Recent molecular genetic findings on endometriosis and normal endometrium suggest a modified model in which circulating epithelial progenitor or stem cells intended to regenerate uterine endometrium ...after menstruation may become overreactive and trapped outside the uterus. These trapped epithelium-committed progenitor cells form nascent glands through clonal expansion and recruit polyclonal stromal cells, leading to the establishment of deep infiltrating endometriosis. Once formed, the ectopic tissue becomes subject to immune surveillance, resulting in chronic inflammation. The inflammatory response orchestrated by nuclear factor-κB signaling is exacerbated by aberrations in the estrogen receptor-β and progesterone receptor pathways, which are also affected by local inflammation, forming a dysregulated inflammation-hormonal loop. Glandular epithelium within endometriotic tissue harbors cancer-associated mutations that are frequently detected in endometriosis-related ovarian cancers. In this review, we summarize recent advances that have illuminated the origin and pathogenesis of endometriosis and have provided new avenues for research that promise to improve the early diagnosis and management of endometriosis.
Summary Recent morphologic, immunohistochemical, and molecular genetic studies have led to the development of a new paradigm for the pathogenesis and origin of epithelial ovarian cancer based on a ...dualistic model of carcinogenesis that divides epithelial ovarian cancer into 2 broad categories designated types I and II. Type I tumors comprise low-grade serous, low-grade endometrioid, clear cell and mucinous carcinomas, and Brenner tumors. They are generally indolent, present in stage I (tumor confined to the ovary), and are characterized by specific mutations, including KRAS , BRAF , ERBB2 , CTNNB1 , PTEN , PIK3CA , ARID1A , and PPP2R1A , which target specific cell signaling pathways. Type I tumors rarely harbor TP53 mutations and are relatively stable genetically. Type II tumors comprise high-grade serous, high-grade endometrioid, malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinomas. They are aggressive, present in advanced stage, and have a very high frequency of TP53 mutations but rarely harbor the mutations detected in type I tumors. In addition, type II tumors have molecular alterations that perturb expression of BRCA either by mutation of the gene or by promoter methylation. A hallmark of these tumors is that they are genetically highly unstable. Recent studies strongly suggest that fallopian tube epithelium (benign or malignant) that implants on the ovary is the source of low-grade and high-grade serous carcinoma rather than the ovarian surface epithelium as previously believed. Similarly, it is widely accepted that endometriosis is the precursor of endometrioid and clear cell carcinomas and, as endometriosis, is thought to develop from retrograde menstruation; these tumors can also be regarded as involving the ovary secondarily. The origin of mucinous and transitional cell (Brenner) tumors is still not well established, although recent data suggest a possible origin from transitional epithelial nests located in paraovarian locations at the tuboperitoneal junction. Thus, it now appears that type I and type II ovarian tumors develop independently along different molecular pathways and that both types develop outside the ovary and involve it secondarily. If this concept is confirmed, it leads to the conclusion that the only true primary ovarian neoplasms are gonadal stromal and germ cell tumors analogous to testicular tumors. This new paradigm of ovarian carcinogenesis has important clinical implications. By shifting the early events of ovarian carcinogenesis to the fallopian tube and endometrium instead of the ovary, prevention approaches, for example, salpingectomy with ovarian conservation, may play an important role in reducing the burden of ovarian cancer while preserving hormonal function and fertility.
Since our proposal of a dualistic model of epithelial ovarian carcinogenesis more than a decade ago, a large number of molecular and histopathologic studies were published that have provided ...important insights into the origin and molecular pathogenesis of this disease. This has required that the original model be revised and expanded to incorporate these findings. The new model divides type I tumors into three groups: i) endometriosis-related tumors that include endometrioid, clear cell, and seromucinous carcinomas; ii) low-grade serous carcinomas; and iii) mucinous carcinomas and malignant Brenner tumors. As in the previous model, type II tumors are composed, for the most part, of high-grade serous carcinomas that can be further subdivided into morphologic and molecular subtypes. Type I tumors develop from benign extraovarian lesions that implant on the ovary and which can subsequently undergo malignant transformation, whereas many type II carcinomas develop from intraepithelial carcinomas in the fallopian tube and, as a result, disseminate as carcinomas that involve the ovary and extraovarian sites, which probably accounts for their clinically aggressive behavior. The new molecular genetic data, especially those derived from next-generation sequencing, further underline the heterogeneity of ovarian cancer and identify actionable mutations. The dualistic model highlights these differences between type I and type II tumors which, it can be argued, describe entirely different groups of diseases.
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.
Serous tubal intraepithelial carcinoma (STIC) is the precursor to ovarian high‐grade serous carcinoma. STIC can be reproducibly diagnosed by supplementing the morphologic features with immunohistochemical stains for p53 and Ki‐67
Ovarian cancer is the most lethal gynecologic malignancy. Efforts at early detection and new therapeutic approaches to reduce mortality have been largely unsuccessful, because the origin and ...pathogenesis of epithelial ovarian cancer are poorly understood. Despite numerous studies that have carefully scrutinized the ovaries for precursor lesions, none have been found. This has led to the proposal that ovarian cancer develops de novo. Studies have shown that epithelial ovarian cancer is not a single disease but is composed of a diverse group of tumors that can be classified based on distinctive morphologic and molecular genetic features. One group of tumors, designated type I, is composed of low-grade serous, low-grade endometrioid, clear cell, mucinous and transitional (Brenner) carcinomas. These tumors generally behave in an indolent fashion, are confined to the ovary at presentation and, as a group, are relatively genetically stable. They lack mutations of TP53, but each histologic type exhibits a distinctive molecular genetic profile. Moreover, the carcinomas exhibit a shared lineage with the corresponding benign cystic neoplasm, often through an intermediate (borderline tumor) step, supporting the morphologic continuum of tumor progression. In contrast, another group of tumors, designated type II, is highly aggressive, evolves rapidly and almost always presents in advanced stage. Type II tumors include conventional high-grade serous carcinoma, undifferentiated carcinoma, and malignant mixed mesodermal tumors (carcinosarcoma). They displayTP53 mutations in over 80% of cases and rarely harbor the mutations that are found in the type I tumors. Recent studies have also provided cogent evidence that what have been traditionally thought to be primary ovarian tumors actually originate in other pelvic organs and involve the ovary secondarily. Thus, it has been proposed that serous tumors arise from the implantation of epithelium (benign or malignant) from the fallopian tube. Endometrioid and clear cell tumors have been associated with endometriosis that is regarded as the precursor of these tumors. As it is generally accepted that endometriosis develops from endometrial tissue by retrograde menstruation, it is reasonable to assume that the endometrium is the source of these ovarian neoplasms. Finally, preliminary data suggest that mucinous and transitional (Brenner) tumors arise from transitional-type epithelial nests at the tubal-mesothelial junction by a process of metaplasia. Appreciation of these new concepts will allow for a more rationale approach to screening, treatment, and prevention that potentially can have a significant impact on reducing the mortality of this devastating disease.
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.
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