High-grade serous ovarian carcinoma presents significant clinical and therapeutic challenges. Although the traditional model of carcinogenesis has focused on the ovary as a tumor initiation site, ...recent studies suggest that there may be additional sites of origin outside the ovary, namely the secretory cells of the fallopian tube. Our study demonstrates that high-grade serous tumors can originate in fallopian tubal secretory epithelial cells and also establishes serous tubal intraepithelial carcinoma as the precursor lesion to high-grade serous ovarian and peritoneal carcinomas in animal models targeting the Brca, Tp53, and Pten genes. These findings offer an avenue to address clinically important questions that are critical for cancer prevention and early detection in women carrying BRCA1 and BRCA2 mutations.
•PAX8 can drive murine high-grade serous tumors originating in the fallopian tube•Early alterations in Brca, Tp53, and Pten lead to intraepithelial precursor lesions•Genomic analysis of Pax8-driven tumors shows strong correlation with human tumors•High-grade serous ovarian cancer can arise from the fallopian tubal secretory cell
High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian cancer and has a poor outcome. It has been proposed that fallopian tube cancers may be precursors of HGSOC but ...evolutionary evidence for this hypothesis has been limited. Here, we perform whole-exome sequence and copy number analyses of laser capture microdissected fallopian tube lesions (p53 signatures, serous tubal intraepithelial carcinomas (STICs), and fallopian tube carcinomas), ovarian cancers, and metastases from nine patients. The majority of tumor-specific alterations in ovarian cancers were present in STICs, including those affecting TP53, BRCA1, BRCA2 or PTEN. Evolutionary analyses reveal that p53 signatures and STICs are precursors of ovarian carcinoma and identify a window of 7 years between development of a STIC and initiation of ovarian carcinoma, with metastases following rapidly thereafter. Our results provide insights into the etiology of ovarian cancer and have implications for prevention, early detection and therapeutic intervention of this disease.
Renal malignancies can be divided into cortical- and medullary-based tumors, the latter of which classically infiltrate the renal parenchyma by extending between nonneoplastic structures. Although ...high-grade cortical tumors can rarely exhibit the same growth pattern, the infiltrative morphology should elicit a differential diagnosis to be considered in each case. However, these diagnoses can be challenging to distinguish, especially on small renal biopsy samples.
To provide an overview of the clinical, gross, and microscopic findings; genetic and molecular alterations; and immunohistochemical evaluation of medullary-based renal tumors and other tumor types with overlapping morphologies and growth patterns.
Literature review and personal observations were used to compile the information in this review.
Collecting duct carcinoma is a prototypical medullary-based tumor, and although diagnostic criteria exist, it remains a diagnosis of exclusion, especially with ancillary techniques aiding the recognition of established as well as more recently described neoplasms. Other medullary-based malignancies included in the differential diagnosis include renal medullary carcinoma/renal cell carcinoma unclassified with medullary phenotype, fumarate hydratase-deficient renal cell carcinoma, and upper tract urothelial carcinoma. Moreover, other rare entities should be excluded, including metastatic carcinoma, lymphoma, and melanoma. In addition to potential prognostic differences, accurate diagnoses can have important surgical and clinical management implications.
The tumor immune microenvironment plays a critical role in cancer progression and response to immunotherapy in clear cell renal cell carcinoma (ccRCC), yet the composition and phenotypic states of ...immune cells in this tumor are incompletely characterized. We performed single-cell RNA and T cell receptor sequencing on 164,722 individual cells from tumor and adjacent non-tumor tissue in patients with ccRCC across disease stages: early, locally advanced, and advanced/metastatic. Terminally exhausted CD8+ T cells were enriched in metastatic disease and were restricted in T cell receptor diversity. Within the myeloid compartment, pro-inflammatory macrophages were decreased, and suppressive M2-like macrophages were increased in advanced disease. Terminally exhausted CD8+ T cells and M2-like macrophages co-occurred in advanced disease and expressed ligands and receptors that support T cell dysfunction and M2-like polarization. This immune dysfunction circuit is associated with a worse prognosis in external cohorts and identifies potentially targetable immune inhibitory pathways in ccRCC.
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•scRNA-seq defines the infiltrating immune populations in ccRCC across disease stages•Terminally exhausted CD8+ T cells and M2-like TAMs are enriched in advanced ccRCC•Exhausted CD8+ T cells and TAMs interact to form an immune dysfunction circuit•Signature of terminal exhaustion/TAM interaction is associated with worse prognosis
The immune cell changes that occur with advancing disease stage in renal cell carcinoma are incompletely characterized. Braun et al. show that terminally exhausted CD8+ T cells and M2-like tumor-associated macrophages are enriched in advanced disease and interact to form an immune dysfunction circuit that is associated with poorer prognosis.
