diagnostics Review Serous Tubal Intraepithelial Carcinoma: A Concise Review for the Practicing Pathologist and Clinician S. Emily Bachert 1 , Anthony McDowell Jr. 2, Dava Piecoro 1 and Lauren Baldwin Branch 2,* 1 Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY 40536, USA; [email protected] (S.E.B.); [email protected] (D.P.) 2 Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Kentucky College of Medicine, Lexington, KY 40536, USA; [email protected] * Correspondence: [email protected] Received: 16 December 2019; Accepted: 8 February 2020; Published: 13 February 2020 Abstract: Ovarian cancer is the deadliest gynecologic malignancy, accounting for more than 14,000 deaths each year. With no established way to prevent or screen for it, the vast majority of cases are diagnosed as International Federation of Gynecology and Obstetrics (FIGO) stage III or higher. Individuals with germline BRCA mutations are at particularly high risk for epithelial ovarian cancer and have been the subject of many risk-reducing strategies. In the past ten years, studies looking at risk-reducing salpingo-oophorectomy (RRSO) in this population have uncovered an interesting association: up to 8% of women with BRCA1 or BRCA2 mutations who underwent RRSO had an associated serous tubal intraepithelial carcinoma (STIC). The importance of this finding is highlighted by the fact that up to 60% of ovarian cancer patients will also have an associated STIC. These studies have led to a paradigm shift that a subset of epithelial ovarian cancer originates not in the ovarian epithelium, but rather in the distal fallopian tube. In response to this, many providers have changed their practice by expanding the role of routine salpingectomy, hysterectomy, and sterilization procedures. The American College of Obstetricians and Gynecologists (ACOG) has acknowledged opportunistic salpingectomy as a safe strategy to reduce the risk of epithelial ovarian cancer in Committee Opinion #774. It is thus important for pathologists and clinicians to understand the definition of STIC; how it is diagnosed; and, most importantly, its clinical significance. Keywords: STIC; epithelial ovarian cancer; BRCA mutation 1. Background Information There are three broad categories of primary ovarian tumors: germ cell tumors, sex cord-stromal tumors, and surface/epithelial tumors. Surface epithelial tumors can be subclassified into five different cell types: Brenner, mucinous, clear cell, endometrioid, and serous. In each of these five cell types, tumors can range from benign to borderline (low-malignant potential) to malignant (carcinoma) [1]. Ovarian serous carcinomas can be further divided into low- and high-grade serous carcinomas (HGSOC), the latter being the focus of this review. Women in the United States have a lifetime risk of 1.38% for developing HGSCs, with a mean age of 63 years at presentation. HGSCs have a strong association with BRCA mutations and almost ubiquitously harbor TP53 mutations [2]. Unfortunately, HGSOCs carry a poor prognosis, representing over 70% of all epithelial ovarian cancer deaths [3]. Pathologists and clinicians can thus benefit from a better understanding of tumor pathogenesis. For a multitude of reasons to be discussed in this review, the current prevailing theory is that HGSOCs arise from STICs of the fallopian tube. Diagnostics 2020, 10, 102; doi:10.3390/diagnostics10020102 www.mdpi.com/journal/diagnostics Diagnostics 2020, 10, 102 2 of 8 Diagnostics 2020, 10, x FOR PEER REVIEW 2 of 8 2. Making the Pathologic Diagnosis 2. Making the Pathologic Diagnosis Microscopically, the epithelium of the fallopian tube consists of a mixture of secretory and ciliated Microscopically, the epithelium of the fallopian tube consists of a mixture of secretory and cells. The stroma underlying this epithelium is composed of smooth muscle and fibroconnective ciliated cells. The stroma underlying this epithelium is composed of smooth muscle and tissue, and the serosal surface is lined by mesothelium. Interestingly, there is regional variation fibroconnective tissue, and the serosal surface is lined by mesothelium. Interestingly, there is regional in the composition of the epithelial layer. Secretory cells predominate in the isthmus of the tube, variation in the composition of the epithelial layer. Secretory cells predominate in the isthmus of the and ciliated cells are most conspicuous at the fimbriated end [4]. A spectrum of entities originating tube, and ciliated cells are most conspicuous at the fimbriated end [4]. A spectrum of entities fromoriginating secretory from cells secretory have been cells described, have been including described, secretory including/stem secretory cell outgrowths/stem cell (SCOUTs),outgrowths