In this review, we sought to address 2 important issues in the diagnosis of endometrial carcinoma: how to grade endometrial endometrioid carcinomas and how to incorporate the 4 genomic subcategories ...of endometrial carcinoma, as identified through The Cancer Genome Atlas, into clinical practice. The current International Federation of Gynecology and Obstetrics grading scheme provides prognostic information that can be used to guide the extent of surgery and use of adjuvant chemotherapy or radiation therapy. We recommend moving toward a binary scheme to grade endometrial endometrioid carcinomas by considering International Federation of Gynecology and Obstetrics defined grades 1 and 2 tumors as "low grade" and grade 3 tumors as "high grade." The current evidence base does not support the use of a 3-tiered grading system, although this is considered standard by International Federation of Gynecology and Obstetrics, the American College of Obstetricians and Gynecologists, and the College of American Pathologists. As for the 4 genomic subtypes of endometrial carcinoma (copy number low/p53 wild-type, copy number high/p53 abnormal, polymerase E mutant, and mismatch repair deficient), which only recently have been identified, there is accumulating evidence showing these categories can be reproducibly diagnosed and accurately assessed based on biopsy/curettage specimens as well as hysterectomy specimens. Furthermore, this subclassification system can be adapted for current clinical practice and is of prognostic significance independent of conventional variables used for risk assessment in patients with endometrial carcinoma (eg, stage). It is too soon to recommend the routine use of genomic classification in this setting; however, with further evidence, this system may become the basis for the subclassification of all endometrial carcinomas, supplanting (partially or completely) histotype, and grade. These recommendations were developed from the International Society of Gynecological Pathologists Endometrial Carcinoma project.
This review of challenging diagnostic issues concerning high-grade endometrial carcinomas is derived from the authors' review of the literature followed by discussions at the Endometrial Cancer ...Workshop sponsored by the International Society of Gynecological Pathologists in 2016. Recommendations presented are evidence-based, insofar as this is possible, given that the levels of evidence are weak or moderate due to small sample sizes and nonuniform diagnostic criteria used in many studies. High-grade endometrioid carcinomas include FIGO grade 3 endometrioid carcinomas, serous carcinomas, clear cell carcinomas, undifferentiated carcinomas, and carcinosarcomas. FIGO grade 3 endometrioid carcinoma is diagnosed when an endometrioid carcinoma exhibits >50% solid architecture (excluding squamous areas), or when an architecturally FIGO grade 2 endometrioid carcinoma exhibits marked cytologic atypia, provided that a glandular variant of serous carcinoma has been excluded. The most useful immunohistochemical studies to make the distinction between these 2 histotypes are p53, p16, DNA mismatch repair proteins, PTEN, and ARID1A. Endometrial clear cell carcinomas must display prototypical architectural and cytologic features for diagnosis. Immunohistochemical stains, including, Napsin A and p504s can be used as ancillary diagnostic tools; p53 expression is aberrant in a minority of clear cell carcinomas. Of note, clear cells are found in all types of high-grade endometrial carcinomas, leading to a tendency to overdiagnose clear cell carcinoma. Undifferentiated carcinoma (which when associated with a component of low-grade endometrioid carcinoma is termed "dedifferentiated carcinoma") is composed of sheets of monotonous, typically dyscohesive cells, which can have a rhabdoid appearance; they often exhibit limited expression of cytokeratins and epithelial membrane antigen, are usually negative for PAX8 and hormone receptors, lack membranous e-cadherin and commonly demonstrate loss of expression of DNA mismatch repair proteins and SWI-SNF chromatin remodeling proteins. Carcinosarcomas must show unequivocal morphologic evidence of malignant epithelial and mesenchymal differentiation.
