Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer.

We conducted a preoperative window study of metformin in endometrial cancer (EC) patients and evaluated its antiproliferative, molecular and metabolic effects. Twenty obese women with endometrioid EC were treated with metformin (850 mg) daily for up to 4 weeks prior to surgical staging. Expression of the proliferation marker Ki-67, estrogen receptor (ER), progesterone receptor (PR), adenosine monophosphate-activated protein kinase (AMPK), and downstream targets of the mammalian target of rapamycin (mTOR) pathway were measured by immunohistochemistry. Global, untargeted metabolomics analysis of serum pre- and postmetformin treatment, and matched tumor, was performed. Metformin reduced proliferation by 11.75% (P = 0.008) based on the comparison of pre- and posttreatment endometrial tumors. A total of 65% of patients responded to metformin as defined by a decrease in Ki-67 staining in their endometrial tumors post-treatment. Metformin decreased expression of phosphorylated (p)-AMPK (P = 0.00001), p-Akt (P = 0.0002), p-S6 (51.2%, P = 0.0002), p-4E-BP-1 (P = 0.001), and ER (P = 0.0002) but not PR expression. Metabolomic profiling of serum indicated that responders versus nonresponders to treatment were more sensitive to metformin's effects on induction of lipolysis, which correlated with increased fatty acid oxidation and glycogen metabolism in matched tumors. In conclusion, metformin reduced tumor proliferation in a pre-operative window study in obese EC patients, with dramatic effects on inhibition of the mTOR pathway. Metformin induced a shift in lipid and glycogen metabolism that was more pronounced in the serum and tumors of responders versus nonresponders to treatment.This study provides support for therapeutic clinical trials of metformin in obese patients with EC.

Displaced granulosa cells in the fallopian tube mistaken for metastatic granulosa cell tumor.

A 44-yr-old woman underwent a total hysterectomy and bilateral salpingectomy secondary to uterine leiomyomas. Gross examination of the fallopian tubes revealed no masses or lesions; however, 2 small foci of granulosa cells were identified microscopically within one of the fallopian tubes. These foci were suspicious for granulosa cell tumor metastases. The patient subsequently underwent a bilateral oophorectomy, which revealed no primary granulosa cell tumor. Immunohistochemical studies were used to help support the benign nature of the granulosa cells within the fallopian tube. A review of the literature revealed only 1 similar case report of displaced benign granulosa cells within the fallopian tubes. The ovaries in both this case and the previous case report were found to contain multiple cystic follicles, suggesting ovulation as the likely mechanism of displacement. Knowledge of this rare occurrence and the use of immunohistochemical staining are paramount to making a correct diagnosis, thus preventing a misdiagnosis of malignancy and possible unnecessary treatment.

Undifferentiated uterine sarcoma presenting as a pathologic humerus fracture.

BACKGROUND: Undifferentiated uterine sarcomas are rare malignancies often presenting at advanced stage. CASE: A female in her ninth decade presented to our MEDCEN emergency department complaining of onset of severe right arm pain while performing activities of daily living. A pathologic humeral fracture was diagnosed and subsequent orthopedic evaluation resulted in a biopsy and placement of her arm in a cooptation splint and sling. An abdominal exam revealed a 10-cm mass in the right lower quadrant that was thought to originate from the uterus. Computed tomography imaging was concerning for a primary endometrial process and she was referred to gynecologic oncology. Her humeral biopsy was consistent with a poorly differentiated metastatic sarcoma. An endometrial biopsy was consistent with undifferentiated uterine sarcoma, the origin of her humeral lesion. CONCLUSION: Humeral metastasis is an uncommon presentation for undifferentiated endometrial sarcomas.

Comparison of the clinical significance of the Papanicolaou test interpretations LSIL cannot rule out HSIL and ASC-H.

Despite the two-tiered classification of dysplasia in The Bethesda System (TBS), rare cases fall into the category squamous intraepithelial lesion (SIL) of indeterminate grade. These Pap tests are often interpreted as "LSIL/ASC-H" or "LSIL" with a comment indicating the presence of cells with features approaching HSIL. Patients with LSIL/ASC-H have a significant risk of CIN 2 or worse (29-61.5%) on follow-up cervical biopsies, similar to the risk of CIN 2 or worse in patients with ASC-H Pap tests (24-68%). The purpose of this study was to compare patients with ASC-H and LSIL/ASC-H Pap tests. Women with LSIL/ASC-H had a slightly lower incidence of CIN 2 or worse (PPV = 35.6%, 95% CI: 29.8-41.4%) on follow-up cervical biopsy than the control ASC-H group (PPV = 40.2%, 95% CI: 31.9-56.3%); this difference was not statistically significant. The difference in the distribution of the biopsy results between the two groups was statistically significant (P < 0.001). The current guidelines for the management of cervical cytologic abnormalities from the American Society for Colposcopy and Cervical Pathology (ASCCP) advocate similar treatment algorithms for both LSIL and ASC-H. The main difference is the option of cytologic follow-up or HPV testing for certain "special populations," as an alternative to colposcopy, for LSIL Pap test results. Based on our results, we recommend (1)LSIL/ASC-H to be added to TBS classification and (2) Pap test cases of LSIL/ASC-H may need to be clinically followed in a manner similar to ASC-H, i.e., colposcopy for all patients.

