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The presence of atypical endometrial cells in the Papanicolaou (Pap) test has been associated with an increased rate of endometrial malignancy, with reported rates ranging from 14% to 47%. However, most reported studies have focused on patients who were aged40 years. The purpose of the present study was to investigate the clinical significance of identifying atypical endometrial cells in Pap test samples in women aged40 years of age.A search of the cytology Pap test database was performed from 2000 to 2014 using the keywords "atypical endometrial cells" or "atypical glandular cells favor endometrial origin" in women aged40 years. The available ThinPrep slides were reviewed. The patients' clinical presentation, follow-up endometrial biopsy findings, treatment, and clinical follow-up data were recorded. Endometrial carcinoma tissue sections were screened for Lynch syndrome.The database search yielded 63 study cases. Of these 63 patients, 52 had subsequently undergone endometrial biopsy. Of the 52 patients with follow-up biopsy findings available, 9 (17.3%) had premalignant (5 with atypical hyperplasia) or malignant (4 with endometrioid adenocarcinoma) lesions. In addition, 16 patients (30.8%) had other endometrial pathologic features. The 9 patients with premalignant or malignant endometrial lesions (8 white, 1 black) were overweight or obese; 3 of the patients did not have any clinical symptoms. All 4 patients with endometrioid adenocarcinoma had negative Lynch syndrome screening findings.Our results suggest that it is important to recognize the presence of atypical endometrial cells in the Pap tests from young patients, given its association with the finding of premalignant and malignant pathologic features in subsequent endometrial biopsies.

Objective One indication of fine-needle aspiration biopsy (FNAB) is the diagnostic confirmatory of a clinical suspicion of uveal metastasis. We analyzed our experience in this clinical setting to assess the effectiveness of FNAB technique. Design Retrospective study. Participants 28 patients (28 eyes) underwent FNAB biopsy. Methods Aspirates were performed using 25-gauge needle and were classified into the following categories: positive, atypical, negative, or nondiagnostic. The electronic medical records provided all clinical data. Subsequent clinical course was considered as the diagnostic standard. Results Subsequent clinical course was metastatic tumour in 19 cases (68%) and nonmetastatic tumour in other 9 cases, considered as the diagnostic standard. Cytological interpretations for metastases were positive in 19 cases (68%), atypical in 2 cases (7%), negative in 4 cases (14%), and nondiagnostic in 3 cases (11%). The metastasis-positive cases included 9 adenocarcinoma, 3 uveal lymphoma, 3 small cell carcinomas, 3 non–small cell carcinomas, and 1 metastatic paraganglioma. Both of the atypical cases were suggestive for non-Hodgkin lymphoma. The 4 negative cases for metastases included 2 true negative cases, and 2 false negative aspirates that subsequently proved to be metastatic adenocarcinoma. The 3 nondiagnostic cases included 1 schwannoma, 1 low-grade uveal non-Hodgkin lymphoma, and 1 metastatic adenocarcinoma. The overall sensitivity for FNAB was 87.5%, with a specificity of 100%. Conclusions FNAB of suspected uveal metastases is a reliable diagnostic technique.

Context Leiomyomas have abundant extracellular matrix (ECM), with upregulation of versican, a large proteoglycan. Objective We investigated ADAMTS (a disintegrin-like and metalloprotease with thrombospondin type 1 motifs) protease-mediated versican cleavage in myometrium and leiomyoma and the effect of versican knockdown in leiomyoma cells. Design We used quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, immunohistochemistry, and RNA in situ hybridization for analysis of myometrium, leiomyoma and immortalized myometrium and leiomyoma cells. Short interfering RNA (siRNA) was used to knockdown versican in leiomyoma cells. Setting This study was performed in an academic laboratory. Patients Study subjects were women with symptomatic or asymptomatic leiomyoma. Main Outcome Measures We quantified messenger RNAs (mRNAs) for versican splice variants. We identified ADAMTS-cleaved versican in myometrium and leiomyoma and ADAMTS messenger RNAs and examined the effect of VCAN siRNA on smooth muscle differentiation and expression of estrogen and progesterone receptors. Results The women in the symptomatic group (n = 7) had larger leiomyoma (P = 0.01), heavy menstrual bleeding (P < 0.01), and lower hemoglobin levels (P = 0.02) compared with the asymptomatic group (n = 7), but were similar in age and menopausal status. Versican V0 and V1 isoforms were upregulated in the leiomyomas of symptomatic versus asymptomatic women (P = 0.03 and P = 0.04, respectively). Abundant cleaved versican was detected in leiomyoma and myometrium, as well as in myometrial and leiomyoma cell lines. ADAMTS4 (P = 0.03) and ADAMTS15 (P = 0.04) were upregulated in symptomatic leiomyomas. VCAN siRNA did not effect cell proliferation, apoptosis, or smooth muscle markers, but reduced ESR1 and PR-A expression (P = 0.001 and P = 0.002, respectively). Conclusions Versican in myometrium, leiomyomas and in the corresponding immortalized cells is cleaved by ADAMTS proteases. VCAN siRNA suppresses production of estrogen receptor 1 and progesterone receptor-A. These findings have implications for leiomyoma growth.

Cryptococcal intraocular infection is a rare disease and is usually associated with generalized systemic disease in immunocompromised patients. The diagnosis may be difficult because of the rarity of this disease and its similarities to other uveitic entities. We describe a case of culture-positive cryptococcal iridociliary granuloma diagnosed by anterior chamber tap and fine-needle aspiration biopsy in a 60-year-old immunocompetent woman with acute granulomatous uveitis. She was treated successfully with systemic amphotericin B and fluconazole and intravitreal amphotericin B, with improvement in the inflammation and visual acuity and regression of the iridociliary granuloma. We review previously reported cases of intraocular cryptococcal infection. Cryptococcal iridociliary granuloma should be considered in the differential diagnosis of an atypical iridociliary mass associated with acute uveitis.

Purpose To report the cytologic characteristics of uveal melanoma. Design This is a prospective, single-center study of consecutive patients. Subjects All patients with a clinical diagnosis of uveal melanoma from May 2009 to July 2013 who underwent prognostication fine-needle aspiration biopsy (FNAB) were included. Methods The cytologic characteristics of uveal melanoma were analyzed for 150 consecutive patients with a clinical diagnosis of uveal melanoma who were treated at the Cleveland Clinic Cole Eye Institute between May 2009 and August 2012. Main Outcome Measures Cellular features of all cases were analyzed for cell type, presence of melanin, nuclear grade, tumor-infiltrating lymphocytes, and necrosis. Cytology was then correlated with histopathology in enucleated eyes. Results A total of 150 patients were included. Seven samples of tumor resections were excluded from the study because they were studied by impression smears. A total of 143 FNAB samples of 143 patients formed the basis for analysis. Fifty-three percent of the patients were male, and the average age for all patients was 60 years. Transcorneal (n = 8), transscleral (n = 71), and transvitreal (n = 64) approaches were used. Of 143 samples, 131 were adequate. Among these, spindle cells were observed in 98% (63% mixed and 35% spindle only), whereas only epithelioid cells were observed in 2 samples. Melanin granules were observed in 80% of samples. Tumor nuclear grade (atypia) increased with tumor height and by tumor location (least atypia with iris tumors). Conclusions Cytologic features such as spindle cells and melanin granules, present in 98% and 80% of samples, respectively, are important cytologic diagnostic features. Tumor nuclear grade (atypia) increased with tumor height. Iris melanoma has bland features compared with ciliary and choroidal melanoma.