p53 signatures,(SCOUTs), serous p53 signatures, tubal epithelial serous proliferationstubal epithelial or proliferations lesions of uncertain or lesions significance of uncertain (STEP-US), significance and serous(STEP tubal-US), and intraepithelial serous tubal carcinomas intraepithelial (STIC). carcinomas On this (STIC). spectrum On this of spectrum pathologies, of pathologies, STIC is the STIC most morphologicallyis the most morphologically atypical. It atypical. is characterized It is characterized as secretory as secretory cell lesions cell lesions with some with degreesome degree of cellular of depolarizationcellular depolarization (typically, (typically, but not always, but not with always, epithelial with epithelial stratification), stratification), increased increased nuclear to nuclear cytoplasmic to ratios,cytoplasmic hyperchromasia, ratios, hyperchrom nuclearasia, molding, nuclear prominent molding, nucleoli,prominent and nucleoli, increased and mitoticincreased activity mitotic [5 ,6] (Figureactivity1). [5,6 In] addition(Figure 1). to In these addition morphologic to these morphologic criteria, TP53 criteria,mutations TP53 mutations are present are present in 92% in of 92% STICs. Theof lesionsSTICs. The therefore lesions typicallytherefore demonstratetypically demonstrate strong and strong diff useand p53diffuse immunohistochemical p53 immunohistochemical staining consistentstaining consistent with missense with mutationsmissense mutations (Figure1B). (Figure Less commonly,1B). Less commonly, there is complete there is complete absence ofabsence staining dueof tostaining nonsense due mutationsto nonsense in mutationsTP53 [2]. in TP53 [2]. A B C FigureFigure 1. 1.( A(A)) Serous Serous tubaltubal intraepithelialintraepithelial carcinoma (STIC (STIC)) (left) (left) versus versus uninvolved uninvolved fallopian fallopian tube tube (right).(right). The The STIC STIC demonstrates demonstrates lossloss of polarity with with an an increase increase in in nuclear nuclear size size with with nuclear nuclear crowding crowding andand molding. molding. ( B(B)) p53 p53 immunohistochemistryimmunohistochemistry highlighting highlighting strong strong and and diffuse diffuse expression expression in STIC in STIC (left) (left) versusversus uninvolved uninvolved fallopian fallopian tubetube (right).(right). ( C)) Lower Lower magnification magnification highlighting highlighting the the hyperchromasia hyperchromasia andand marked marked nuclear nuclear pleomorphism pleomorphism associatedassociated with with STIC. STIC. AsAs morphologic morphologic findings findings may may sometimes sometimes bebe subtle,subtle, interpretationsinterpretations are unavoidably subjective. subjective. It isIt thus is thus not unexpectednot unexpect thated that there there is poor is poor reproducibility reproducibility in diagnosingin diagnosing these these precursor precursor lesions. lesions. At At least twoleast studies two studies have confirmed have confirmed this low this interobserver low interobserver agreement. agreement. First, First, Carslon Carslon et al. et circulated al. circulated digital imagesdigital of images 30 cases of (1430 cases (14 of STICcases and of STIC 16 cases and with 16 cases benign with tubal benign epithelium) tubal epithelium) to 12 pathologists. to 12 Thepathologists. majority agreed The majority on STIC agreed in only on nineSTIC ofin 14only cases, nine resulting of 14 cases, in aresultingκ statistic in ofa κ 0.333 statistic [7]. of A 0.333 second study[7]. byA second Visvanathan study et by al. Visvanathan highlighted thatet al. even highlighted intraobserver that variabilityeven intra forobserver diagnosing variability STIC versusfor non-STICdiagnosing was STIC lackluster versus basednon-STIC on morphologicwas lackluster findings based on alone morphologic (κ ranged findings from 0.41 alone to (κ 0.68 ranged for five pathologists)from 0.41 to [ 60.68]. As for such, five pathologists) Vang et al. validated [6]. As such, an algorithm Vang et al. using validated an on-line an algorithm training setusing of H&Ean on and- immunohistochemicalline training set of H&E stained and slides immunohistochemical (p53 and Ki-67) originally stained developedslides (p53 by andVisvanathan Ki-67) originally et al. [6 ,8]. developed by Visvanathan et al. [6,8]. In these studies, foci morphologically suspicious for STIC In these studies, foci morphologically suspicious for STIC needed to show a Ki-67 labeling index needed to show a Ki-67 labeling index >10% and a mutant p53 staining pattern to be diagnosed as >10% and a mutant p53 staining pattern to be diagnosed as such. The group was able to increase such. The group was able to increase the interobserver κ value for STIC vs. non-STIC