Adjuvant Chemotherapy plus Radiation for Locally Advanced Endometrial Cancer.

BACKGROUND: Stage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence. METHODS: In this randomized phase 3 trial, we tested whether 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) is associated with longer relapse-free survival (primary end point) than six cycles of combination chemotherapy alone in patients with stage III or IVA endometrial carcinoma. Secondary end points included overall survival, acute and chronic toxic effects, and quality of life. RESULTS: Of the 813 patients enrolled, 736 were eligible and were included in the analysis of relapse-free survival; of those patients, 707 received the randomly assigned intervention (346 received chemoradiotherapy and 361 received chemotherapy only). The median follow-up period was 47 months. At 60 months, the Kaplan-Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group. CONCLUSIONS: Chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone in patients with stage III or IVA endometrial carcinoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00942357.).

Updated 2013 College of American Pathologists/American Society of Clinical Oncology (CAP/ASCO) guideline recommendations for human epidermal growth factor receptor 2 (HER2) fluorescent in situ hybridization (FISH) testing increase HER2 positive and HER2 equivocal breast cancer cases; retrospective study of HER2 FISH results of 836 invasive breast cancers.

For dual probe HER2 FISH assay, the 2013 CAP/ASCO guideline recommendations lowered the HER2/CEP17 ratio cut off for HER2 amplification to ≥2.0 and introduced an average HER2 copy number criterion for HER2 amplification (≥6.0/cell) and HER2 equivocal categories (≥4 and <6/cell). The HER2/CEP17 equivocal category is eliminated. The aim of this study is to assess the impact of 2013 HER2 FISH testing guideline recommendations update on the assignment of HER2 status with dual probe HER2 FISH assay. Dual probe HER2 FISH assay results on breast cancers from 09/2009 to 07/2015 that underwent reflex HER2 FISH testing after equivocal HER2 (2+) immunohistochemistry (IHC) were reviewed. HER2 copy number, CEP17 signals, and HER2/CEP ratios were noted. HER2 status was assigned as HER2 negative (HER2-), HER2 equivocal (HER2e), and HER2 amplified (HER2+) by applying both 2007 and 2013 CAP/ASCO HER2 FISH guideline recommendations and results were compared. New guidelines reclassified HER2 FISH status in a significant proportion of cases (8.3 %, 69/836; p = .021). There were 22 (2.6 %) more HER2+, 17 (2.1 %) more HER2e, and 39 (4.1 %) fewer HER2- tumors. Change of HER2 status correlated significantly with ≥3 CEP17 signals (38 vs. 2 %; p < .001). The 2013 CAP/ASCO guideline recommendations for HER2 FISH testing by dual probe assay increased the HER2 amplified and HER2 equivocal tumors. Increase in HER2 equivocal tumors would potentially increase the frequency of repeat HER2 testing. Tumors with ≥3 CEP17 signals, so-called chromosome 17 polysomy, are more likely to be impacted and classified as HER2 equivocal.

Long-term follow-up of vulvar cancer patients evaluated with sentinel lymph node biopsy alone.

OBJECTIVE: The objective of this study was to examine SLN evaluation alone in women with squamous cell carcinoma (SCC) of the vulva and evaluate the inguinal recurrence and complication rates. METHODS: An IRB approved prospective study enrolled patients with SCC of the vulva. Peritumoral injection of Tc-99 sulfur colloid and blue dye was used to identify SLNs intraoperatively. Patients with negative SLN for metastasis were followed clinically without further treatment. Patients with metastasis to a SLN underwent full groin node dissection followed by standard treatment protocols. RESULTS: A total of 73 women were enrolled onto protocol with 69 patients undergoing SLN dissection. Mean age was 66.9years (range: 29-91) with 47 stage I, 12 stage II, 9 stage III, 2 stage IV and 3 unstaged patients. SLN dissections were successful in 63 patients. Of the 111 groins evaluated with a SLN dissection 93% had a SLN identified with an average of 2 SLN per groin. There were 92 groins with negative SLN and 11 groins with positive SLN. 57 patients had negative SLN and underwent conservative management with the median follow-up of 58.3months. Three patients experienced groin recurrences (2 unilateral, 1 bilateral) for a recurrence rate of 5.2% (3/57). The complication rate for the inguinal incisions was 17.5% (1 cellulitis, 1 abscess, 2 lymphoceles, 5 lymphedema and leg pain). CONCLUSIONS: Isolated SLN dissection alone has a low inguinal recurrence rate with decreased complications and should be considered as an option for women with SCC of the vulva.