Sertoli-Leydig cell tumors are characterized by the presence of somatic DICER1 hotspot mutations. In this study, we sought to define the association between DICER1 hotspot mutations and different ...morphologic subtypes of ovarian Sertoli-Leydig cell tumors. Furthermore, we aimed to assess whether DICER1 hotspot mutations occur in other ovarian sex cord-stromal tumors, testicular sex cord-stromal tumors, or other female genital tract tumors with rhabdomyosarcomatous differentiation. We subjected a series of ovarian Sertoli-Leydig cell tumors (n=32), Sertoli cell tumors (n=5) and gynandroblastomas (n=5), testicular sex cord-stromal tumors (n=15) and a diverse group of female genital tract tumors with rhabdomyosarcomatous morphology (n=10) to DICER1 hotspot mutation analysis using Sanger sequencing. We also tested two gynandroblastomas for the presence of FOXL2 hotspot mutations (p.C134W; c.402C>G). Twenty of 32 (63%) Sertoli-Leydig cell tumors harbored a DICER1 hotspot mutation, of which 80% had the p.E1705K mutation. No association was found between DICER1 mutation status and the presence of heterologous or retiform differentiation in Sertoli-Leydig cell tumors. DICER1 mutations were found at similar frequencies in gynandroblastoma (2/5; 40%) and ovarian Sertoli cell tumors (5/8; 63%; P>0.1), and all mutated tumors harbored a p.E1705K mutation. DICER1 hotspot mutations were also identified in a single cervical rhabdomyosarcoma and in the rhabdomyosarcomatous component of a uterine carcinosarcoma. No DICER1 mutations were detected in testicular sex cord-stromal tumors. Two DICER1 wild-type gynandroblastomas harbored a p.C134W FOXL2 hotspot mutation in both tumor components. In this study we confirmed that DICER1 hotspot mutations occur in over half of ovarian Sertoli-Leydig cell tumors, and are unrelated to tumor differentiation. We also widened the spectrum of ovarian sex cord-stromal tumors with sertoliform differentiation, in which DICER1 mutations are known to occur, to include Sertoli cell tumors and gynandroblastomas. Our results suggest that DICER1 mutations may not have a role in testicular sex cord-stromal tumorigenesis.
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare ovarian neoplasm that occurs in young women and has a poor prognosis. The histologic diagnosis of SCCOHT can be challenging ...due to its rarity and relatively nonspecific histologic features, which range from the classic, first-described small cell morphology to a pattern in which there are large cells with abundant eosinophilic cytoplasm. Many entities can be in the differential diagnosis and to date, immunohistochemical stains have shown no distinctive profile and have been of limited aid. SMARCA4 (also known as BRG1) mutations have recently been reported at high frequency in these tumors. SMARCA4 is an important component of the SWI/SNF complex that regulates gene expression through alteration of nucleosome conformation. Studies to date have suggested that immunohistochemical loss of expression of SMARCA4 is associated with the presence of a SMARCA4 mutation in most cases. In this study, the sensitivity and specificity of the immunohistochemical loss of SMARCA4 expression for the diagnosis of SCCOHT is examined in the context of the differential diagnosis with other primary or metastatic ovarian tumors. All but one of the SCCOHT showed loss of SMARCA4 expression (16/17; 94%), while of 279 other tumors tested, only two tumors (one clear cell carcinoma and one ovarian melanoma) showed loss of SMARCA4 expression. We conclude that SMARCA4 immunohistochemistry is highly sensitive and specific for a diagnosis of SCCOHT and is of clinical utility in the differential diagnosis of poorly differentiated ovarian tumors.
Uterine carcinosarcomas (CSs) are aggressive neoplasms, with 5-year overall survival (OS) rates of less than 35%. They are customarily separated into types harboring either heterologous or homologous ...mesenchymal elements, but the prognostic significance of this finding is controversial. Our goal was to study clinicopathologic features of possible prognostic relevance in surgical stage I uterine CS. A retrospective clinical and histopathologic review was performed for all women diagnosed with surgical stage I uterine CS. These tumors were compared with stage I high-grade endometrial (HGEm) carcinomas for clinical outcomes. There were 42 cases of surgical stage I uterine CS identified between January 1990 and January 2004. The disease-free survival and OS rates for patients with stage I CS were significantly worse compared with stage I HGEm (P=0.001; P=0.01). The median disease-free survival for patients with heterologous CS was 15 months and had not been reached for women with homologous CS (P=0.001). The 3-year OS rates were 45% versus 93% in women with heterologous compared with homologous stage I CS (P<0.001). The 3-year OS rates for homologous CS and HGEm were both >90%. Homologous stage I CSs have survival outcomes that are similar to HGEm. This further supports the concept that homologous stage I CSs are carcinomas with sarcomatoid features, not sarcomas. More importantly, the presence of heterologous sarcomatous elements is a powerful negative prognostic factor in surgical stage I uterine CS.