Purpose To report outcomes and complications of fine-needle aspiration biopsy (FNAB) of uveal melanoma performed for diagnostic and prognostic purposes. Methods Prospective interventional case series of 150 consecutive patients with a clinical diagnosis of uveal melanoma. The FNAB approach (transcorneal (TCO), transscleral (TSC) and transvitreal (TVT) was primarily determined by the location of the tumour. The FNAB was performed using a 25-gauge needle using a previously published technique. Prognostication was done using fluorescent in situ hybridisation detection of monosomy of chromosome 3. Results FNAB was obtained via TCO (8), TSC (71) and TVT (64) approach and impression smear in seven cases. Diagnostic yield was 92%. False-negative results were observed in 8%. Diagnostic yield was significantly correlated to biopsy approach (TCO 100%, TSC 96%, TSV 86%; p=0.029) and tumour size (basal diameter >5.0 mm; height >2.5 mm). Persistent haemorrhage (subretinal haemorrhage or vitreous) requiring surgical intervention (1%) and rhegmatogenous retinal detachment (1%) were rare. Endophthalmitis, hypotony, tumour recurrence, episcleral seeding were not observed over the average follow-up of 37 months. Prognostication could be performed in 85% of cases. Overall, only 47% of eligible patients enrolled into the adjuvant therapy trial. Conclusions FNAB for uveal melanoma with 25-gauge needle is a safe procedure that can yield diagnostic and prognostic information in vast majority of cases (92% and 85%, respectively). Even so, only about half of the eligible cases eventually enrolled into the adjuvant therapy trial. Possibility of negative FNAB yield should be considered when counselling patients with small tumours. Alternative means of diagnostic biopsy and methods of prognostication need to be assessed for small tumours.

Objectives Aberrant homeobox (HOX) gene expression is reported in high-grade serous ovarian carcinoma (HGSOC), however, its prognostic significance remains unclear. Methods HOX genes associated with progression-free survival (PFS) in a discovery cohort of primary HGSOC samples with RNA sequencing data, and those previously reported to be associated with clinical outcomes, were selected for qPCR testing in an independent training cohort of primary HGSOC samples ( n =71). A prognostic model for PFS was developed using univariate and multivariate Cox regression. Patients were stratified into risk groups that optimized the test statistic. The model was tested in an independent HGSOC cohort from The Cancer Genome Atlas (TCGA) ( n =320). The effect of selected HOX genes on drug sensitivity and reactive oxygen species (ROS) accumulation was examined in vitro. Results Of 23 HOX genes tested in the training cohort, HOXA4 (HR=1.20, 95% CI=1.07–1.34, P =0.002) and HOXB3 (HR=1.09, 95% CI=1.01–1.17, P =0.027) overexpression were significantly associated with shorter PFS in multivariate analysis. Based on the optimal cutoff of the HOXA4/HOXB3 risk score, median PFS was 16.9months (95% CI=14.6–21.2months) and not reached (>80months) for patients with high and low risk scores, respectively (HR=8.89, 95% CI=2.09–37.74, P HOXA4/HOXB3 risk score was significantly associated with disease-free survival (HR=1.44, 95% CI=1.00–2.09, P =0.048). HOXA4 or HOXB3 overexpression in ovarian cancer cells decreased sensitivity to cisplatin and attenuated the generation of cisplatin-induced ROS ( P Conclusions HOXA4/HOXB3 gene expression-based risk score may be useful for prognostic risk stratification and warrants prospective validation in HGSOC patients.

Lynch syndrome (LS) is a hereditary condition that increases the risk for endometrial and other cancers. Recognizing women at risk for LS based on personal/family history is burdensome and imprecise. Tumor testing using microsatellite instability (MSI) testing and immunohistochemistry (IHC) for mismatch repair protein expression can be an effective strategy for identifying potential LS in patients presenting with colorectal or endometrial cancer. Here we describe our experience implementing a screening program for endometrial cancers.Endometrial cancers diagnosed ≤50 years or those with suspicious personal history or histopathologic features were screened with MSI/IHC, June 2009-June 2011. Criteria were later (July 2011-July 2012) expanded to patients diagnosed60 years, or at any age with suspicious features, and finally (after August 2012) universal screening was implemented. Screening techniques began with both MSI and IHC for every tumor, and later converted to IHC for two proteins, and MLH1 promoter methylation analysis when indicated. A genetic counselor contacted patients directly to offer genetic counseling appointments.Two hundred and forty-five endometrial cancers (average age, 57 years) were screened. Sixty-two patients (25%) had abnormal results, and 42 patients were referred for genetic counseling. Of the 42 patients, 34 underwent genetic counseling, 28 pursued genetic testing, and 11 were diagnosed with LS. When age and pathology criteria were used, 27 eligible cases were overlooked for screening and 3 cases of LS were found only because a clinician requested screening.Universal screening of endometrial cancers for LS is practical and successfully implemented with collaboration among genetic counselors, gynecologic oncologists, and pathologists.

Background Differentiation between the various pathologies presenting as a cystic pancreatic lesion is clinically important but often challenging. We have previously advocated the performance of endoscopic ultrasound (EUS) with aspiration and determination of mucin and carcinoembryonic antigen (CEA) content. We sought to report the results of this ongoing protocol and determine the relative importance of cyst fluid mucin and CEA for the diagnostic process. Methods The institutions prospectively maintained pancreatic cyst database was accessed to identify patients who had undergone pancreatic EUS and cyst aspiration as part of their evaluation. Only those patients who had subsequently undergone resection were selected, with histopathology being the gold standard for comparison. Results From January 2000 to July 2009, 174 patients with pancreatic cystic disease underwent surgery, 121 of whom had an EUS with aspiration attempted at our institution with specimens sent for mucin and CEA. Based on histopathology, 86 mucinous lesions were identified, including 44 cystadenomas, 34 intraductal papillary mucinous neoplasms, 7 mucinous adenocarcinomas, and 1 intraductal oncocytic papillary neoplasm; 42 were nonmucinous lesions. The median cyst CEA levels were significantly higher in the mucinous lesions group at 850 versus 2 ng/mL (P = .001). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive diagnostic likelihood ratio, and negative diagnostic likelihood ratio (NDLR) were calculated respectively for mucin alone (0.80, 0.40, 0.61, 0.63, 1.33, 0.68); CEA alone (0.93, 0.43, 0.51, 0.91, 1.63, 0.16); cytology alone (0.38, 0.9, 0.92, 0.31, 3.67, 0.69); mucin or CEA (0.83, 0.65, 0.87, 0.57, 2.51, 0.26); mucin or CEA or cytology (0.92, 0.52, 0.86, 0.68, 1.91, 0.15); mucin plus CEA (0.96, 0.34, 0.25, 0.97, 1.45, 0.12); mucin plus cytology (0.25, 0.97, 0.96, 0.29,7.25, 0.78); CEA plus cytology (0.12, 1.00, 1.00, 0.26, ∞, 0.88); and mucin plus CEA plus cytology (0.08, 1.00, 1.00, 0.25, ∞, 0.92). Conclusion Assessment of cyst mucin and CEA are complementary, with the best profile obtained when both markers are determined along with cytology. This combination provides a good sensitivity, PPV, and NDLR, as well as reasonable PPV and PDNR.

Endometriotic foci, especially ovarian ones, with epithelial cytologic atypia may be precursors of cancer. This study presents an overview of the atypical cytological and histopathological findings associated with endometriosis. Six cases of endometriosis, with atypical histological and cytological changes, were obtained from the archives of the Department of Pathology at Cleveland Clinic Foundation between year 2000 and 2003. The size of the base from which these cases were drawn was 2000 cases of endometriosis. The age range of the patients was from 29 to 52 years. The clinical presentations included infertility (three cases), pelvic pain (three cases), adenexal and pelvic masses (four cases). Stage IV endometriosis with extensive pelvic involvement was found in two patients. Intraoperatively, the endometriotic lesions involved the ovaries (all cases); Cul de sac (four cases); urinary bladder (two cases); sigmoid colon, hemidiaphragms, and uterine vessels (one case each). The endometriotic lesions were associated with uterine leiomyomas (two patients) and adenocarcinoma of the vagina (one patient). Histologically, in addition to endometrial type glands and stroma, usually found in endometriosis, we observed both cytologic and pattern atypism involving the epithelium in all cases. The features of cytologic atypia included nuclear stratification, hyperchromatism, and pleomorphism. The features of pattern atypia were complex glandular pattern, papillary formations and psammoma bodies. In two cases, these features were sufficient for diagnosis of borderline Mullerian seromucinous tumours. One patient had recurred with metastatic adenocarcinoma of the vault. She died later from disseminated metastatic disease. There is a rare association between pelvic endometriosis and borderline ovarian tumours (three cases), cytologic and pattern atypia (two cases); mesothelial hyperplasia, endosalpingiosis (two cases), and metastasis (one case). Cytologic and pattern atypia can develop in the endometriotic foci and therefore, these lesions should be thoroughly scrutinized for presence of these changes. Our findings recommend surgical excision of these foci rather than their simple cauterization.