Endometrial carcinomas with significant mucinous differentiation associated with higher frequency of k-ras mutations: a morphologic and molecular correlation study.

OBJECTIVES: K-ras gene product in the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway is critical in the development of certain types of malignancies. K-ras mutation-associated pancreatic and ovarian carcinomas often display mucinous differentiation. Previous studies have shown that k-ras mutation is found in 10% to 30% of endometrial carcinomas. We investigated k-ras mutations in several morphologic subtypes of endometrial carcinomas with particular emphasis on various degrees of mucinous differentiation. METHODS: Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue sections. Polymerase chain reaction amplification for k-ras codons 12 and 13 were performed, followed by sequencing using capillary electrophoresis. The Fisher exact test is used to compare the prevalent difference of k-ras mutation among the groups. P < 0.05 was considered significant. RESULTS: K-ras mutations were detected in 8 (80%) of 10 mucinous carcinomas, 12 (67%) of 18 endometrioid carcinomas (ECs) with significant mucinous differentiation (ECMD), 4 (25%) of 16 ECs, and 1 (9%) of 11 serous carcinomas. The differences were statistically significant between mucinous carcinomas versus EC (P < 0.01) and ECMD versus EC (P < 0.05). CONCLUSION: The findings suggest that mucinous carcinoma and endometrioid carcinoma with significant mucinous component are more likely to be associated with k-ras mutation. Potential clinical implications of k-ras mutation lies in the management of recurrent or higher-stage endometrial mucinous tumors, which would not be responsive to treatment protocols containing epidermal growth factor receptor inhibitors.

Reclassification of serous ovarian carcinoma by a 2-tier system: a Gynecologic Oncology Group Study.

BACKGROUND: A study was undertaken to use the 2-tier system to reclassify the grade of serous ovarian tumors previously classified using the International Federation of Gynecology and Obstetrics (FIGO) 3-tier system and determine the progression-free survival (PFS) and overall survival (OS) of patients treated on Gynecologic Oncology Group (GOG) Protocol 158. METHODS: The authors retrospectively reviewed demographic, pathologic, and survival data of 290 patients with stage III serous ovarian carcinoma treated with surgery and chemotherapy on GOG Protocol 158, a cooperative multicenter group trial. A blinded pathology review was performed by a panel of 6 gynecologic pathologists to verify histology and regrade tumors using the 2-tier system. The association of tumor grade with PFS and OS was assessed. RESULTS: Of 241 cases, both systems demonstrated substantial agreement when combining FIGO grades 2 and 3 (overall agreement, 95%; kappa statistic, 0.68). By using the 2-tier system, patients with low-grade versus high-grade tumors had significantly longer PFS (45.0 vs 19.8 months, respectively; P = .01). By using FIGO criteria, median PFS for patients with grade 1, 2, and 3 tumors was 37.5, 19.8, and 20.1 months, respectively (P = .07). There was no difference in clinical outcome in patients with grade 2 or 3 tumors in multivariate analysis. Woman with high-grade versus low-grade tumors demonstrated significantly higher risk of death (hazard ratio, 2.43; 95% confidence interval, 1.17-5.04; P = .02). CONCLUSIONS: Women with high-grade versus low-grade serous carcinoma of the ovary are 2 distinct patient populations. Adoption of the 2-tier grading system provides a simple yet precise framework for predicting clinical outcomes.

Iniparib plus paclitaxel and carboplatin as initial treatment of advanced or recurrent uterine carcinosarcoma: a Gynecologic Oncology Group Study.