Although grading has been demonstrated to be an important prognostic factor in ovarian serous carcinoma, there is no system universally used to perform this task. A few years ago, we proposed a ...two-tier system for grading ovarian serous carcinoma that is based primarily on the assessment of nuclear atypia (uniformity vs. pleomorphism) in the worst area of the tumor. Tumor grade in this two-tier system is correlated with survival. After being used by numerous pathologists and trainees at The University of Texas M.D. Anderson Cancer Center (MDACC) for 15 years, we have observed that this system is user-friendly and reproducible. We undertook this study to evaluate the interobserver and intraobserver variability among a group of 7 gynecologic pathologists and 2 general surgical pathologists using this grading system. A total of 80 cases of ovarian serous carcinoma, 40 low-grade and 40 high-grade, were circulated twice among these pathologists. Slides with examples of low-grade and high-grade serous carcinoma were sent with the unknowns. A website was used to provide diagnostic criteria, images of examples of ovarian low-grade and high-grade carcinoma, and a log form to facilitate data entry. Statistical analysis demonstrated an overall kappa statistic among the different observers of 0.909. The intergrader kappa's ranged from 0.717 to 1.000 in the first round of the review and from 0.701 to 1.000 in the second round. Eight of the participants had an intragrader kappa ranging from 0.775 to 1.000 (excellent agreement), whereas a single participant had an intragrader kappa of 0.725 (good agreement). This study demonstrates that the two-tier grading system (the MDACC grading system) for ovarian serous carcinoma on the basis of the assessment of nuclear atypia is easy to learn and is highly reproducible. These findings would support its universal use, which would be beneficial for the standardization of clinical trials and protocols, thus facilitating the understanding of this disease and investigation into the treatment of patients affected by these tumors.
Although targeted therapies against HER2 have been one of the most successful therapeutic strategies for breast cancer, patients eventually developed acquired resistance from compensatory ...upregulation of alternate HERs and mitogen-activated protein kinase-phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling. As we and others have shown that the soluble ectodomain fragment of E-cadherin exerts prooncogenic effects via HER1/2-mediated binding and activation of downstream prosurvival pathways, we explored whether targeting this ectodomain DECMA-1 monoclonal antibody (mAb) was effective in the treatment of HER2-positive (HER2(+)) breast cancers.
MMTV-PyMT transgenic mice and HER2(+)/E-cadherin-positive MCF-7 and BT474 trastuzumab-resistant (TtzmR) cells were treated with the DECMA-1 mAb. Antitumor responses were assessed by bromodeoxyuridine incorporation, apoptosis, and necrosis. The underlying intracellular prooncogenic pathways were explored using subcellular fractionation, immunoprecipitation, fluorescence microscopy, and immunoblotting.
Treatment with DECMA-1 mAb significantly delayed tumor onset and attenuated tumor burden in MMTV-PyMT mice by reducing tumor cell proliferation and inducing apoptosis without any detectable cytotoxicity to mice or end-organs. In vitro treatment of MCF-7 and BT474 TtzmR cells reduced proliferation and induced cancer cell apoptosis. Importantly, this inhibition of breast tumorigenesis was due to concomitant downregulation, via ubiquitin-mediated degradation through the lysosome and proteasome pathways, of all HER family members, components of downstream PI3K/Akt/mTOR prosurvival signaling and suppression of inhibitor of apoptosis proteins.
Our results establish that the E-cadherin ectodomain-specific mAb DECMA-1 inhibits Ecad(+)/HER2(+) breast cancers by hindering tumor growth and inducing apoptosis via downregulation of key oncogenic pathways involved in trastuzumab resistance, thereby establishing a novel therapeutic platform for the treatment of HER2(+) breast cancers.
Defective DNA mismatch repair is commonly present in sporadic manifestations of gastrointestinal, endometrial, and other cancers. The pathognomonic molecular manifestation of this repair defect is ...microsatellite instability (MSI). Here, we test the hypothesis that MSI predicts the clinicopathologic features of endometrial carcinoma.