A proportion of patients under surveillance for recurrent bladder carcinoma with no immediate evidence of bladder tumor recurrence have positive multitarget fluorescence in situ hybridization (FISH; UroVysion, Vysis, Downers Grove, IL) results. The course of these "anticipatory positive" cases and the time to bladder tumor recurrence remains unknown. We followed up 250 patients with urine cytologic results, concurrent multitarget FISH, and cystoscopic examination for recurrent urothelial carcinoma. Of 81 cases (32.4%) with FISH-positive results, tumor recurrence developed in 60 (74.0%). Of 169 (67.6%) FISH-negative cases, recurrent urothelial carcinoma developed in 22 (13.0%). Of 211 patients (84.4%) with negative cystoscopic examination results, 56 (26.5%) had positive FISH results, and in 35 (62.5%) of these patients, recurrent urothelial carcinoma developed. Approximately 27% of patients under bladder carcinoma surveillance without immediate evidence of tumor recurrence will have a positive FISH result, defining the anticipatory positive subset. In about 65% of this anticipatory positive group, recurrent bladder urothelial carcinoma developed within 29 months.

Tumor recurrence, following initial response to adjuvant chemotherapy, is a major problem in women with high-grade serous ovarian cancer (HGSOC). Microarray analysis of primary tumors has identified genes that may be useful in risk stratification/overall survival, but are of limited value in predicting the70% rate for tumor recurrence. In this study, we performed RNA-Seq analysis of primary and recurrent HGSOC to first identify unique differentially expressed genes. From this dataset, we selected 21 archetypical coding genes and one noncoding RNA, based on statistically significant differences in their expression profile between tumors, for validation by qPCR in a larger cohort of 110 ovarian tumors (71 primary and 39 recurrent) and for testing association of specific genes with time-to-recurrence (TTR). Kaplan-Meier tests revealed that high expression of collagen type II, alpha 1 (COL2A1) was associated with delayed TTR (HR = 0.47, 95% CI: 0.27-0.82, p = 0.008), whereas low expression of the pseudogene, solute carrier family 6 member 10 (SLC6A10P), was associated with longer TTR (HR = 0.53, 95% CI: 0.30-0.93, p = 0.027). Notably, TTR was significantly delayed for tumors that simultaneously highly expressed COL2A1 and lowly expressed SLC6A10P (HR = 0.21, 95% CI: 0.082-0.54, p = 0.0011), an estimated median of 95 months as compared to an estimated median of 16 months for subjects expressing other levels of COL2A1 and SLC6A10P. Thus, evaluating expression levels of COL2A1 and SLC6A10P at primary surgery could be beneficial for clinically managing recurrence of HGSOC.

The objective of this study was to describe histologic healing patterns of bladder injuries during laparoscopic hysterectomy. This was a prospective experimental analysis (Canadian Task Force classification II-1) performed at the Cleveland Clinic Foundation, Minimally Invasive Surgery Center animal laboratory using virgin female mongrels. Sixteen animals divided into groups of four underwent laparoscopic hysterectomy and bladder injury. In group 1, the bladder injury consisted of a 1-cm bladder base injury with bipolar electrosurgical current. In group 2, suture placement through full thickness bladder was performed during closure of the vaginal cuff. A 1-cm bladder base laceration with monopolar cautery was induced and repaired laparoscopically in group 3; group 4 underwent a similar injury to that of group 3 but the repair incorporated full thickness anterior vaginal cuff. Animals were euthanized at least 28 days after the surgery; the bladders and vaginas were harvested en bloc for histologic tissue preparation. Histologic qualifications of inflammation, fibrosis, granuloma formation, necrosis, cautery artifact, granulation tissue, the presence of arteritis, recanalization thrombus, foreign body giant cells, and fistula formation were evaluated at the sites of bladder injury. When analyzed separately, the difference in these post-injury histologic manifestations was not statistically significant. The same was true when comparison was made between groups 1 and 2 (no bladder laceration) vs groups 3 and 4 (monopolar-induced bladder base lacerations). After a healing period of at least 28 days, the histologic manifestations of the various bladder injuries in all groups are similar.

The optimal treatment for incidental asymptomatic pancreatic cysts is not known. The purpose of this study was to determine whether nonmucinous cysts by cyst-aspiration analysis can be observed safely.A prospective protocol was initiated in September of 1999 for all suspected cystic neoplasms. Asymptomatic patients with negative cyst aspirates (no extracellular mucin, and concentration of carcinoembryonic antigen in the cyst fluid200 ng/mL) were followed-up clinically and radiographically.Through December 2004, 221 patients have been evaluated, and 80 (36%) initially were operated. There were 141 (64%) patients with indeterminate cysts, 98 have been followed-up for more than 12 months. Compared with resected patients, observed patients were older (62 vs 56 y, P.006), and had smaller cysts (2.4 vs 4.0, P = .001). At a mean follow-up period of 24 months, 4 patients (4%) were resected. The indication, time to resection, and pathology were as follows: 2 patients for symptoms (abdominal pain and obstructive jaundice) at 24 and 72 months, respectively: mucinous and serous cystadenomas; 1 patient for an increase in size (6.6 to 7.8 cm) at 18 months: lymphoepithelial cyst; and 1 patient for abdominal pain and increase in size (2.0 to 3.7 cm) at 41 months: pseudocyst. The only patient resected for a mucinous neoplasm had a cyst fluid carcinoembryonic antigen level of 896 ng/mL. In the remaining observed patients, 20 (23%) showed a decrease in cyst size, and 16 (19%) showed an increase in size (mean diameter change, 21%).Initial follow-up evaluation indicates that asymptomatic patients without evidence of a mucinous neoplasm by cyst aspiration can be followed clinically and with interval imaging.

Objective To test the feasibility of transplanting an intact frozen-thawed ovary with microvascular anastomosis of the ovarian vascular pedicle to the deep inferior epigastric vessels. Design Chronic survival study. Setting Biological Resources Unit, The Cleveland Clinic Foundation. Animal(s) Adult merino ewes. Intervention(s) Bilateral laparoscopic oophorectomy was performed on 17 synchronized ewes. In one group of animals (Group I, n=11), both ovaries were cryopreserved intact with their vascular pedicles. In another group of animals (Group II, n=6), ovarian cortical strips were prepared from each ovary and cryopreserved. After thawing, follicular viability and apoptosis rates were assessed using one ovary. The other ovary was transplanted to the abdominal wall with microvascular anastomosis (Group I). In Group II, the ovarian cortical strips were placed in the anterior abdominal wall. Ovaries were harvested after 8–10 days in situ and subjected to histological evaluation. Main outcome measure(s) Blood flow, apoptotic signals, follicular viability, serum estradiol (E 2 ), follicle-stimulating hormone (FSH), and histology. Result(s) No significant differences were found in the mean values of apoptosis (mostly in the atretic and some secondary follicles) and follicular viability in both groups. In Group I, immediate and long-term patency were documented in 100% and 27% (3/11) of the grafts, respectively; and postoperative FSH levels were similar to preoperative values in animals with patent vessels. In Group II, postoperative FSH levels were significantly higher than the preoperative ones ( P =.03). Conclusion(s) Transplantation of an intact frozen-thawed ovary is technically feasible. Using this approach, immediate restoration of vascular supply and ovarian hormonal functions is possible.

