general, pathologists use one of two methods when evaluating fallopian tubes. The classical method, also known as representative sampling, involves collection of three “ring-shaped” sections from various parts of each tube [10]. The other method, called “Sectioning and Extensively Examining the Fimbria” or the SEE-FIM protocol, optimizes visualization of the fimbriae by sectioning the ampullary portion of the fallopian tube by 2–3 mm intervals and then the infundibulum is sectioned longitudinally to thoroughly evaluate the fimbrial mucosa [10]. A study by Lakkulrath et al compared the diagnostic probability of identifying a STIC with both approaches among 70 patients with ovarian HGSC. Among the 25 patients (35.7% of the cohort) diagnosed with a STIC lesion 24 (96%) were missed on representative sampling but were discovered when using the SEE-FIM protocol [4]. A study by Koc et al. compared 39 cases of HGSC examined by the SEE-FIM protocol with 113 cases of HGSC in which representative sampling was utilized on the fallopian tubes [10]. Within the SEE-FIM group, there were 15 (38% of the cohort) STIC lesions identified, while the representative sampling method identified only 1 STIC (0.9% of the cohort) [10]. When SEE-FIM protocol is utilized, the rate of STIC identification appears to be higher [6]. In an average risk patient, the pathologist typically uses the classical method for sampling the tube. Therefore, the true incidence of STIC diagnoses in patients presumed to be at average risk for ovarian cancer and undergoing opportunistic salpingectomy is not known. This brings up the discussion as to whether SEE-FIM protocol should be used for all fallopian tube specimens. There are few studies examining the added time and cost of using SEE-FIM protocol. In the study done by Laakulrath et al they examined cost of using SEE-FIM protocol on the cases of HGSC and found that on average it cost an additional 3 United States Dollars to identify one case of HGSC [4]. While the rates of STIC lesions in average risk women are low, the impact of identifying a STIC could be lifesaving if that leads to the diagnosis of a hereditary breast and ovarian cancer (HBOC) PV.

The prevalence of HBOC PVs differs among various ethnic groups and there are limited studies assessing the prevalence of HBOC PVs in Asian populations. Current BRCA1 and BRCA2 prediction models, including BRCAPRO [11], Couch [12], Myriad II [13], BOADICEA [14], and Manchester [15] were formulated using PV data from Caucasian populations. Studies assessing the BRCA prediction models suggest there is an underestimate of the risk of BRCA1 or BRCA2 PVs in Asian populations [16]. A study by Kurian et al. found that the BRCAPRO and Myriad II models underestimated BRCA1 or BRCA2 mutation in Asian Americans by two-fold [17]. A second study on the Korean population found that both BRCAPRO and Myriad II underestimated the number of BRCA 1 and BRCA2 PVs [18]. In addition, a study looking at the Chinese population found that Myriad II and BOADICEA underestimated the prevalence BRCA 1 or BRCA 2 [19]. Therefore, an overwhelming amount of evidence suggests that Asian populations are not accurately assessed by current BRCA prediction models. Studies are needed in each Asian ethnicity to better understand the true prevalence of HBOC genes and to provide better care for these patients.

Genetic testing for BRCA1 and BRCA 2 PVs has many factors, including personal history, family history, pathology/histology, and requires extensive counseling and risk assessments. The National Comprehensive Cancer Network (NCCN) criteria for testing HBOC genes are used to identify patients eligible for genetic testing and insurance coverage. Currently, these guidelines have no recommendations for genetic testing when a STIC is found in a presumed average risk patient. Studies have shown in RRSO surgeries for known BRCA1 and BRCA2 PVs the incidence of STICs ranges from 0.4–11% [20]. Since STIC lesions are significantly more common among HBOC PV patients, an incidental finding of a STIC in an average risk patient should be criteria for genetic counseling and testing. Furthermore, studies show that HBOC PV patients found to have a STIC have an increased risk of developing primary peritoneal carcinoma. A study done by Steenbeek et al. found that BRCA PV carriers with STIC at the time of RRSO had 10.5% risk at 5-years and a 27.5% risk at 10-years of developing primary peritoneal carcinoma [21]. This further shows the importance of identifying HBOC PVs and that genetic testing could be life saving for patients and their families in average risk women found to have STIC lesions.

Our case highlights the three main points of discussion. First, STIC lesions are difficult to identify, using the SEE-FIM protocol increases detection. Our patient incidentally had her STIC identified because the random representative sample chosen of the fimbriated end included it. If the STIC was missed the patient would not have undergone genetic testing which led to her diagnosis of being a BRCA1 PV carrier. Consideration of using SEE-FIM protocol on all fallopian tube specimens is needed to better understand the true prevalence of STIC lesions and increase identifying unknown high-risk patients. Research is needed to examine the cost and effort that incorporating this would take. Next, we highlight that Asian populations are understudied when it comes to HBOC genes. Asian populations likely have increased prevalence of HBOC genes but are inaccurately predicted by the current models meaning high risk patients are not being identified. Lastly, when a STIC is found in an ‘average risk’ patient genetic counseling and testing should be offered as it can lead to diagnosis of HBOC PVs.

Teaching points.

• Using SEE-FIM protocol on all fallopian tubes regardless of HBOC gene status would lead to less missed STICs, but it is unclear how much extra cost and time this would add.

• There is a knowledge gap when it comes to HBOC gene prevalence in understudied populations, especially Asian populations where current BRCA prediction models underestimate prevalence.

• When a STIC is found in an otherwise ‘average risk’ person, genetic counseling and testing should be offered.