Implementation of the ThinPrep Imaging System in a tertiary military medical center.

BACKGROUND: The ThinPrep Imaging System (TIS) was implemented at Brooke Army Medical Center (BAMC) in February 2006 and has been a crucial part of the ability of the Department of Pathology and Laboratory Services ability to improve efficiency and turnaround times for Papanicolaou (Pap) test reporting. The increased detection rate of squamous abnormalities, specifically high-grade squamous intraepithelial lesions (HSIL), has been well documented by many studies. In addition, the TIS has increased productivity for many laboratories. The objective of this study was to evaluate the effects of implementing the TIS at BAMC, a tertiary military medical center. Specifically, the following were assessed: 1) whether the detection of squamous abnormalities was increased with the TIS, 2) how the rate of high-risk human papillomavirus (HR-HPV) detection in atypical squamous cells (ASC) of undetermined significance (ASC-US) cases changed (or did not change) before and after implementation of the TIS, and 3) how the TIS influenced productivity. METHODS: All gynecologic cytology at BAMC has been collected and processed using the ThinPrep system since 2002. Before February 2006 and before implementation of the TIS, Pap tests were screened manually by the cytotechnologists. Detection rates of squamous abnormalities were compared between the period from February 2005 to December 2005 (manual screening) and the period from February 2006 to December 2006 (image-assisted screening). Squamous abnormalities included ASC-US; ASC, cannot rule out HSIL (ASC-H); low-grade squamous intraepithelial lesion (LSIL); HSIL; glandular abnormalities; and malignancies (squamous or glandular). In addition, the rates of HR-HPV-positive, HR-HPV-negative, and HR-HPV-quantity not sufficient were compared for the same periods. During both periods, testing for HR-HPV was performed only on ASC-US Pap tests. HR-HPV was tested with Digene Hybrid Capture 2 methodology. Productivity was calculated as the change in average slides screened per hour before and after imager implementation. RESULTS: In total, 107,647 Pap tests were analyzed in the 2005 (54,438 Pap tests) and 2006 (53,209 Pap tests) timeframes. Increases in the detection of ASC-H, atypical glandular cells (AGC), LSIL, and HSIL were statistically significant. The proportion of negative for intraepithelial lesion or malignancy (NILM) and unsatisfactory cases decreased significantly with implementation of the TIS. The ASC to squamous intraepithelial lesion (ASC:SIL) ratio decreased from 1.5 to 1.0 after TIS implementation. Decreases in the ASC-US HR-HPV-positive proportion and increases in the ASC-US HR-HPV-negative proportion after implementation of the TIS were statistically significant. In our laboratory, a 60% increase in productivity was noted with use of the TIS. CONCLUSIONS: Implementation of the TIS at BAMC significantly increased the detection of ASC-H, AGC, LSIL, and HSIL but had no significant impact on the ASC-US detection rate. Although the ASC-US rate did not change, both the HR-HPV-positive rate and the ASC:SIL ratio decreased. The data from the current study suggested that, at least initially, the use of imager-directed screening may increase the number of clinically insignificant ASC-US Pap tests.

Cervical signet-ring cell carcinoma presenting as a synchronous primary carcinoma with uterine adenocarcinoma.

BACKGROUND: Synchronous primary gynecologic tumors are relatively uncommon with the diagnosis often made following initial surgery. CASE: A multiparous female in her 50s with postmenopausal bleeding was referred to our institution with a biopsy-proven diagnosis of endometrial cancer. Preoperative physical exam revealed a suspicious cervical lesion and upon biopsy she was found to have a signet-ring cell carcinoma of the cervix. Secondary to morbid obesity, the patient was not a candidate for a radical hysterectomy and was treated with curative radiation for stage IB 1 cervical carcinoma and clinical stage I endometrial carcinoma. CONCLUSION: Cervical signet-ring cell carcinoma is an extremely rare pathologic diagnosis. The preoperative discovery of synchronous primary gynecological tumors necessitates individualized planning and treatment.

Well-differentiated fetal adenocarcinoma: rare tumor in the pediatric population.

Well-differentiated fetal adenocarcinoma (WDFA) is a rare tumor of the lung, which has gone by many names over the years. The lesion was first described by Kradin et al., in 1982, who called it "pulmonary blastoma with argyrophil cells and lacking sarcomatous features (pulmonary endodermal tumor resembling fetal lung)." Since then, there have been at least 65 cases reported in the literature. Although there has been no consensus in the literature as to the best pathological term for this entity, the most recent World Health Organization classification of lung and pleural tumors uses the term well-differentiated fetal adenocarcinoma. Characteristically, this lesion consists of an epithelium, which recapitulates fetal lung at 3-5 months of gestation and demonstrates neuroendocrine differentiation. Although the classic age range is 30-40 years, there have been seven reports of WDFA in the pediatric age. We report an additional pediatric case of this tumor and review the pediatric cases in the existing literature.