Background. Optimal management of pancreatic cystic neoplasms includes identification and resection of mucinous neoplasms. This study was performed to assess the accuracy of preoperative variables in determining a mucinous lesion. Methods. Patients referred for a cystic neoplasm were prospectively assessed by presenting symptoms, blinded radiologic review, and endoscopic ultrasound-guided cyst aspirate analysis. Patients who were symptomatic, or had aspirate findings of a mucinous neoplasm were resected. Results. Eighty-seven patients were enrolled over a 22-month period ending in December 2001. There were 56 (64%) women and 31 (36%) men, with a mean age of 63 (27-86) years. Thirty-five (40%) patients were resected including 24 (69%) women and 11 (31%) men with a mean age of 58 years. Twenty-eight (80%) patients who had resection were symptomatic. Specimen histology included 18 (51%) mucinous neoplasms, 8 (23%) serous neoplasms, 4 (11%) ductal or neuroendocrine carcinomas, and 3 (9%) pseudocysts. The positive predictive value (PPV) for cyst-aspirate extracellular mucin (83%) was significant in predicting a mucinous neoplasm (P =.009). No other aspirate variables (amylase, carcinoembryonic antigen, CA15-3, viscosity), or patient characteristics were predictive of final histology. Diagnostic agreement between all 3 radiologists was 8% (P =.98). At a median follow-up of 12 months, no patients who were observed required resection. Conclusions. Patients with suspected pancreatic cystic neoplasms can be selectively treated on the basis of symptoms and cyst-aspirate mucin analysis. Symptomatic and mucin containing lesions should be resected. Surgery 2002;132:628-34.

Objective. The objective of this study was to study further the management of cervical adenocarcinoma in situ (AIS) with particular regard to the results of conservative management without hysterectomy and the use of large loop excision of the transformation zone (LLETZ). Methods. Based upon the files of the Pathology Department at the Cleveland Clinic Foundation, recently encountered AIS patients were combined with patients from a previous study that ended in 1994. Charts and clinical materials were retrospectively reviewed and abstracted. Results. Fifty-two patients were identified for a combined study group of 98 patients. The mean age was 37 years. Fifty-two percent were identified due to abnormal squamous elements on a Pap smear and 43% due to abnormal glandular cells. In patients treated with hysterectomy, 67% were found to have residual disease following conization with positive margins including 3 patients with invasive cancer. Among all patients, LLETZ was associated with a positive margin rate of 57.1% vs 27.3% with cold knife conization (CKC) (χ 2 , P = 0.008). Among patients treated conservatively with conization, the rates of positive margins were 40.0 and 20.0%, respectively, for LLETZ and CKC (χ 2 , P = 0.11); 9.5% of conservatively managed patients with negative initial conization margins eventually had recurrent AIS. Conclusion. Cold knife conization is the preferred method of management for cervical AIS patients selecting conservative treatment. Despite initial conization margins being uninvolved, such patients have an approximate risk of 10% for recurrent AIS.

Objective: To test the feasibility of transplanting an entire ovary with anastomosis of the ovarian vascular pedicle. Design: Long-term survival study. Setting: Biological Resources Unit, Cleveland Clinic Foundation. Animal(s): Five adult, nonpregnant ewes. Intervention(s): Laparoscopic bilateral oophorectomy was performed. Ovaries were autotransplanted into the abdominal wall, and microsurgical vascular anastomosis of the ovarian to the inferior epigastric vessels was performed. The transplant was removed and evaluated after 7 ± 1 days. Main Outcome Measure(s): Blood flow, serum E 2 and FSH levels, and histologic characteristics. Result(s): At follow-up three transplants were viable; they showed no signs of necrosis, and patency of the vascular anastomosis was confirmed. Serum E 2 levels did not change significantly after transplantation in the patent vessel group (155.3 ± 46.1 vs. 125.7 ± 44.6 pg/mL) or the nonpatent vessel group (99 vs. 158 pg/mL). Serum FSH level in the patent vessel group did not change significantly from before to after transplantation (70.6 ± 37.2 ng/mL vs. 95.1 ± 17.7 ng/mL), whereas a large increase in FSH level was observed in the nonpatent vessel group (52.3 ng/mL vs. 522 ng/mL). The patent vessel group had significantly more follicles after transplantation than did the nonpatent vessel group (6 ± 1 vs. 1 ± 1). Conclusion(s): In conjunction with improved protocols for cryopreservation, ovarian autotransplantation with vascular anastomosis may be superior to current ovarian tissue banking and grafting techniques.

The aim of this study was to evaluate the 5-year survival probability (SP) of patients treated for ovarian clear cell adenocarcinoma (OCCA) at a single tertiary institution and to compare it to the 5-year SP of patients with other histologic subtypes of epithelial ovarian cancer.Sixty-four patients with pure OCCA treated at the Cleveland Clinic Foundation from 1981 to 1996 were retrospectively identified and clinical information was abstracted. All histologic materials were reviewed by a single gynecologic pathologist. SP was calculated by the Kaplan-Meier method. SPs for OCCA patients were compared to that of other high-grade epithelial ovarian cancer patients in the gynecologic tumor registry. Cox proportional hazards modeling was used to identify varibles associated with decreased SP.The FIGO stages of OCCA study patients were Stage I, 31 (50%), Stage II, 6 (10%), Stage III, 17 (27%), and Stage IV, 8 (13%) (2 patients unstaged). Forty-four patients had no gross residual cancer at the completion of initial surgery while 9 patients had/=1 cm diameter residual and 10 had1 cm residual. Forty-five (73%) received postoperative chemotherapy. The median follow-up for surviving patients is 97 months (range 38 to 209 months). The overall 5-year SP of OCCA patients is 50% with limited disease (Stages I and II) patients having a 5-year SP of 72% versus 17% 5-year SP in patients with advanced disease (P0.001). FIGO stage was most predictive of outcome. The overall 5-year SP of OCCA patients (50%) differed significantly (P0.05) from that of other ovarian cancer registry patients (30%). OCCA patients with limited cancer survived similarly to registry patients (72 vs 72%) as did patients with advanced OCCA compared with registry patients (17 vs 22%).When controlled for grade and stage, the overall survival with OCCA is identical to that of other high-grade epithelial ovarian cancers. Factors that account for the better overall survival of OCCA patients are more favorable disease stage, younger age, and improved debulking status.

To evaluate the occurrence of apoptotic bodies in endocervical adenocarcinoma in situ (AIS) and investigate the relationship of apoptosis to mitotic activity, we performed counts of apoptotic bodies and mitotic figures in 43 patients with AIS and in a comparable control group with nonneoplastic endocervical glandular epithelium. The ages of the patients with AIS ranged from 27 to 74 years (mean = 40). Mitotic figures were present in all AIS cases, and apoptotic bodies were seen in all but two extremely small lesions. In 28 AIS cases in which lesions were large enough to count 10 consecutive high-power fields (HPF), counts of apoptotic bodies ranged from 1 to 36/10 HPF (mean and median = 16), and counts of mitotic figures ranged from 1 to 53 mitotic figures/10 HPF (mean and median = 18). Counts of apoptotic bodies correlated directly with counts of mitotic figures. The ages of the 28 control patients ranged from 32 to 56 years (mean = 43). Counts of apoptotic bodies in the control cases ranged from 0 to 10 per case (mean = 1.1). Apoptotic bodies were present in only 13 (46%) control cases. The highest counts in these cases ranged from 1 to 6 apoptotic bodies/10 HPF (mean = 2.3). Mitotic figures were present in only 4 (14%) control cases. The counts in these cases ranged from 1 to 3 mitotic figures/10 HPF (mean = 1.8). Counts per 10 HPF were significantly (p0.001) more for AIS cases than for controls for apoptotic bodies and mitotic figures. Our results indicate that apoptotic bodies, as well as mitotic figures, occur almost universally in AIS. Both occur significantly more often and in greater numbers in AIS than in nonneoplastic endocervical glandular epithelium. Apoptotic bodies are a consistent morphologic feature of AIS, and their identification may be diagnostically useful.