OBJECTIVE: To estimate the activity and tolerability of iniparib plus paclitaxel and carboplatin as initial therapy of uterine carcinosarcoma. METHODS: Eligible patients had advanced, persistent or recurrent carcinosarcoma of the uterus, measurable disease and no prior chemotherapy. Patients received paclitaxel 175 mg/m(2) IV over 3h followed by carboplatin area under the curve (AUC)=six over 30 min on day one of 21 day cycles plus iniparib 4 mg/kg IV over 1h twice weekly beginning on day one. Treatment continued until disease progression or adverse effects prohibited further therapy. Common Terminology Criteria for Adverse Events (CTCAE) v3.0 was used to grade adverse events. The primary endpoint was tumor response. The study was conducted with a 2-stage group sequential design, targeting 20 and 25 patients in each stage. The study was designed to distinguish between 45% versus 65% responding with alpha=10% and 90% power. RESULTS: Twenty-two patients were entered onto the study with five excluded from analysis, leaving 17 evaluable for analysis. Treatment resulted in the expected hematologic and non-hematologic toxicities of the paclitaxel-carboplatin backbone. The observed proportion responding was 23.5% (4/17 patients). The two-sided, 90% confidence interval for the true probability of response was 8.5-46.1%. The required minimal number of responses to proceed to second stage was eight. CONCLUSIONS: Iniparib plus paclitaxel and carboplatin did not show significant activity to warrant further study. The rate of exclusion upon central pathology review (23%) suggests that review of pathology slides for confirmation of eligibility is important in this tumor type.

Serum HE4 levels are less frequently elevated than CA125 in women with benign gynecologic disorders.

OBJECTIVE: The human epididymis protein 4 (HE4) is a novel biomarker for ovarian cancer. This study measured the HE4 and CA125 levels in women with benign gynecological disorders. STUDY DESIGN: Sera were obtained from women prior to surgery for a pelvic mass and HE4 and CA125 levels were determined. The proportions of patients with elevated biomarker levels were compared. RESULTS: There were 1042 women with benign disease. HE4 levels were less often elevated than CA125 (8% vs 29%, P < .001). A marked difference was observed in patients with endometriosis in which HE4 was elevated in 3% of patients and CA125 in 67% (P < .0001). Serous ovarian tumors were associated with elevated levels of HE4 in 8% of patients and CA125 in 20% (P = .0002); uterine fibroids in 8% vs 26% (P = .0083); dermoids in 1% vs 21% (P = .0004); and inflammatory disease in 10% vs 37% (P = .014). CONCLUSION: HE4 is elevated less frequently than CA125 in benign disease, particularly in premenopausal patients.

Tubal metaplasia of the endometrium with cytologic atypia: analysis of p53, Ki-67, TERT, and long-term follow-up.

Tubal metaplasia of the endometrium may occasionally display cytologic atypia (atypical tubal metaplasia) resembling serous carcinoma or endometrial intraepithelial carcinoma. Although atypical tubal metaplasia is presumed to be reactive or degenerative in etiology, its clinical significance is unknown. In this study, we investigated atypical tubal metaplasia in regard to its immunoexpression of p53, Ki-67, and human telomerase reverse transcriptase (TERT), and its long-term clinical outcome. A total of 63 cases of atypical tubal metaplasia and 200 cases of endometrial samples with typical tubal metaplasia were followed for a mean of 64 and 61 months, respectively. Of the 63 atypical tubal metaplasia cases, formalin-fixed, paraffin-embedded tissue sections from 16 cases were immunostained with antibodies to p53, Ki-67, and TERT. Sections from 13 cases of uterine serous carcinoma were also stained for TERT as control. After long-term follow-up, 5% of patients in the atypical tubal metaplasia group developed hyperplasia without atypia compared with 4% of patients in the control group (P=0.44), whereas 3% in the atypical tubal metaplasia group developed atypical hyperplasia or carcinoma compared with 2% in the control group (P=0.44). p53 immunoreactivity was either focal and weak or negative in all cases of both atypical and typical tubal metaplasia (P>0.05). Ki-67 immunoreactivity was present in 0-5% of cells in 94% of both atypical and typical tubal metaplasia (P>0.05). TERT immunoexpression was absent in all 16 cases of atypical tubal metaplasia, but present in all 13 cases of uterine serous carcinoma (P<0.0001). Our study indicates that atypical tubal metaplasia displays an immunostaining pattern similar to otherwise typical tubal metaplasia of the endometrium, and distinct from uterine serous neoplasms. The presence of atypical tubal metaplasia in endometrial samplings does not increase the risk of developing endometrial hyperplasia or malignancy.

