Nisreen Abushahin

Tubal origin of 'ovarian' low-grade serous carcinoma.

Ovarian low-grade serous carcinomas are thought to evolve in a stepwise fashion from ovarian epithelial inclusions, cystadenomas, and borderline tumors. The current study was designed to gain insight into the origins of low-grade serous carcinomas (tubal versus ovarian) by comparatively evaluating the morphologic (secretory and ciliated cell distribution) and immunophenotypic (using antibodies to PAX8, tubulin, calretinin, and Ki67) attributes of its putative precursor lesions, the normal tubal epithelium, and the overt malignancy. A total of 226 adnexal tissues from 178 patients were studied, including 98 adnexae removed for non-neoplastic indications, 48 serous cystadenomas, 42 serous borderline tumors, and 38 low-grade serous carcinomas. Normal distal tubal epithelium comprised an admixture of PAX8+/tubulin− secretory cells and PAX8−/tubulin+ ciliated cells with a proliferative index of ∼3%. The vast majority of ovarian surface epithelia displayed a mesothelial phenotype (calretinin+/PAX8−/tubulin−) and low proliferative index (0% (12 per 1000)), although 4% of cases also displayed foci with tubal phenotype (calretinin−/PAX8+/tubulin+). In contrast, most (78%) of the ovarian epithelial inclusions displayed a tubal phenotype and had a significantly higher proliferative index (1%) than ovarian surface epithelium, indicating that in most cases, the ovarian surface epithelium and ovarian epithelial inclusions are of different lineages. There was a progressive decrease in the population of ciliated cells, as evidenced by increasing secretory/ciliated cell ratio, from ovarian epithelial inclusions/cystadenomas to borderline tumors to low-grade serous carcinoma, indicating that the latter is a clonal expansion of secretory cells. Overall, the findings make a strong argument that the ovarian epithelial inclusions with a tubal phenotype is likely derived from fallopian tube through an intraovarian endosalpingiosis rather than through Mullerian metaplasia from ovarian surface epithelium. Genetic and molecular studies are needed to further confirm this finding as tubal origination of ovarian serous cancers will have a significant impact on ovarian cancer prevention and management.

Secretory cell expansion with aging: risk for pelvic serous carcinogenesis.

OBJECTIVE Recent advances suggest that precancerous lesions of pelvic serous carcinoma (PSC) originate from tubal secretory cells. The purpose of our study was to determine if increased number of secretory cells shows difference in age and location and to examine their association with serous neoplasia. MATERIALS AND METHODS Three groups (benign control, high-risk, and PSC) of patients with matched ages were studied. The age data was stratified into 10-year intervals ranging from age 20 to older than 80. The number of secretory and ciliated cells from both tubal fimbria and ampulla segments was counted by microscopy and immunohistochemical staining methods. The data was analyzed by standard contingency table and Poisson distribution methods after age justification. RESULTS We found that the absolute number of tubal secretory cells increased significantly with age within each age group. Age remained a significant risk factor for serous neoplasia after age adjustment. In addition, a dramatic increase of secretory cells was observed in high-risk and PSC patients. Further, secretory cell expansion (SCE) was more prevalent than secretory cell outgrowth in both fimbria and ampulla tubal segments and was significantly associated with serous neoplasia (p<0.001). CONCLUSIONS These findings suggest that SCE could potentially serve as a sensitive biomarker for early serous carcinogenesis within the fallopian tube. Findings support a relationship between serous neoplasia and increased secretory to ciliated cell ratios. Findings also support a relationship between frequency of SCE and increasing age, presence of high-risk factors and co-existing serous cancers.

Serous endometrial intraepithelial carcinoma arising in adenomyosis: a report of 5 cases.