BACKGROUND & AIMS: A less costly cancer surveillance method for Barrett's esophagus is desirable. The aim of this study was to compare nonendoscopic balloon cytology with biopsy and brush cytology for detecting dysplasia and carcinoma in patients with Barrett's esophagus. METHODS: Patients in a surveillance program underwent balloon cytology before endoscopy with biopsy and brush cytology. Results of cytology were compared with those of histology. RESULTS: Adequate columnar epithelium was obtained in 52 of 63 (83%) patients with balloon cytology and 59 of 61 (97%) with brush cytology. Balloon cytology obtained abnormal cells in 6 of 8 patients with adenocarcinoma, 2 of 2 patients with high-grade dysplasia, and 2 of 8 patients with low-grade dysplasia. Sensitivity of balloon cytology for high-grade dysplasia or carcinoma was 80% but only 25% for low-grade dysplasia. No patients without dysplasia or carcinoma had abnormal cells. Brush cytology was abnormal in all 11 patients with high-grade dysplasia or carcinoma but only 2 of 9 patients with low-grade dysplasia (sensitivity, 22%). Two of 39 patients without dysplasia had abnormal cells (specificity, 95%). Balloon cytology cost was sixfold less than endoscopy with biopsy. CONCLUSIONS: Balloon cytology detected 80% of patients with high-grade dysplasia or carcinoma when sampling was adequate. Brush cytology data suggest that a more abrasive balloon may improve balloon cytology sensitivity. The potential cost savings of balloon cytology compared with endoscopic cancer surveillance in Barrett's esophagus support further studies of this technique. (Gastroenterology 1997 Jun;112(6):1787-97)

The reported histopathologic findings in leiomyomas treated with leuprolide acetate (LA) differ. We examined 233 myomectomy specimens, including 107 myomas from 30 patients (mean age, 34.7 +/- 4.6 years) treated with LA. Their histopathologic findings were compared with those from a control group of 126 myomas from 30 untreated patients (mean age 32.7 +/- 5.3 years). The LA-treated leiomyomas had myxoid change (n = 2; 1.9%), total necrosis (n=4; 3.7%), focal necrosis (n = 5; 4.7%), calcifications (n = 5; 4.7%), hemorrhage (n = 8, 7.5%), vascular changes (n = 12; 11.2%), hydropic degeneration (n = 22; 20.5%), and hyalinization (n = 61; 57.0%). None of these changes differed significantly from the untreated controls. None of the LA-treated leiomyomas had nuclear atypia, whereas nuclear atypia occurred in four (3.2%) of the untreated leiomyomas; this difference was also not significant. Mitotic figures were present in 8.4% of the LA-treated myomas and 8.5% of untreated controls. The number of mitotic figures per 10 high-power fields was slightly higher in the untreated myomas, but the difference was not statistically significant (range, 0-3 for treated, 0-5 for controls). The degree of cellularity did not differ between the two groups. In conclusion, (a) LA-treated myomas do not significantly differ from untreated myomas with respect to nuclear atypia, calcification, total coagulative necrosis, focal coagulative necrosis, hemorrhage, vascular changes, myxoid change, hydropic degeneration, hyalinization, mitotic activity, or cellularity; and (b) the mechanism leading to a reduction in the size of myomas treated with LA is not apparent from routine histologic examination.

Background Metastasis of nongynecologic tumors to the cervix is a rare event. Isolated breast cancer metastasis to the cervix has only been reported in two other cases. Case A 43-year-old with a history of intraductal breast cancer presented with vaginal bleeding. Colposcopic pathology revealed a lesion similar to her primary breast lesion. She underwent an extensive work up and hysterectomy that revealed no other lesions. Currently, she is alive and well. Conclusions Aggressive treatment of isolated cervical metastasis from breast cancer is warranted in appropriate patients.

There is increasing evidence that oxidative stress is one of the key factors for progression of endometriosis. In this prospective controlled trial, we measured 6 different biomarkers of oxidative stress targeting protein, lipid, and DNA to quantify the severity and progression of endometriosis and establish a diagnostic marker for the disease.A total of 62 consecutive patients were identified and enrolled in this study. After exclusion criteria, 44 patients were allocated to 3 groups: stage I/II (n = 14), stage III/IV (n = 16), and a control group (n = 14). The levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), 8-oxoguanine DNA glycosylase (OGG1), protein carbonyl (PC), lipid peroxidation (LPO), reactive oxygen species (ROS), and total antioxidant capacity (TAC) were accessed in peritoneal fluid and tissue.Significantly higher levels of 8-OHdG and PC were seen in patients with endometriosis, in addition OGG1 expression was found to be significantly lower in patients with endometriosis (P.001, P = .001, P = .033, respectively); ROS, TAC, and LPO were similar in stages I/II, stages III/IV, and control group. A predictive model was built using multivariable analyses and receiver-operating characteristics curves. The ability to predict and distinguish between patients without endometriosis, stage I/II endometriosis, and stage III/IV was very high. This model was highly discriminatory and had a concordance index of 0.87.In this cohort, higher DNA damage and lower DNA repair activity was related to endometriosis progression. Our results indicate that oxidative stress as a biomarker of cell injury can be used as a reliable quantitative test of endometriosis severity.

Prognostic blood biomarkers for patients with uveal melanoma have not been identified. Tumor monosomy-3 is strongly associated with the development of metastatic disease. Tumor expression of human leukocyte antigen class I molecules and insulin-like growth factor (IGF)-1 receptor has also been associated with the development of metastatic disease. The relationship of blood levels of the human leukocyte antigen-class-I-associated β-2 microglobulin (β2M), IGF-1, and its binding protein, IGFBP-3, with tumor monosomy-3 was evaluated. Blood was drawn from patients with a clinical diagnosis of primary uveal melanoma without metastatic disease before fine-needle aspiration biopsy at the time of brachytherapy or enucleation. Tumor chromosome 3 status was determined by fluorescence in-situ hybridization. β2M, IGF-1, and IGFBP-3 levels were determined using enzyme-linked immunosorbent assays. A total of 76 patients were studied; 47 (62%) underwent brachytherapy and 29 (38%) underwent enucleation. Thirty-three (43%) of the tumors manifested monosomy-3. Most tumors were large, located in the choroid, mixed cell type, and nuclear grade 2. Most tumors did not manifest extraocular extension. Blood levels of IGF-1 and IGFBP-3 were not associated with tumor monosomy-3. In contrast, increases in blood β2M (P≤0.02) were associated with tumor monosomy-3. The independent association of increased blood level of β2M and tumor monosomy-3 status was confirmed in multivariable analysis. In conclusion, measurement of blood levels of β2M in patients with primary uveal melanoma may have prognostic value and may help guide surveillance and adjuvant therapy recommendations.

Oxidative stress is associated with many disease states including gynecologic disease. This process can damage lipids, proteins and DNA. The present study highlights the role of oxidative stress induced DNA damage as measured by 8-hydroxy-2-deoxyguanosine in development of benign gynecological conditions (BGC). Our aim was to map the oxidative DNA damage on female reproductive organs and highlight the high amount found in a variety of benign gynecologic disorders. Seventeen biopsy specimens from female pelvic organs were divided in two groups: healthy organs tissue and BGC tissue. Healthy organs biopsy tissue included the cervix, tubes, uterus, peritoneum, and topic endometrium in secretory phase. Benign gynecological biopsy tissue included hydrosalpinges, leiomyoma, adenomyosis and tubal cysts. Immunohistochemical staining showed significantly higher levels of DNA damage between BGC and healthy organs [19.36 % (6.20; 32.51) vs. 4.61 % (0.63; 8.53); P

Bronchogenic cysts are congenital anomalies of the bronchial tree that are often asymptomatic at presentation in adults. Management of asymptomatic bronchogenic cyst in this population remains controversial. Eighteen patients with bronchogenic cysts were treated at our institution since 1975. At initial presentation, 10 patients (56 percent) were asymptomatic and 8 (44 percent) were symptomatic. Cough and pain were the most frequent symptoms. Two patients presented with potentially serious complications, one with respiratory distress from airway compression and the other with infection and airway fistulae. Chest radiographs were abnormal but nondiagnostic in 17 out of 18 (94 percent) patients. Chest computerized tomography (CT) scans were abnormal in eight of eight (100 percent) patients, but they confirmed the benign cystic nature in only five of eight (62.5 percent). Overall, considering the use of all imaging modalities and clinical suspicion, bronchogenic cyst was considered in the preoperative differential diagnosis in only 11 of 18 (61 percent) patients. Fifteen of 18 cysts were resected initially. Three of the asymptomatic patients who were followed up initially ultimately required resection because of the development of symptoms. A trend toward increased postoperative complications was noted in patients who were symptomatic at the time of surgery (27 percent vs 14 percent). In conclusion, adult patients with asymptomatic bronchogenic cyst may develop symptoms over time. Symptoms in adults can sometimes be potentially serious. Since a confident preoperative diagnosis is not always possible and because surgical complications may be more common in the symptomatic patient, we recommend surgical resection of all suspected bronchogenic cysts in operable candidates.