A retrospective cohort of 473 patients treated for endometrial carcinoma at this institution was identified. All cases were reviewed by a gynecologic pathologist, and clinical information was abstracted from medical records. Using consensus criteria, DNA samples from nontumor and tumor tissue pairs were genotyped for MSI. Associations between MSI status and pathologic and clinical variables were assessed.
Ninety-three (20%) of 473 tumors were MSI+. In the MSI+ tumor group compared with the MSI- tumor group, the proportion of advanced compared with early-stage tumors was higher (92% v 81%; P = .01), as was the proportion of tumors of endometrioid compared with nonendometrioid histologic subtype (94% v 23%; P = .001), and the proportion of tumors with myometrial invasion compared with those with none (92% v 78%; P = .01). By multivariate analyses, disease-free survival (hazard ratio, 0.3; 95% CI, 0.2 to 0.7) and disease-specific survival (hazard ratio, 0.3; 95% CI, 0.1 to 0.8) were significantly improved in patients with MSI+ tumors.
In endometrial carcinoma, the presence of MSI was independently associated with a more favorable clinical outcome.
Carcinomas arising from breast hamartomas are exceedingly rare. We present the first reported case of an African-American female presenting with a right breast lump and a subsequent mammogram ...suggestive of a hamartoma. She later underwent lumpectomy and was found to have HER2+ invasive ductal carcinoma (IDC) arising from a hamartoma. She was amenable to HER2-targeted trastuzumab, hormone therapy and adjuvant radiation but declined chemotherapy. In a review of the literature, IDC is the predominant neoplastic type found in hamartomas. The average hamartoma size at time of neoplasm diagnosis is 6.0 cm. Patients with hamartomas greater than 6.0 cm, with changes in calcification pattern; new nodules or asymmetry should be considered for additional evaluation with ultrasound, MRI and/or biopsy. HER2 status is under-reported among cases and should be evaluated in any malignancy found within hamartomas as HER-2 therapy has improved overall survival and recurrence free survival in HER2+breast cancer patients.
Metastatic breast carcinoma to the ovary is sometimes difficult to differentiate from primary ovarian carcinoma. This problem is often encountered in breast carcinoma patients who develop adnexal ...masses. ER and PR can be positive in a high percentage of breast and ovarian carcinomas, and therefore cannot be used in the differential diagnosis of these entities. WT1 and CA125 have been identified as possible markers for ovarian cancer. However, no studies have been done that specifically compare the immunophenotype of breast carcinoma metastatic to ovary with that of primary ovarian cancer. Thirty-nine cases of metastatic breast carcinoma to the ovary, 36 primary breast carcinomas, and 42 primary ovarian carcinomas were examined immunohistochemically for the expression of WT1, CA125, carcinoembryonic antigen, MUC2, MUC1, and GCDFP. The percentage of cells stained and the intensity of staining were recorded. Thirty-two ovarian carcinomas (76%) were positive for WT1, including 31 of 33 (94%) serous carcinomas. Most of them had strong and diffuse staining. None of the breast cancers either primary or metastatic to the ovary expressed WT1. Thirty-eight (90%) ovarian carcinomas were positive for CA125, most of them with strong and diffuse staining. Most breast carcinomas were negative for CA125, with only 6 (16%) of the primary ones and 5 (12%) of the metastatic showing weak and focal positivity. All ovarian carcinomas were negative for GCDFP. Five primary breast cancers (14%) and 17 (43%) metastatic to the ovary were positive for GCDFP. Nine (21%) ovarian carcinomas, 8 (22%) primary breast carcinomas, and 13 (33%) metastatic to the ovary were positive for carcinoembryonic antigen. Almost all tumors examined were positive for MUC1 (100% ovarian carcinomas, 100% primary breast carcinomas, and 95% metastatic breast carcinomas to ovary). MUC2 was positive in 10 (24%) ovarian carcinomas, 3 (8%) primary breast cancers, and 12 (30%) metastases to the ovary. The presence of immunoreactivity for WT1 and CA125 in a carcinoma involving ovary strongly favors a primary lesion. Most ovarian carcinomas are positive for both markers, whereas the majority of metastatic breast carcinomas to the ovary are negative. GCDFP can be complementary in this differential diagnosis.
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