Utility of tumor marker HE4 to predict depth of myometrial invasion in endometrioid adenocarcinoma of the uterus.

OBJECTIVE: The purpose of this pilot study was to determine whether the biomarker human epididymis protein 4 (HE4) correlates with depth of myometrial invasion, histologic grade, lymph vascular space invasion, positive cytologic washings, and nodal metastases in patients with endometrioid adenocarcinoma of the uterus. METHODS: This was a prospective, observational study in women with biopsy-proven endometrioid adenocarcinoma. Concentrations of HE4 were assessed before surgery, and all surgical specimens were reviewed by dedicated gynecologic pathologists. RESULTS: Included were a total of 96 women with endometrioid adenocarcinomas of the uterus, most (77%) with stage I disease. Levels of serum HE4 greater than 70 pM displayed a sensitivity of 94% and a negative predictive value of 97% in identifying stage IA (<50% myometrial invasion) versus stage IB (≥ 50% myometrial invasion) tumors and a sensitivity of 82% and negative predictive value of 82% versus all more advanced tumors. CONCLUSIONS: Human epididymis protein 4 may be a useful marker preoperatively in the clinical decision process for determining the need for lymph node dissection in women with endometrioid endometrial cancer.

In vitro maturation of oocytes via the pre-fabricated self-assembled artificial human ovary.

PURPOSE: create a 3-Dimensional artificial human ovary to mature human oocytes. METHODS: theca and granulosa cells were isolated from antral follicles of reproductive-aged women, seeded into micro-molded gels and self-assembled into complex 3D microtissues. Immunohistochemistry and live-dead staining confirmed theca cell identity and cellular viability at one week respectively. Placement of granulosa cell spheroids or cumulus-oocyte complexes into theca cell honeycomb openings resulted in creation of an artificial human ovary. Oocytes from this construct were assessed for polar body extrusion. RESULTS: theca and granulosa cells self-assembled into complex microtissues, remaining viable for one week. At 72 h after artificial human ovary construction, theca cells completely surrounded the granulosa spheroids or COCs without stromal invasion or disruption. Polar body extrusion occurred in one of three COCs assessed. CONCLUSIONS: an artifical human ovary can be created with self-assembled human theca and granulosa cell microtissues, and used for IVM and future oocyte toxicology studies.

Utility of PTEN expression of endometrial "surface epithelial changes" and underlying atypical endometrial hyperplasia.

Surface epithelial changes (SECs) have been reported to be associated with endometrial carcinoma in about 49% of cases. They have also been seen to be associated with endometrial hyperplasia. Although morphologically benign, these lesions are considered a marker for underlying malignancy. Their true biologic nature, however, is not known. PTEN has been reported to be altered in endometrial carcinomas and endometrial precancers where no morphologic changes are appreciated. The current study aims to investigate PTEN status in the endometrial SECs. Thirty-two cases of endometrial biopsy are divided into 2 groups: group 1 had 18 cases of SEC and underlying endometrial atypical hyperplasia and group 2 had 14 cases of SEC alone. Four-micron sections were cut from each block and stained with antibodies to PTEN. One section was stained with hematoxylin and eosin to confirm the presence of the area of interest. Positive and negative control slides were run with each batch of staining. All 32 cases were followed for a median period of 54 (range, 21 to 84) months. Overall, PTEN alteration (NULL) was found in 12 of the 32 cases of endometrial samples (37.5%) examined. In group 1, 10 of the 18 cases (56%) of atypical endometrial hyperplasia with "SECs" showed PTEN NULL. Of these 10 cases, 6 (60%) cases showed FIGO grade 1 endometrioid carcinoma in subsequent hysterectomy specimens. Two other cases (20%) had atypical endometrial hyperplasia only. In group 2, two of the 14 (14%) cases of SECs alone showed PTEN NULL phenotype. These 2 patients were followed for 26 and 63 months, respectively, and subsequent endometrial biopsies and pap smears were negative. Of the remaining 12 cases that retained PTEN, 9 cases (75%) were negative when followed for a median of 54 months (range, 21 to 84 mo). SECs seem to be a heterogeneous entity. Presence of PTEN NULL phenotype in SECs and associated endometrial hyperplasia does not necessarily predict an increased incidence of endometrioid carcinoma in subsequent follow-up. However, absence of PTEN NULL phenotype in SECs alone may predict a benign follow-up.