We report a schwannoma with well differentiated ducts resembling cutaneous sweat ducts. The tumor presented as a painless mass near the left knee of a 41-year-old female. The mass had been present for many years. Some increase in size had been noticed over the previous 2 to 3 yr. The bulk of the tumor was composed of spindle cells with the appearance of Antoni A and Antoni B tissue. Rare mitotic figures were noted. In several areas of the tumor, numerous well-differentiated ducts were present. Most resembled normal cutaneous sweat ducts. In some areas, cystic dilatation of the ducts was present. Focal areas demonstrated poorly formed ducts and single cells with prominent nuclei and ample cytoplasm. Well formed ducts, poorly formed ducts, and single cells marked with AE 1/3 (keratin) and epithelial membrane antigen. The spindle cell proliferation marked for S 100 protein and vimentin. Sweat duct differentiation has not been reported previously in either benign or malignant schwannoma. Light and electron microscopic features of this tumor are presented.

BACKGROUND: %Osseous metaplasia of the uterus is a rare pathologic entity usually affecting the endometrial cavity without cervical extension. It has been reported after abortion, in cases of chronic endometritis, and as a result of metabolic disorders as hypervitaminosis D, hyperparathyroidism, hypercalcemia, and hyperphosphatemia. CASE: A woman developed osseous metaplasia of the cervix shortly after loop electrosurgical excision procedure (LEEP) for severe cervical dysplasia. Normal transvaginal ultrasonograms before the LEEP, and failure to detect osseous metaplasia after histologic review of the tissue obtained from that procedure indicate that the osseous metaplasia had been induced by the LEEP. The heterotopic bone formation rapidly recurred after initial removal. Her serum calcium, phosphorus, and vitamin D levels were normal. CONCLUSION: LEEP may result in healing with metaplastic bone formation.

✓ The authors present a case involving the formation of several carbon granulomas in the scalp of a woman 7 years after she underwent craniotomy. Her operation had included the use of carbon fiber pins for refixation of a stereotactic head frame. Carbon granulomas have been noted in multiple organs following surgical or traumatic carbon deposition, but have not been reported in association with neurosurgical carbon fiber pins used for head fixation. The lesions in this case arose a few months after initiation of chemotherapy for the patient's brain tumor. The relationship of carbon and cutaneous granuloma formation to adjuvant therapies and treatment strategies is discussed.

CCL2, a chemokine, is expressed in normal human ovarian epithelium but down-regulated in ovarian adenocarcinomas. The association of CCL2 expression with chemotherapy response, invasion and survival outcomes was studied in patients with primary ovarian cancer (OC) and in ovarian cancer cell lines (OCCLs). Tumor specimens (80% tumor) from patients with primary, advanced serous OC obtained at the time of cytoreductive surgery was used to isolate total RNA. The CCL2 gene expression evaluated by RT-PCR was investigated in relation to chemo-response/clinical outcomes in the OC patients and to sensitivity to cisplatin/paclitaxel in the OCCLs. In vitro invasion was measured by matrigel invasion and matrixmetallo-proteinase-9 (MMP-9) zymogram assays. Thirty-seven patients were included. In multivariable analyses that adjusted for the impact of debulking status, the CCL2 mRNA expression was correlated with objective complete response (p = 0.01), chemosensitivity (p = 0.04), and progression-free survival (PFS; p = 0.006). These findings were corroborated in vitro in the OCCLs. The cells expressing higher levels of CCL2 were more sensitive to paclitaxel and cisplatin as compared to those lines expressing lower levels of this chemokine. Up-regulation of CCL2 in the PAT-7 cell line further enhanced the response of these cells to paclitaxel (p = 0.0001) and led to decreased invasion (p = 0.0009). Increased ovarian tumoral expression of CCL2 is associated with improved chemoresponse and survival outcomes, and higher levels of CCL2 in ovarian cancer cell lines are associated with increased chemosensitivity and decreased invasion in vitro.

Primary peritoneal serous micropapillomatosis of low malignant potential, or serous borderline tumor of the peritoneum, is a relatively rare lesion that is histologically indistinguishable from peritoneal "implants" associated with ovarian papillary serous tumors of low malignant potential. We analyzed 17 cases to further define the pathologic features and prognosis of this entity. The ages of the patients ranged from 16 to 67 years (mean, 33 years). Eight patients were symptomatic with chronic pelvic or abdominal pain (five patients), adnexal mass (one patient), small-bowel obstruction (one patient), and possible endometriosis (one patient). In nine cases (53%), peritoneal serous micropapillomatosis of low malignant potential was an incidental finding discovered during evaluation or treatment of other conditions. Grossly, the peritoneal lesions were focal or diffuse. They commonly appeared as miliary granules and often were believed to be peritoneal carcinomatosis. Microscopically, peritoneal serous micropapillomatosis of low malignant potential had all of the patterns seen in superficial ("noninvasive") peritoneal implants of ovarian serous borderline tumors. Psammoma bodies were a prominent feature of all cases. Twelve patients also had typical endosalpingiosis. Most patients were treated by hysterectomy and bilateral salpingo-oophorectomy. Surgical treatment in seven patients consisted only of biopsy. Ten patients had residual unresected disease at the time of their initial operation. Several patients received adjuvant chemotherapy. Follow-up was available for 14 of the 17 patients. One patient died of metastatic breast carcinoma at 3.8 years; another patient died 7 weeks after operation, possibly as a complication of therapy. The other 12 patients were alive at last known contact after follow-up intervals of 8 months to 16.2 years (mean, 7.5 years). Two of these 12 patients developed multiple episodes of small-bowel obstruction due to persistent peritoneal serous micropapillomatosis of low malignant potential; neither received adjuvant chemo- or radiotherapy. Both were alive without progressive disease 10.9 and 16.2 years after initial diagnosis, respectively. This excellent prognosis supports a regimen of conservative therapy for these patients.

Endometrium directly sampled from endocervical mucosal endometriosis can mimic endocervical adenocarcinoma in situ (AIS) in Papanicolaou (Pap) tests. We analyzed a series of Pap tests to investigate the cellular features of mucosal endometriosis and to assess the utility of stroma and apoptotic bodies in the differential diagnosis with AIS. Pap test samples from patients known to have endocervical mucosal endometriosis were compared with samples containing AIS. Pap tests from patients with mucosal endometriosis had lesional cells in 13 (62%) cases which includes glandular and stromal cells (10 cases), stroma only (two cases), and glandular cells only (one case). Three (23%) cases had gland-stromal aggregates. Three (23%) cases had mitotic figures and two (15%) had apoptotic bodies. By comparison, only one (8%) AIS case had endometrial-type stroma. Seven (58%) AIS cases had apoptotic bodies and three (25%) had mitotic figures. We conclude that Pap tests from patients with mucosal endometriosis usually (62%) have lesional cells. These lesional cells almost always include stroma, which is useful in the differential diagnosis with AIS. We identified stroma significantly more often in endometriosis cases (92%) than in AIS cases (8%). Pathologists should look for endometrial stroma when considering an interpretation of directly sampled endometrium. In the absence of stroma, AIS should be considered. Diagn. Cytopathol. 2010;38:551–554. 2009 Wiley-Liss, Inc.

Analysis of pancreatic cyst fluid can play a role in the management of asymptomatic cystic neoplasms.Our aim was to determine whether cyst size or location can predict the success of cyst fluid collection and analysis.Review of prospective management protocol.Tertiary care referral center.Three-hundreds and 70 patients with suspected pancreatic cystic neoplasms evaluated over 6 years.Endoscopic ultrasound aspiration for up to 3 variables: cytology including extracellular mucin, CEA, and amylase.The number of variables obtained were compared with cyst size and location.The distribution of unilocular cystic lesions was: 125 (33.8%) head, 105 (28.4%) tail, 77 (20.8%) body, 37 (10.0%) uncinate and 13 (3.5%) multiple cysts. In addition, 13 (3.5%) patients had uncertain cyst location. There was no association between cyst location and number of variables obtained (P=0.148). An aspirate was obtained in 284 patients (76.8%) with a mean volume of 8.3 mL. There was a significant correlation between cyst size and volume aspirated (P0.001). The number of variables obtained was significantly correlated with cyst size (P0.001): 3 variables were obtained in 109 out of 284 (38.4%) with a median size of 3.0 cm. Logistic regression curves predict likelihood of success based on cyst size. An unsuccessful attempt at EUS aspiration for cysts occurred in 31 of the 284 cases (10.9%) with a median size of 1.5 cm.Successful endoscopic ultrasound aspiration of pancreatic cysts is independent of cyst location, but correlates with size, which can be useful in deciding which patients should undergo endoscopic ultrasound and aspiration.

