Mana Moghadamfalahi

Withaferin A Alone and in Combination with Cisplatin Suppresses Growth and Metastasis of Ovarian Cancer by Targeting Putative Cancer Stem Cells

Currently, the treatment for ovarian cancer entails cytoreductive surgery followed by chemotherapy, mainly, carboplatin combined with paclitaxel. Although this regimen is initially effective in a high percentage of cases, unfortunately within few months of initial treatment, tumor relapse occurs because of platinum-resistance. This is attributed to chemo-resistance of cancer stem cells (CSCs). Herein we show for the first time that withaferin A (WFA), a bioactive compound isolated from the plant Withania somnifera, when used alone or in combination with cisplatin (CIS) targets putative CSCs. Treatment of nude mice bearing orthotopic ovarian tumors generated by injecting human ovarian epithelial cancer cell line (A2780) with WFA and cisplatin (WFA) alone or in combination resulted in a 70 to 80% reduction in tumor growth and complete inhibition of metastasis to other organs compared to untreated controls. Histochemical and Western blot analysis of the tumors revealed that inclusion of WFA (2 mg/kg) resulted in a highly significant elimination of cells expressing CSC markers - CD44, CD24, CD34, CD117 and Oct4 and downregulation of Notch1, Hes1 and Hey1 genes. In contrast treatment of mice with CIS alone (6 mg/kg) had opposite effect on those cells. Increase in cells expressing CSC markers and Notch1 signaling pathway in tumors exposed to CIS may explain recurrence of cancer in patients treated with carboplatin and paclitaxel. Since, WFA alone or in combination with CIS eliminates putative CSCs, we conclude that WFA in combination with CIS may present more efficacious therapy for ovarian cancer.

Impact of immediate evaluation of touch imprint cytology from computed tomography guided core needle biopsies of mass lesions: Single institution experience

Background: Computed tomography (CT) guided core needle biopsy (CT-guided CNB) is a minimally invasive, safe and effective manner of tissue sampling in many organs. The aim of our study is to determine the impact of on-site evaluation of touch imprint cytology (TIC) to minimize the number of passes required to obtain adequate tissue for diagnosis. Design: A retrospective review of all CT-guided CNBs performed during 4 year period, where pathologists were present for on-site TIC evaluation. Each case was evaluated for the number of passes required before TIC was interpreted as adequate for diagnosis. Results: A total of 140 CT-guided CNBs were included in the study (liver, lung, kidney, sacral, paraspinal, omental, splenic and adrenal masses). Of the 140 cases, 109 were diagnosed as malignant, 28 as benign and three insufficient. In 106 cases (75.7%), the biopsies were determined adequate by TIC on the first pass, 19 cases (13%) on the second pass and 7 cases (5%) on the third pass. Only in 5 cases (3.6%), more than three passes were required before diagnostic material was obtained. Three cases (2.14%) were interpreted as inadequate both on TIC and on the final diagnosis. Of the biopsies deemed adequate on the first pass, 71% resulted in either termination of the procedure, or only one additional pass was obtained. In five cases, based on the TIC evaluation, a portion of the sample was sent for either flow cytometric analysis or cytogenetic studies. Conclusions: In the majority of cases, adequate material was obtained in the first pass of CT-guided CNB and once this was obtained, either no additional passes, or one additional pass was performed. This study demonstrates the utility of on-site evaluation in minimizing the number of passes required for obtaining adequate diagnostic material and for proper specimen triage for ancillary studies, which in turn decreases the risk to the patient and costs. However, tumor exhaustion in the tissue as a result of TIC is an important pitfall of the procedure, which occurred in 9 (8.2%) of our malignant cases.

Assessment of CK17 as a Marker for the Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia.

Differentiated vulvar intraepithelial neoplasia (dVIN), precursor of vulvar squamous cell carcinoma, is human papilloma virus independent and often found in a background of lichen sclerosus (LS) and lichen simplex chronicus (LSC). Subtle histologic findings make the diagnosis of dVIN difficult, and, although the use of p53 and Ki-67 has been of some value, there is a need for a better immunohistochemical marker. Cytokeratin 17 (CK17), a cytoskeletal intermediate filament protein, has previously been used in the diagnosis of anogenital lesions. Here we evaluated CK17 in dVIN in comparison with LS, LSC, and usual VIN (uVIN/HSIL). Twenty-nine cases of dVIN, 9 cases of uVIN, 8 cases of LS, and 7 of LSC were evaluated using CK17, Ki-67, and p53. All 29 dVIN cases displayed immunoreactivity for CK17, with 27 (93%) showing intermediate to strong and diffuse reactivity. No cases of uVIN displayed diffuse CK17 expression, whereas 63% of LS and 29% of LSC displayed intermediate to strong diffuse immunoreactivity, confined to the upper half of the epithelium. P53 and Ki-67 expression was present in varying degrees in all types of lesions, displaying limited discriminatory power for dVIN. Our findings suggest that CK17, although not specific for dVIN, when combined with histologic findings, Ki-67, and p53 immunohistochemistry, can be a marker of vulvar dysplasia and serve as an adjunct in the diagnosis of dVIN. Specifically, in small biopsies, the presence of diffuse suprabasal or full thickness expression strongly favors a diagnosis of dVIN over LSC, whereas focal and/or superficial expression supports a diagnosis of LSC.