Serous endometrial intraepithelial carcinoma (serous EIC) arising in adenomysis is rare. It may be underrecognized because of its deceiving morphology when embedded in the foci of adenomysis. Although there is no connection to peritoneal cavity, some cases may be associated with extrauterine disease. It is currently unknown what the etiology for such a disease is. More studies are in need to elucidate the pathogenesis of such a grave malady. We report a series of 5 cases of serous EIC, which may arise in adenomyosis. The 5 cases are in 5 different patients or whom on histopathological examination of their hysterectomy specimens, the finding of adenomyosis involved with serous intraepithelial neoplasia was identified. The finding of interest was the presence of multifoci of adenomyosis; some of those foci were involved in serous EIC. In addition to EIC, lesions of endometrial glandular dysplasia were present in the foci of adenomyosis. To rule out the possibility of endometrial serous carcinoma (ESC) invading into the areas of the adenomyosis, all of the 5 uteri were extensively examined. Among the 5 uteri, the eutopic endometirum showed 1 invasive ESC, 2 serous EIC, and 2 benign resting endometrium without any cancer or precancerous lesions. In 1 uterus with ESC, we did not see any direct spatial connection between the invasive component of ESC and the areas of EIC in the foci of adenomyosis. In 2 uteri with serous EIC within the endometrial cavity, there was a distance of at least 0.5 cm between the lesions within the endometrial cavity and the serous EIC in adenomyosis. The remaining 2 uteri showed no evidence of endometrial malignancy in the endometrial cavity, whereas serous EIC was present only in areas of adenomyosis. Clinicopathologic data including characterized immunohistochemical stainings and p53 gene sequence analysis are presented and clinical significance is discussed.

Flutamide and Biomarkers in Women at High Risk for Ovarian Cancer: Preclinical and Clinical Evidence

We hypothesized that (i) preclinical biologic evidence exists for the role of androgens in ovarian cancer development and (ii) flutamide treatment of women at high risk for ovarian cancer may identify meaningful tissue biomarkers of androgen action and of ovarian cancer initiation. We showed that androgen ablation of male mice led to a 24-fold decrease in tumor burden from serous ovarian cells. In a phase II study, we studied the effect of preoperative flutamide treatment (125 mg/day × 6 weeks) in 12 women versus 47 controls, 47% with BRCA mutation. We analyzed immunohistochemical scores of candidate proteins CSF-1, CSF-1R, and ErbB4 in the epithelium and stroma of fallopian tube, ovary, and ovarian endosalpingiosis. Flutamide decreased the levels, notably, of CSF-1 and ErbB4 in ovarian stroma (P ≤ 0.0006) and ovarian endosalpingiosis (P ≤ 0.01), ErbB4 in ovarian epithelium (P = 0.006), and CSF-1R in ovarian endosalpingiosis (P = 0.009). Our logistic regression model clearly distinguished the flutamide patients from controls (P ≤ 0.0001). Our analysis of the precision of this model of CSF-1 and ErbB4 expression in ovarian stroma achieved 100% sensitivity and 97% specificity (AUC = 0.99). Thus, our data suggest that a short 6-week exposure of flutamide reversed elevated levels of CSF-1 and ErbB4 (both of which we had previously found correlated with high risk status). CSF-1 and ErbB4 in ovarian stroma led to a model with high predictive value for flutamide sensitivity. The effect of flutamide on marker expression in ovarian endosalpingiosis, previously associated with BRCA carrier status, suggests that ovarian endosalpingiosis may be a latent precursor to pelvic serous cancers. Cancer Prev Res; 7(9); 896–905. ©2014 AACR.

Autocrine inhibition of the c-fms proto-oncogene reduces breast cancer bone metastasis assessed with in vivo dual-modality imaging