To assess the value of repeating a biopsy when the initial thyroid fine-needle aspiration (FNA) biopsy is nondiagnostic.Between 1990 and 2003, 4,311 thyroid FNAs were performed at the Cleveland Clinic Foundation, of which 220 (5%) were nondiagnostic. Among 189 patients whose medical records were available for retrospective review, 106 underwent a repeated FNA (FNA #2), and 14 had a second repeated FNA (FNA #3). Thyroid ultrasonography was used in the evaluation in 113 FNAs.The first and second repeated FNAs were diagnostic in 58% (62 of 106 patients) and 50% (7 of 14 patients), respectively. The rate of malignant disease in patients with no repeated FNAs versus 1 or more repeated FNAs was 4.8% (4 of 83) versus 11.3% (12 of 106), respectively. Ultrasound-guided FNA yielded a diagnosis among 33 of 113 biopsies (29.2%), and FNA without ultrasound guidance provided a diagnosis in 30 of 159 biopsies (18.9%). Thus, the use of thyroid ultrasonography significantly improved the likelihood of establishing a diagnosis (P = 0.017). We found that repeating the FNA up to 2 times provides a diagnosis in up to 60% of cases.The overall prevalence of thyroid cancer in patients with nondiagnostic FNA is not trivial--8.5% in our study group of 189 patients. An aggressive approach toward nondiagnostic FNA biopsies is recommended, with performance of at least 2 repeated FNA biopsies, preferably with the help of ultrasound guidance.

We report the clinical trial studies for the ThinPrep Imaging System (TIS; Cytyc, Boxborough, MA). Between December 2000 and July 2001, 10,742 ThinPrep specimens were collected at 4 US clinical sites representative of the normal clinical population of the laboratories, including screening patients and referred patients. After nonstudy screening diagnoses were completed, the vials were relabeled and randomized, and study slides were prepared and stained. TIS-trained cytotechnologists and pathologists screened the slides twice, first manually, then TIS-assisted after an appropriate interval. Afterward, 3 independent pathologists performed an adjudication study to determine definitive diagnoses for the nonnegative slides and 5% of the negative slides; the adjudicated diagnoses served as the "gold standard" for subsequent sensitivity and specificity analyses. TIS-assisted screening was statistically more sensitive than manual screening for atypical squamous cells of undetermined significance (ASCUS) or higher (+) and statistically equivalent for low- (LSIL)+ and high-grade squamous intraepithelial lesion (HSIL)+ diagnoses. TIS-assisted screening had equivalent specificity for ASCUS+ and LSIL+ and significantly higher specificity for HSIL+. Average cytologists' daily screening rates doubled with TIS-assisted screening. The sensitivity of the TIS-assisted screening system equals or exceeds the sensitivity of manual primary screening without adversely affecting specificity, and TIS-assisted screening can improve cervical cancer screening productivity. Cost issues require further study.

Human papillomavirus (HPV) is widely accepted as the primary agent involved in the development of squamous intraepithelial neoplasia and cervical carcinoma. Several commercial tests are available for detecting HPV DNA. This study compares the efficacy of INFORM HPV (in situ hybridization [ISH] HPV) and HCII (HC HPV) in predicting cervical lesions. A total of 762 sequential Papanicolaou (Pap) smears determined by cytologic examination to be either atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL) were tested by both Hybrid Capture (HC) HPV and ISH HPV; 250 follow-up biopsies were reviewed as the reference standard for presence or absence of a lesion. ISH HPV and HC HPV differed significantly in accurately predicting biopsy findings from ASC-US and LSIL cases. The overall sensitivity and specificity of ISH HPV were 97% (28/29) and 86% (191/221); and HC HPV was 79% (23/29) and 56% (123/221). The positive predictive value (PPV) of ISH HPV was 48% (28/58) vs HC HPV value of 19% (23/121). Negative predictive value (NPV) was also better with ISH HPV at 99% (191/192) and HC HPV at 95% (123/129). Of equal importance, ISH HPV demonstrated a lower false-positive rate compared to HC HPV, 12% (30/250) vs 39% (98/250), as well as having a slightly lower false-negative rate 0.4% (1/250) vs 2.4% (6/250). ISH HPV is more predictive of biopsy histopathology in patients with detectable cervical lesions than is HC HPV. Effective triage of patients by HPV analysis using ISH HPV as compared to HC HPV has the potential of significant public health impact by reducing unnecessary colposcopies, as well as adverse medical, social, and psychological patient consequences.

Objective To determine the sensitivity and specificity of liquid-based cytology in a high-risk, unscreened population. Study design A cross-sectional comparative trial of multiple screening techniques. This report focuses on the performance of liquid-based cytology using biopsy as the standard. Results In total, 1,997 women were screened. All subjects had a minimum of five cervical biopsies. Of the subjects, 4.3% had CIN 2 on biopsy. The ThinPrep Pap with ASCUS as positive had a sensitivity for CIN 2 of 94% and specificity of 78%; the sensitivity for CIN 3 was 98% and for cancer, 100%. The unsatisfactory rate due to bloody specimens was 7.9% (158/1,997). After reprocessing, the unsatisfactory rate was 0.15% (3/1,997). Conclusion Reprocessing effectively recovers ThinPrep samples otherwise unsatisfactory due to blood and mucus. The ThinPrep Pap test is a highly sensitive screening test when used in a high-risk, unscreened population.

To analyze our experience with 400 Thin-Prep (TP) split samples (Cytyc Corp., Boxborough, Massachusetts) as an initial assessment of this new technology's effect in our laboratory.Three gynecologic oncologists and two general gynecologists obtained the 400 split samples using a broom sampling device. Following conventional smear (CS) preparation, they rinsed the broom in Preservcyt solution (Cytyc) for subsequent TP processing. The paired samples were separated, independently analyzed and classified by the Bethesda System. All available follow-up surgical pathology material was reviewed and compared to the cytologic diagnoses.TP had significantly more abnormal results (22% vs. 16%, P = .007), including more atypical squamous cells of undetermined significance (ASCUS) (9.5% vs. 6.3% P = .07) and low grade squamous intraepithelial lesion (LSIL) (7.8% vs. 5.3%, P = .03). Both methods had 3.3% high grade squamous intraepithelial lesion (HSIL). For TP, ASCUS/squamous intraepithelial lesion (SIL) = 0.86 and for CS, ASCUS/SIL = 0.74. Ten TP SILs had a paired negative CS, including LSIL (nine cases) and HSIL (one case). Consensus review of these 10 TP slides confirmed the HSIL and four LSILs. No CS SILs had a paired negative TP. Only 36 (9%) cases had surgical pathology follow-up. The surgical specimens included 17 cervical intraepithelial neoplasia (CIN) 2 or above. The TP method had no false negatives, while the CS method had 3 false negatives among the 17 confirmed cases of CIN 2 or above.TP appears to be superior to CS for detecting SILs.

We present a patient with a symptomatic pleural effusion resulting from papillary carcinoma of the thyroid metastatic to the pleura. Distinctive features include clinically evident pleural metastasis and the presence of psammoma bodies in the pleural fluid, which are characteristic (albeit not pathognomonic) of papillary carcinoma of the thyroid.