A case of Peutz-Jeghers syndrome with breast cancer, bilateral sex cord tumor with annular tubules, and adenoma malignum caused by STK11 gene mutation.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder, and women with this syndrome are at an increased risk of developing intestinal and extraintestinal malignancies including breast and gynecologic malignancies. This case report presents a patient with PJS with a concomitant breast cancer, bilateral stromal tumors with annular tubules of the ovaries, and adenoma malignum of the cervix. CASE: A 43-year-old woman presented with an advanced-stage breast cancer and a pelvic mass. The patient was treated with neoadjuvant chemotherapy followed by laparotomy with a hysterectomy and oophorectomy. Final pathologic examination revealed a concomitant breast cancer with metastasis to the ovaries, bilateral stromal tumors with annular tubules of the ovaries, and adenoma malignum of the cervix. CONCLUSIONS: Patients with PJS are at a high risk for intestinal and extraintestinal malignancies and can present with multiple concomitant malignancies.

Does the ThinPrep Imaging System increase the detection of high-risk HPV-positive ASC-US and AGUS? The Women and Infants Hospital experience with over 200,000 cervical cytology cases.

BACKGROUND: Published reports have demonstrated that introduction of the ThinPrep Imaging System (Imager) to the cytology screening services has increased the detection rate of high-grade squamous intraepithelial lesions (HSILs). In accordance with recent clinical treatment guidelines, patients with atypical squamous or glandular cells of undetermined significance (ASC-US or AGUS) are often tested for high-risk HPV infection using the Hybrid Capture HPV DNA test. We took the opportunity to investigate whether the Imager had resulted in any significant differences in our diagnostic categories, as well as whether the Imager increased the detection of high-risk HPV-DNA-positive (HRHPV+) ASC-US or AGUS. MATERIALS AND METHODS: Cytology cases with the diagnosis of ASC-US and AGUS were retrieved from the archival files of our institution during periods of 11 months prior to and 11 months after the introduction of the Imager. The total number of cases in each category was correlated with results of reflex high-risk HPV DNA testing when the latter were available. All AGUS diagnoses were correlated with subsequent biopsy follow-up. Statistical analyses were performed using the chi-Square test with Yate's Correction and Fisher's Exact test. RESULTS: A total of 108,371 and 104,555 of ThinPrep Pap Test (TPPT) cases were reviewed during 11 months pre- and post-imager introduction. The ASC-US rate was 5.4% in the pre-Imager and 5.3% in the post-Imager period. The HPV reflex test was 38% and 34% positive respectively in the pre- and post-Imager period (P>0.124). Similarly, 0.14% and 0.12% AGUS were found in the pre- and post-Imager period. The positive HPV reflex test was 14% versus 23% (P = 0.1690). The abnormal biopsy follow-up rate in the AGUS category was increased from 20.9% in the pre-Imager period to 31% in the post-Imager period (P = 0.1471). The ASCUS/SIL ratios were 1.9 and 1.6 respectively. CONCLUSIONS: The ASC-US and AGUS rates did not change statistically before and after the introduction of the Imager in our cytology laboratory. Although use of the Imager did not increase detection of HPV+ ASC-US, it did appear to increase the detection rate of HPV+ AGUS and subsequent abnormal biopsy follow-up rates in all categories. However, the increase in the detection rate did not reach the point of statistical significance.

Axillary lymph nodes: US-guided fine-needle aspiration for initial staging of breast cancer--correlation with primary tumor size.

PURPOSE: To retrospectively assess the sensitivity and specificity of ultrasonographic (US)-guided fine-needle aspiration (FNA) of axillary lymph nodes for preoperative staging of breast cancer across a range of primary tumor sizes, by using histologic findings as a reference standard. MATERIALS AND METHODS: Institutional review board approval was obtained for this HIPAA-compliant study; informed consent was waived. US-guided FNA results in 74 patients with breast cancer (75 axillae) were compared with final pathologic results. Lymph nodes were classified as benign, indeterminate, or suspicious on the basis of US characteristics at retrospective review. US-guided FNA in the most suspicious node at US, or the largest node if all appeared benign, was performed. Final pathologic results (sentinel lymph node biopsy [SNB] or axillary lymph node dissection [ALND]) were compared with US and preoperative US-guided FNA results. Results were assessed according to tumor size. Sensitivity, specificity, and positive predictive value of US and US-guided FNA were calculated. RESULTS: Primary tumor sizes were 0.3-12 cm (mean, 3 cm). Patient age range was 31-81 years (mean age, 51 years). Sensitivity of US-guided FNA for predicting positive results at ALND or SNB was 71%-75%. Specificity was 100%. Sensitivity of US-guided FNA increased with primary tumor size. CONCLUSION: US-guided FNA of axillary lymph nodes in patients with newly diagnosed breast cancer had a sensitivity that increased with increasing size of the primary tumor.