Breast cancer cells preferentially home to the bone microenvironment, which provides a unique niche with a network of multiple bidirectional communications between host and tumor, promoting survival and growth of bone metastases. In the bone microenvironment, the c-fms proto-oncogene that encodes for the CSF-1 receptor, along with CSF-1, serves as one critical cytokine/receptor pair, functioning in paracrine and autocrine fashion. Previous studies concentrated on the effect of inhibition of host (mouse) c-fms on bone metastasis, with resulting decrease in osteolysis and bone metastases as a paracrine effect. In this report, we assessed the role of c-fms inhibition within the tumor cells (autocrine effect) in the early establishment of breast cancer cells in bone and the effects of this early c-fms inhibition on subsequent bone metastases and destruction. This study exploited a multidisciplinary approach by employing two non-invasive, in vivo imaging methods to assess the progression of bone metastases and bone destruction, in addition to ex vivo analyses using RT-PCR and histopathology. Using a mouse model of bone homing human breast cancer cells, we showed that an early one-time application of anti-human c-fms antibody delayed growth of bone metastases and bone destruction for at least 31 days as quantitatively measured by bioluminescence imaging and computed tomography, compared to controls. Thus, neutralizing human c-fms in the breast cancer cell alone decreases extent of subsequent bone metastasis formation and osteolysis. Furthermore, we are the first to show that anti-c-fms antibodies can impact early establishment of breast cancer cells in bone.

Endometrial Clear Cell Carcinoma: An Update on Recent Concepts

Endometrial clear cell carcinoma is an uncommon endometrial cancer that is biologically, clinically, and pathologically distinct from the more common endometrioid and serous carcinomas. The differential diagnosis for endometrial clear cell carcinoma includes benign and nonneoplastic lesions, as well as a variety of neoplastic processes that may potentially display clear cells. Resolution of this differential diagnosis in a given case of putative endometrial clear cell carcinoma requires the recognition that (1) the diagnosis of endometrial clear cell carcinoma in the gynecologic tract is based more on the presence of the classic architectural patterns of this entity than the presence of clear cells, (2) clear cells are not unique to clear cell carcinomas, and (3) clear cell carcinomas need not display a prominent complement of clear cells and occasionally display a significant population of cells with oxyphilic cytoplasm. Stage is an important prognostic factor in endometrial clear cell carcinoma. Accordingly, the identification of precancerous lesions and the application of an intervention before the development or progression of the malignancy may contribute to improved outcomes in patients with this cancer. A spectrum of lesions that have been frequently identified adjacent to endometrial carcinomas with a clear cell component (clear cell endometrial glandular dysplasia and clear cell endometrial intraepithelial carcinoma) may represent precursor lesions to the malignancy. We present herein a case of endometrial clear cell carcinoma associated with these precursor lesions and evaluate the current state of knowledge on various clinicopathologic aspects of endometrial clear cell carcinoma.

Endometrial Intraepithelial Neoplasia

Nisreen Abushahin1,4, Shuje Pang1,2, Jie Li1,3, Oluwole Fadare5 and Wenxin Zheng1,6,7 1Department of Pathology, University of Arizona College of Medicine, Tucson, AZ, 2Department of Pathology, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, 3Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong, 4Department of Pathology, Jordan University HospitalUniversity of Jordan, Amman, 5Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN 6Department of Obstetrics and Gynecology, University of Arizona, Tucson, AZ 7Arizona Cancer Center, University of Arizona, Tucson, AZ, 1,5,6,7USA 2,3China 4Jordan

Coinfection by Cytomegalovirus and BK Polyomavirus in the Renal Allograft

Abstract Viral-induced allograft dysfunction is a significant cause of morbidity and mortality in renal allograft recipients. BK polyomavirus nephropathy continues to be the most common viral disease in renal allografts, although other viruses such as cytomegalovirus (CMV) and adenovirus can have devastating impact on graft function. Proper identification of viral pathogens and distinction from other types of nephritis can be challenging, particularly when the viral infection is at an early stage or when viral inclusions are not frequent. BK polyomavirus nephropathy has occasionally been reported in patients with coexisting CMV infection of other sites or with coinfection documented by serological examination. However, the finding of dual viral infection within a single renal allograft biopsy is unusual. Identification of 1 type of virus within the renal allograft does not preclude the possibility of a second pathological process. This review addresses the key pathological features of BK and CMV nephritis, which should prompt the pathologist to order confirmatory studies to distinguish viral infection from cellular rejection or other forms of allograft nephritis.