Objective: To study p53 and HER-2/neu expression in borderline ovarian tumors (BLOT) by assessing their frequency, coexpression, and relationship to histologic type, FIGO stage, tumor recurrence, and survival. Methods: Forty-two patients with confirmed BLOT (25 serous, 13 mucinous, and 4 seromucinous) were followed for 1.5 to 14 years (mean, 6.3). Thirty (71%) patients had FIGO stage I and 12 (29%) had FIGO stage III disease. Paraffin-embedded sections from the 42 BLOT, 5 normal ovaries, and 10 benign ovarian cystadenomas were stained using monoclonal antibodies against human p53 (DAKO-p53, DAKO, Denmark) and HER-2/neu (C-erB-2, Triton, Parkway, CA). Positive staining was semiquantitated depending on the number of positively stained tumor cells. p53 and HER-2/neu overexpressions were correlated to each other, to histologic subtype, stage, tumor recurrence, and survival. Results: None of the patients had tumor recurrence. The 5- and 10-year disease-free survival was 100%. None of the normal ovaries or ovarian cystadenomas demonstrated overexpression of p53 or HER-2/neu. Ten (24%) BLOT demonstrated overexpression of p53 and 9 (21%) demonstrated overexpression of HER-2/neu. HER-2/neu overexpression was significantly greater in stage III than in stage I tumors ( P = 0.0157). Seromucinous BLOT demonstrated significantly greater p53 overexpression compared with other histologic subtypes ( P = 0.030). Coexpression of p53 and HER-2/neu occurred in 4 patients (9.5%). There was no significant correlation between the overexpression of p53 and HER-2/neu ( P = 0.180) and no significant relationship between p53 and HER-2/neu overexpression and the presence of microinvasion, ability to perform optimal cytoreductive surgery, tumor recurrence, or survival. Conclusions: p53 and HER-2/neu overexpression occurred in about 20–25% of BLOT overall and more commonly in seromucinous and advanced stage tumors. Coexpression occurred in 9.5% of the cases with no significant correlation between the expression of p53 and HER-2/neu.

A 23-year-old black woman presented with abdominal pain of sudden onset, high fever, chills, and an elevated serum alkaline phosphatase level. Examination revealed a tender abdominopelvic mass consistent with an ovarian mass. Her medical history was significant for an osteosarcoma of the left humerus removed 7 years earlier and excision of multiple pulmonary and chest wall metastases 2 years earlier. Exploratory laparotomy revealed a solid hemorrhagic left ovarian mass and ascites. There was no other evidence of disease. A left salpingo-oophorectomy was performed. Pathological examination of the mass showed metastatic osteosarcoma. Four months later, the patient died of widespread osteosarcoma. The clinicopathologic features of ovarian osteogenic sarcomas reported in the literature are reviewed. Pain, fever, and elevated serum alkaline phosphatase levels may be the presenting clinical features of this rare ovarian tumor.

Adenocarcinoma in situ (AIS) of the cervix is a controversial entity which is being encountered with increasing frequency. Current critical issues in its management are the safety of uterine preservation in younger patients and the use of LLETZ conization. A 28-year-old patient was diagnosed with AIS and managed with LLETZ. Despite apparently negative margins of resection in the initial conizations, the patient was found to have invasive adenocarcinoma 1 year later. It is concluded, after review of the pathologic features of AIS, that if conservative management of AIS is elected, then standard cold knife conization should be performed and not LLETZ. Further study is required to establish the overall safety of conservative treatment of cervical AIS, including the use of LLETZ.

Purpose To compare fluorescence in situ hybridization (FISH) using a centromeric probe for chromosome 3 (CEP3) and 3p26 locus-specific probe with single-nucleotide polymorphism array (SNP-A) analysis in the detection of high-risk uveal melanoma. Methods Fifty cases of uveal melanoma (28 males, 22 females) treated by enucleation between 2004 and 2010 were analyzed. Fresh tissue was used for FISH and SNP-A analysis. FISH was performed using a CEP3 and a 3p26 locus-specific probe. Tumor size, location, and clinical outcome were recorded during the 7-year study period (median follow-up: 35.5 months; mean: 38.5 months). The sensitivity, specificity, positive predictive value, and negative predictive value were calculated. Results Monosomy 3 was detected by FISH-CEP3 in 27 tumors (54%), FISH-3p26 deletion was found in 30 (60%), and SNP-A analysis identified 31 (62%) of the tumors with monosomy 3. Due to technical failures, FISH and SNP-A were noninterpretable in one case (2%) and two cases (4%), respectively. In both cases of SNP-A failure, tumors were positive for FISH 3p26 deletion and in a single case of FISH failure, monosomy 3 was found using SNP-A. No statistically significant differences were observed in any of the sensitivity or specificity measures. Conclusions For prediction of survival at 36 months, FISH CEP3, FISH 3p26, and SNP-A were comparable. A combination of prognostication techniques should be used in an unlikely event of technical failure (2%-4%).

Unlike other ovarian epithelial cancers, histologic measures of differentiation of ovarian clear cell adenocarcinoma have not been found to be reliable predictors of progression-free interval and survival. Forty-two consecutively treated patients with pure ovarian clear cell adenocarcinoma were identified and all histologic materials were reviewed. The following histologic features were assessed: architectural pattern (tubular/tubulocystic, papillary, solid, and mixed), average and maximal mitotic activity per 10 high-power fields (hpf's), percentage of cells with clear cytoplasm, and nuclear grading (both Fuhrman et al.'s (Am. J. Surg. Pathol. 6, 655-663, 1982) and Christopherson et al.'s (Cancer 49, 1511-1523, 1982) methods). Surgical stage was most predictive of survival (P0.01) and subsequent comparisons using Cox proportional hazards modeling were adjusted for Stages III and IV. Greater than six mitotic figures per 10 hpf's predicted a poorer survival (P = 0.05) but was not predictive of progression-free interval (P = 0.28). Survival and progression-free interval in patients with tumors of mixed architectural pattern tended to be shorter than those for patients where one type did predominate, but this was not statistically significant (P = 0.06). The tubulocystic pattern was not predictive of patient outcome nor was either method of nuclear grading. Stage and average mitotic activity seem to be the best predictors of survival for patients with ovarian clear cell adnocarcinoma, while architectural pattern and nuclear grading are not as reliable.

Long-term survival following the diagnosis of ovarian malignant mixed mullerian tumor (MMMT) is unusual. This report analyzes two such long-term survivors. One patient presented with a FIGO Stage III, homologous MMMT treated initially with a combination of surgery and chemotherapy. Residual disease, present at the time of initial operation, responded to the chemotherapy; however, the tumor recurred 2 1/2 years postoperatively. This recurrence responded to a combination of surgery and chemotherapy, including continuous adjuvant chemotherapy. This patient is alive, on maintenance chemotherapy, and without evidence of disease, approximately 7 years after the recurrence and 9 years after the initial presentation. The other patient presented with a FIGO Stage III heterologous MMMT treated initially with combined surgery and chemotherapy. Residual disease was present at the time of initial operation. Persistent pelvic disease led to exploratory laparotomy, excision of an 8-cm diameter pelvic mass, and postoperative radiation therapy. The tumor recurred in the left supraclavicular lymph nodes 2 years later (3 years after the initial presentation). This recurrence responded to radiation therapy. This patient was last seen 2 years later (5 years after the initial presentation). At that time, she was without evidence of recurrence. She died 7 1/2 years after her initial presentation. These two patients represent examples of the unusual occurrence of patients with advanced-stage ovarian MMMT experiencing long-term survival following surgical and adjuvant therapy.

The clinical and pathologic features of 29 cases of ovarian clear cell adenocarcinoma (OCCA) were studied to evaluate outcome and potential predictors of survival. Patients' ages ranged from 30 to 89 years (median, 54 years). The study group, using the FIGO classification, consisted of 10 Stage I, 5 Stage II, 7 Stage III, 5 Stage IV, and 2 unstaged patients. Previous or concurrent endometriosis was noted in 45% of patients. Three patients (10.3%) had hypercalcemia. Only stage and the presence of macroscopic residual disease had a statistically significant association with survival. Stage I and II patients experienced a survival similar to a group of 305 patients with adenocarcinomas of non-clear cell type in our ovarian cancer registry with the exception of the very poor survival among Stage IC OCCA patients. Patients with Stage III and IV OCCA had a worse survival than non-OCCA registry patients of similar stage. Few objective responses to adjuvant chemotherapy could be demonstrated in these high-stage OCCA patients. Further study of postoperative adjuvant therapies is warranted.