PAX8 is a paired-box gene important in embryogenesis of the thyroid, Müllerian, and renal/upper urinary tracts, and expression of PAX8 has been previously described in carcinomas from each of these ...sites. However, a large study including a wide variety of epithelial neoplasms from multiple organ sites other than the thyroid, kidney, or Müllerian system has not been performed. The goal of this study was to evaluate the utility of PAX8 immunostaining based on the evaluation of a wide range of epithelial tumors. PAX8 immunohistochemistry was performed on 1357 tumors (486 tumors in whole-tissue sections and 871 tumors in tissue microarrays, predominantly epithelial) from multiple organs. Only nuclear staining was scored as positive, and tumors were evaluated for the extent and intensity of staining. Western blot analysis with PAX8 was also performed on multiple tumor cell lines. Nuclear PAX8 staining was present in 91% (60 of 66) of thyroid tumors, 90% (158 of 176) of renal cell carcinomas (RCCs), 81% (13 of 16) of renal oncocytomas, 99% (164 of 165) of high-grade ovarian serous carcinomas, 71% (32 of 49) of nonserous ovarian epithelial neoplasms, 91% (10 of 11) of cervical epithelial lesions, and 98% (152 of 155) of endometrial adenocarcinomas. Of the remaining 719 evaluated tumors, only 30 cases (4%), including 12 thymic neoplasms, 3 bladder urothelial carcinomas, 4 lung squamous cell carcinomas, 2 esophageal adenocarcinomas, 1 pancreatic adenocarcinoma, 2 cholangiocarcinomas, 1 ovarian Sertoli-Leydig cell tumor, 1 ovarian sex cord stromal tumor, 3 testicular mixed germ cell tumors, and 1 acinic cell carcinoma, showed at least weak or focal PAX8 positivity. The unexpected finding was diffuse, moderate staining of PAX8 in a subset of thymomas and thymic carcinomas. The 689 remaining tumors, including but not limited to those from the prostate, colon, stomach, liver, adrenal gland, and head and neck, and small cell carcinomas from the lung, cervix, and ovary, were PAX8 negative. PAX8 specificity was confirmed by Western blot analysis, as expression was detected only in ovarian and RCC cell lines. These results show that PAX8 is a highly sensitive marker for thyroid, renal, Müllerian, and thymic tumors. Importantly, all lung adenocarcinomas, breast and adrenal neoplasms, and the majority of gastrointestinal tumors were negative for PAX8. Therefore, PAX8 is an excellent marker for confirming primary tumor site. In a subset of cases, additional markers, including but not limited to thyroid transcription factor-1, RCC, and Wilms tumor-1, may be needed to distinguish between the 3 most common PAX8-positive tumors.
Morphologic (ie, hematoxylin and eosin) evaluation of the Mullerian tract remains the gold standard for diagnostic evaluation; nevertheless, ancillary/biomarker studies are increasingly utilized in ...daily practice to assist in the subclassification of gynecologic lesions and tumors. The most frequently utilized "biomarker" technique is immunohistochemistry; however, in situ hybridization (chromogenic and fluorescence), chromosomal evaluation, and molecular analysis can also be utilized to aid in diagnosis. This review focuses on the use of immunohistochemistry in the Mullerian tract, and discusses common antibody panels, sensitivity and specificity of specific antibodies, and points out potential diagnostic pitfalls when using such antibodies.
GATA3 is a transcription factor critical for embryogenesis, development, and cell differentiation. Recent studies have suggested that GATA3 is a sensitive and relatively specific biomarker for ...urothelial and breast carcinomas, with most Müllerian carcinomas being negative. We investigated GATA3 expression in mesonephric/Wolffian remnants and tumors in the female genital tract. A western blot was performed to assess specificity for the GATA3 antibody. GATA3 immunohistochemistry was performed on 59 formalin-fixed paraffin-embedded mesonephric samples, including 17 mesonephric remnants (MR; 11 cervical and 6 fallopian tube), 15 mesonephric hyperplasias, 21 mesonephric carcinomas, and 6 female adnexal tumors of probable Wolffian origin. Thirty conventional endocervical adenocarcinomas (ENDO-CA), 9 gastric-type cervical adenocarcinomas, and 165 endometrial adenocarcinomas (EM-CA) were also evaluated. GATA3 nuclear intensity and extent of staining was evaluated. The western blot revealed GATA3 expression in seminal vesicle and cell lines derived from breast and urothelial carcinomas, but not in other cell lines including ovarian, cervical, and endometrial cancers. All cervical MRs and mesonephric hyperplasias, 5/6 (83%) fallopian tube MRs, and 20/21 (95%) mesonephric carcinomas were GATA3 positive, although with great variability in both intensity (weak to strong) and extent (1+ to 3+) of staining. Only 1/6 (17%) female adnexal tumors of probable Wolffian origin showed weak multifocal staining. One of 30 (3%) usual-type ENDO-CAs and 3/165 EM-CAs exhibited weak-moderate GATA3 immunoreactivity; all gastric-type cervical adenocarcinomas were negative. GATA3 is a highly sensitive and specific marker for mesonephric lesions in the lower genital tract; however, its utility in the upper genital tract may be more limited. In addition, GATA3 can aid in distinguishing lower genital mesonephric lesions from usual-type and gastric-type ENDO-CAs and uterine EM-CAs.