Isolated sentinel lymph node dissection with conservative management in patients with squamous cell carcinoma of the vulva: a prospective trial.

OBJECTIVES: Sentinel lymph node (SLN) dissections have a high sensitivity and negative predictive value for the detection of metastatic disease. The objective of this study was to examine the inguinal recurrence rate along with complication rates for patients undergoing inguinal SLN dissection alone for vulvar carcinoma. METHODS: An IRB approved prospective study enrolled patients with biopsy proven squamous cell carcinoma of the vulva. Peritumoral injection of Tc-99 sulfur colloid and methylene blue dye was used to identify SLNs intraoperatively. Patients with SLNs negative for metastatic disease were followed clinically. Patients with metastasis detected in a SLN subsequently underwent a full groin node dissection followed by standard treatment protocols. RESULTS: Thirty-six patients were enrolled onto study with 35 undergoing a SLN dissection. All SNL dissections were successful with a mean of 2 SLN obtained per groin. There were 24 patients with stage I disease, 8 stage II, 3 stage III and 1 stage IV. A total of 56 SLN dissections were performed with 4 patients found to have inguinal metastasis by SLN dissection. There were 31 patients with a total of 46 SLN dissections found to be negative for metastatic disease. The median follow-up has been 29 months (range 8 to 51) with 2 groin recurrences for a groin recurrence rate of 4.3% and a recurrence rate per patient of 6.4%. There have been no reports of groin breakdown, extremity cellulitis or lymphedema. CONCLUSIONS: The recurrence rate for patients undergoing inguinal sentinel node dissection alone is low. These patients did not experience any complications as seen with complete groin node dissections. Sentinel lymph node dissection should be considered as an option for evaluation of inguinal nodes for metastatic disease.

The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass.

OBJECTIVES: The CA125 tumor marker is used to help predict the presence of ovarian cancer in patients with an adnexal mass. Because elevated CA125 levels occur in many benign gynecologic conditions, we set out to identify other novel biomarkers that would increase the sensitivity and specificity of CA125. METHODS: Serum and urine samples were obtained preoperatively from women undergoing surgery for an adnexal mass. The samples were analyzed for levels of CA125, SMRP, HE4, CA72-4, activin, inhibin, osteopontin, epidermal growth factor (EGFR), and ERBB2 (Her2) and were compared to final pathology results. Logistic regression models were estimated for all markers and combinations, with cross-validation analysis performed to obtain the sensitivities at set specificities of 90%, 95%, and 98%. RESULTS: Two hundred and fifty-nine patients with adnexal masses were enrolled. Of these, 233 patients were eligible for analysis with 67 invasive epithelial ovarian cancers and 166 benign ovarian neoplasms. Mean values for all marker levels except Her2 differed significantly between patients with benign masses and cancer. As a single marker, HE4 had the highest sensitivity at 72.9% (specificity 95%). Comparatively, combined CA125 and HE4 yielded the highest sensitivity at 76.4% (specificity 95%), with additional markers adding minimally to the sensitivity of this combination. HE4 was the best single marker for Stage I disease, with no increase in sensitivity when combined with CA125 or any other marker. CONCLUSIONS: As a single tumor marker, HE4 had the highest sensitivity for detecting ovarian cancer, especially Stage I disease. Combined CA125 and HE4 is a more accurate predictor of malignancy than either alone.

Evaluating agreement, histological features, and relevance of separating pleomorphic and florid lobular carcinoma in situ subtypes.