Ependymoma and Carcinoid Tumor Associated with Ovarian Mature Cystic Teratoma in a Patient with Multiple Endocrine Neoplasia I

Ovarian teratomas rarely undergo new neoplastic transformation and account for a small percentage of malignant ovarian germ cell neoplasms. Here we report a case of a 51-year-old woman with multiple endocrine neoplasia type I (MEN I) who was found to have an ependymoma and neuroendocrine tumor (trabecular carcinoid) associated with mature cystic teratoma of her left ovary. The ependymoma component displayed cells with round nuclei and occasional small nucleoli which were focally arranged in perivascular pseudorosettes and true rosettes. Rare mitoses were identified. No necrosis was present. Immunohistochemical staining was positive for S-100 and GFAP. The Ki67 proliferation index was very low (2-3%). In contrast, the endocrine tumor component was composed of small uniform cells with eosinophilic cytoplasm, round nuclei, and speckled chromatin. Immunohistochemical staining was positive for synaptophysin and focally positive for chromogranin. This rare case illustrates that MEN I may have an influence on the pathogenesis of ovarian teratomas as they undergo malignant transformation.

Renal cell carcinoma with extensive oncocytic features.

Oncocytic features are a hallmark of renal oncocytoma, but can be seen in other renal tumors such as clear cell renal cell carcinoma with granular cells and eosinophilic variant of chromophobe cell tumors. Up to 5% of renal neoplasms are ultimately diagnosed as unclassified renal cell carcinoma with oncocytic features accounting for a significant number of these tumors. Also a recent morphological variant of mucinous tubular and spindle cell carcinoma with oncocytic changes has been described, adding another challenge. Here we report an unusual case of unclassified renal cell carcinoma with extensive oncocytic changes and we discuss the differential diagnosis.

Multiple Extrauterine Adenomyomas Presenting in Upper Abdomen and Pelvis: A Case Report and Brief Review of the Literature

Adenomyomas are benign tumors composed of smooth muscle and endometrial tissue. These tumors usually arise from the myometrium. Extrauterine adenomyomas are rare with only a few case reports available in the literature. Here, we report an unusual case of multiple adenomyomas in a 39-year-old woman six years after hysterectomy for multiple leiomyomata. To the best of our knowledge, this is the first case of extrauterine adenomyoma presenting as an upper abdominal mass.

Squamous cell carcinoma of the rectum, primary or metastatic?

Primary squamous cell carcinoma of the rectum is very rare. In this article we report a case of squamous cell carcinoma arising from an ovarian dermoid cyst presenting as a rectal mass with gastrointestinal symptoms. To the best of our knowledge, this clinical presentation has not been reported before. This article emphasizes the importance of applying the appropriate guidelines before assigning the diagnosis of primary colorectal squamous cell carcinoma , since the treatment and the management are different.

Clear Cell Adenocarcinoma Arising in an Adenomyoma of the Broad Ligament

Extrauterine adenomyomas are extremely rare benign tumors of smooth muscles, endometrial glands, and endometrial stroma. Ectopic endometrial glands can undergo malignant change. The ovary is the most common site of malignant change in endometriosis. Cancer arising in extraovarian endometriosis is a rare event with limited cases in the literature. To the best of our knowledge, we present the first case of a clear cell adenocarcinoma arising from foci of ectopic endometrial tissue in an adenomyoma of the broad ligament. It supports the association between endometriomas and clear cell adenocarcinoma. Therefore, patients with a significant history of endometriosis may benefit from close follow-up or definitive surgery.

Low-grade central osteosarcoma of the rib: a case report and brief review of the literature.

Low-grade central osteosarcoma is a rare variant of osteosarcoma which comprises less than 1-2% of all osteosarcomas. Most low-grade osteosarcomas involve long bones, most commonly distal femur, and proximal tibia. Histologically this tumor is difficult to diagnose, and an unusual location makes this diagnosis even more challenging. Here we report a case of low-grade osteosarcoma presenting as a chest wall mass involving the left 6th–8th ribs. This unusual site of presentation significantly added to the diagnostic difficulties of this rare tumor with challenging histologic features. To the best of our knowledge, only six cases of low-grade central osteosarcoma of the ribs have been reported in the English literature.

Sarcomatous Component in Uterine Carcinosarcomas Correlates With Advanced Stage and Poorer Prognosis

Uterine carcinosarcomas, also known as malignant-mixed mullerian tumors, are rare and highly aggressive tumors whose prognostic factors remain controversial. The stage at the time of presentation is the most important prognostic factor thus far, but little information exists on the prognostic impact of the sarcomatous component (SC) in these tumors. We reviewed 21 cases of uterine carcinosarcomas and estimated the volume of the SC in each case. This information was correlated with the stage of the tumor at presentation. The percentage of the SC was also used to stratify the patients into 2 cohorts (high percentage of SC and low percentage of SC), and the 2 patient cohorts were compared based on the available follow-up data to identify prognostic differences. Patients with a lower concentration of SC (<30%) typically presented with low stage of disease when compared with their counterparts. Although not statistically significant (P=0.1966), our data suggest a correlation between a lower concentration of SC with longer follow-up and longer survival rates when compared with those of patients presenting with higher volumes of the SC (≥30%). Greater volume of the SC is seen in advanced stage tumors, which could serve as an indicator of prognosis.