Primary peritoneal malignant mesothelioma (MM) can demonstrate morphologic overlap with low-grade and high-grade tubo-ovarian serous neoplasms; it is also biologically and prognostically distinct ...from benign mesothelial proliferations. Currently, there is no single biomarker that can definitively distinguish these neoplasms. Sex-determining region Y box 6 (SOX6) immunohistochemistry has been recently described to differentiate pleural epithelioid MM from lung adenocarcinoma, but it has not been evaluated in the peritoneum. SOX6 immunohistochemistry was performed on 43 peritoneal epithelioid MM, 7 peritoneal biphasic MM, 5 well-differentiated papillary mesotheliomas, 5 serous borderline tumors, 29 low-grade serous carcinomas (LGSCs), 20 high-grade serous carcinomas (HGSCs), and 25 cases of peritoneal reactive mesothelial hyperplasia. Quantitative SOX6 expression in epithelioid MM (median, 100% of tumor cells) was significantly greater than in LGSC/serous borderline tumor (median, 90%; P=0.004) and HGSC (median, 45%; P=0.0001). However, when SOX6 is expression is defined as ≥10% of tumor cells, there was no significant difference in the rate of SOX6 positivity between epithelioid MM (41/43, 95%), LGSC (28/29, 97%; P=1.0), and HGSC (17/20, 85%; P=0.16). Quantitative extent of SOX6 expression in epithelioid MM was significantly greater than in biphasic MM (median, 0%; P=0.0001), well-differentiated papillary mesothelioma (median, 20%; P=0.001), and reactive mesothelial hyperplasia (median, 20%; P=0.0001), but not significantly different from flat quiescent mesothelium (median, 90%; P=0.82). SOX6 immunohistochemistry is 95% sensitive for peritoneal epithelioid MM, but is also consistently expressed in LGSC and HGSC, negating its usefulness in this common differential diagnosis. SOX6 also shows variable expression across the spectrum of reactive, benign neoplastic, and malignant mesothelial lesions of the peritoneum, and does not appear to be diagnostically useful in distinguishing benign from malignant mesothelial proliferations.
A diagnosis of primary peritoneal serous carcinoma (PPSC) requires exclusion of a source in other reproductive organs. Serous tubal intraepithelial carcinoma (STIC; stage 0) has been described in ...asymptomatic women with BRCA mutations and linked to a serous cancer precursor in the fimbria. This study examined the frequency of STIC in PPSC and its clinical outcome in BRCA-positive women.
Presence or absence of STIC was recorded in consecutive cases meeting the 2001 WHO criteria for PPSC, including 26 patients with nonuniform sampling of the fallopian tubes (group 1) and 19 patients with complete tubal examination (group 2; sectioning and extensively examining the fimbriated end, or SEE-FIM protocol). In selected cases, STIC or its putative precursor and the peritoneal tumor were analyzed for p53 mutations (exons 1 to 11). Outcome of STIC was ascertained by literature review.
Thirteen (50%) of 26 PPSCs in group 1 involved the endosalpinx, with nine STICs (35%). Fifteen (79%) of 19 cases in group 2 contained endosalpingeal involvement, with nine STICs (47%). STIC was typically fimbrial and unifocal, with variable invasion of the tubal wall. In five of five cases, the peritoneal and tubal lesion shared an identical p53 mutation. Of 10 reported STICs in BRCA-positive women, all patients were without disease on follow-up.
The fimbria is the source of nearly one half of PPSCs, suggesting serous malignancy originates in the tubal mucosa but grows preferentially at a remote peritoneal site. The generally low risk of recurrence in stage 0 (STIC) disease further underscores STIC as a possible target for early serous cancer detection and prevention.
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