Although ovarian cancer is the most lethal gynecologic malignancy in women, little is known about how the cancer initiates and metastasizes. In the last decade, new evidence has challenged the dogma that the ovary is the main source of this cancer. The fallopian tube has been proposed instead as the primary origin of high-grade serous ovarian cancer, the subtype causing 70% of ovarian cancer deaths. By conditionally deleting Dicer, an essential gene for microRNA synthesis, and Pten, a key negative regulator of the PI3K pathway, we show that high-grade serous carcinomas arise from the fallopian tube in mice. In these Dicer-Pten doubleknockout mice, primary fallopian tube tumors spread to engulf the ovary and then aggressively metastasize throughout the abdominal cavity, causing ascites and killing 100% of the mice by 13 mo. Besides the clinical resemblance to human serous cancers, these fallopian tube cancers highly express genes that are known to be up-regulated in human serous ovarian cancers, also demonstrating molecular similarities. Although ovariectomized mice continue to develop high-grade serous cancers, removal of the fallopian tube at an early age prevents cancer formation-confirming the fallopian tube origin of the cancer. Intriguingly, the primary carcinomas are first observed in the stroma of the fallopian tube, suggesting that these epithelial cancers have a mesenchymal origin. Thus, this mouse model demonstrates a paradigm for the origin and initiation of high-grade serous ovarian carcinomas, the most common and deadliest ovarian cancer.epithelial ovarian cancer | oviduct | mesenchymal-to-epithelial transition | carcinoma initiation E pithelial ovarian cancer, accounting for 90% of all ovarian tumors, is grouped into four major histologic types: serous (70%), endometrioid (10-15%), clear-cell (10%), and mucinous (3%) carcinomas (1). The serous-type cancers are also overwhelmingly high-grade (90%)-the culprit of 70% of ovariancancer deaths and a key contributor to an overall ovarian cancer 5-yr survival rate of 31% (2-4). Most cases of high-grade serous ovarian cancers are diagnosed at advanced stages, when the tumors have already metastasized. Despite the steady improvement of surgery and chemotherapy, >90% of women with advanced ovarian cancers die after the cancer relapses (5). Early detection of these high-grade serous carcinomas is thus key to reducing ovarian cancer deaths (6). However, the origin and molecular pathogenesis of these high-grade serous ovarian cancers are largely unknown (1, 6).Despite widespread peritoneal metastasis commonly seen in ovarian cancer at diagnosis, the ovary has long been considered the primary origin of this cancer-hence the name ovarian cancer. However, precursor lesions have not been identified in the ovary (1, 7). Over the past decade, new evidence has emerged to propose a different source of ovarian cancer: the fallopian tube (7,8). After women with hereditary breast and ovarian cancer-susceptibility gene (BRCA1, BRCA2) mutations have their ovaries and fallop...

PAX 8 is a transcription factor that is essential for embryonic development of the kidney, Mü llerian organs, and thyroid. It may also have a role in tumor development in these organs. The diagnostic utility of PAX 8 has not been comprehensively studied. Formalin-fixed, paraffin-embedded tissue samples for non-neoplastic tissues (n ¼ 1601), primary neoplasms (n ¼ 933), and metastatic neoplasms (n ¼ 496) were subjected to PAX 8 immunostain. In non-neoplastic tissues, PAX 8 was consistently noted in glomerular parietal epithelial cells, renal collecting ductal cells, atrophic renal tubular epithelial cells regardless of nephronic segments, and epithelial cells of the endocervix, endometrium, fallopian tube, seminal vesicle, epidydimis, thyroid, pancreatic islet cells, and lymphoid cells. PAX 8 was not seen in the rest of the tissue samples. In primary neoplasms, PAX 8 was expressed by 194 of 240 (89%) renal cell neoplasms, by 238 of 267 (89%) Mü llerian-type neoplasms, by 65 of 65 (100%) thyroid follicular cell neoplasms, by 8 of 8 (100%) nephrogenic adenomas, and by 17 of 17 (100%) lymphomas. Weak focal staining was noted in 5 of 12 (42%) cases of parathyroid hyperplasia/adenoma and in 6 of 17 (35%) well-differentiated neuroendocrine tumors of the pancreas. PAX 8 was not seen in other neoplasms. In metastatic neoplasms, PAX 8 was expressed by 90 of 102 (88%) metastatic renal cell carcinomas, by 57 of 63 metastatic Mü llerian tumors (90%), and by 6 of 6 metastatic papillary thyroid carcinomas (100%). There was also weak focal staining for 1 of 15 metastatic small cell carcinomas and for 1 of 9 metastatic well-differentiated neuroendocrine carcinomas. PAX 8 was not seen in other metastatic neoplasms. It can be successfully identified in routinely processed tissue samples, and its expression is mostly nuclear. PAX 8 expression in nonneoplastic mature tissues is limited to the organs, the embryonic development of which depends on this transcription factor. This tissue/cell-specific expression is maintained during both neoplastic transformation and metastasis. PAX 8 is a sensitive and specific marker for tumors of renal, Mü llerian, or thyroid origin in both primary and metastatic sites.

High-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), is the most common and deadliest type of ovarian cancer. HGSC appears to arise from the ovary, fallopian tube, or peritoneum. As most HGSC cases present with widespread peritoneal metastases, it is often not clear where HGSC truly originates. Traditionally, the ovarian surface epithelium (OSE) was long believed to be the origin of HGSC. Since the late 1990s, the fallopian tube epithelium has emerged as a potential primary origin of HGSC. Particularly, serous tubal intraepithelial carcinoma (STIC), a noninvasive tumor lesion formed preferentially in the distal fallopian tube epithelium, was proposed as a precursor for HGSC. It was hypothesized that STIC lesions would progress, over time, to malignant and metastatic HGSC, arising from the fallopian tube or after implanting on the ovary or peritoneum. Many clinical studies and several mouse models support the fallopian tube STIC origin of HGSC. Current evidence indicates that STIC may serve as a precursor for HGSC in high-risk women carrying germline BRCA1 or 2 mutations. Yet not all STIC lesions appear to progress to clinical HGSCs, nor would all HGSCs arise from STIC lesions, even in high-risk women. Moreover, the clinical importance of STIC remains less clear in women in the general population, in which 85–90% of all HGSCs arise. Recently, increasing attention has been brought to the possibility that many potential precursor or premalignant lesions, though composed of microscopically—and genetically—cancerous cells, do not advance to malignant tumors or lethal malignancies. Hence, rigorous causal evidence would be crucial to establish that STIC is a bona fide premalignant lesion for metastatic HGSC. While not all STICs may transform into malignant tumors, these lesions are clearly associated with increased risk for HGSC. Identification of the molecular characteristics of STICs that predict their malignant potential and clinical behavior would bolster the clinical importance of STIC. Also, as STIC lesions alone cannot account for all HGSCs, other potential cellular origins of HGSC need to be investigated. The fallopian tube stroma in mice, for instance, has been shown to be capable of giving rise to metastatic HGSC, which faithfully recapitulates the clinical behavior and molecular aspect of human HGSC. Elucidating the precise cell(s) of origin of HGSC will be critical for improving the early detection and prevention of ovarian cancer, ultimately reducing ovarian cancer mortality.