Morphological variants of lobular carcinoma in situ (LCIS) include classical (CLCIS), pleomorphic (PLCIS) and florid type (FLCIS). Treatment guidelines suggest managing PLCIS and FLCIS like ductal carcinoma in situ (DCIS); therefore accurate identification of LCIS subtypes is critical. However, the significance of separating PLCIS from FLCIS is not clear. Also, interobserver agreement in identifying LCIS subtypes, using contemporary criteria, is not known. We aimed to evaluate interobserver agreement amongst breast pathologists in diagnosing LCIS subtypes and use the agreement data to justify LCIS classification for management purposes. Six breast pathologists independently reviewed 50 hematoxylin and eosin-stained slides comprised of a mix of LCIS subtypes. After reviewing published criteria, participants diagnosed PLCIS, CLCIS and apocrine change in a marked region of interest and FLCIS based on entire section. PLCIS was identified in 8 to 37 slides with overall moderate agreement (Fleiss' κ = 0.565) and pairwise κ (Cohen's) ranging from -.008 to 0.492. FLCIS was diagnosed in 15-26 slides with overall substantial agreement (Fleiss' κ = 0.687) and pairwise κ ranging from -.068 to 0.706. Both FLCIS and PLCIS coexisted in 45% of slides with consensus on non-classical LCIS. Comedo-type necrosis (odds ratio = 5.5) and apoptosis (odds ratio = 1.8) predicted FLCIS. We found moderate and substantial agreement in diagnosing PLCIS and FLCIS respectively. Objective histological features linked with aggressive behavior were more frequent with FLCIS. PLCIS and FLCIS patterns frequently coexist, contain similar molecular aberrations, and are managed similarly (like DCIS); therefore, combining FLCIS and PLCIS into one category (non-classical LCIS) should be considered.

Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma.

PURPOSE: To determine the overall survival for patients with locally advanced, HER2 overexpressing, esophageal adenocarcinoma receiving trastuzumab, paclitaxel, cisplatin, and radiation on a Phase I-II study. METHODS AND MATERIALS: Patients with adenocarcinoma of the esophagus without distant organ metastases and 2+/3+ HER2 overexpression by immunohistochemistry (IHC) were eligible. All patients received cisplatin 25 mg/m2 and paclitaxel 50 mg/m2 weekly for 6 weeks with radiation therapy (RT) 50.4 Gy. Patients received trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg. RESULTS: Nineteen patients were entered: 7 (37%) had celiac adenopathy, and 7 (37%) had retroperitoneal, portal adenopathy, or scalene adenopathy. Fourteen of 19 patients (74%) had either 3+ HER2 expression by immunohistochemistry, or an increase in HER2 gene copy number by HER2 gene amplification or high polysomy by fluorescence in situ hybridization. The median survival of all patients was 24 months and the 2-year survival was 50%. CONCLUSIONS: Assessment of the effect of trastuzumab in the treatment of patients with esophageal adenocarcinoma overexpressing HER2 is limited by the small number of patients in this study. Overall survival, however, was similar to prior studies without an increase in toxicity. Evaluation of HER2 status should be performed in future trials for patients with adenocarcinoma of the esophagus that investigate therapies targeting the HER family.

Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression.

PURPOSE: The seven transmembrane receptor, GPR30, is linked to estrogen binding and heparan-bound epidermal growth factor release. Here, the significance of GPR30 in human breast cancer was evaluated by comparing its relationship to steroid hormone receptor expression and tumor progression variables. EXPERIMENTAL DESIGN: Immunohistochemical analysis of a National Cancer Institute-sponsored tumor collection comprised of 361 breast carcinomas obtained at first diagnosis (321 invasive and 40 intraductal tumors). Biopsies from 12 reduction mammoplasties served as controls. The distribution pattern of GPR30, estrogen receptor (ER), and progesterone receptor (PR) was correlated with clinicopathologic variables obtained at diagnosis. RESULTS: GPR30, ER, and PR were positive in all 12 normal controls. In contrast, GPR30 expression varied in breast tumors, in which 62% (199 of 321) of invasive tumors and 42% (17 of 40) of intraductal tumors were positive. Codistribution of ER and GPR30 was measured in 43% (139 of 321) of invasive breast tumors, whereas both receptors were lacking (ER-GPR30-) in 19% (61 of 321) of the tumors analyzed, indicating a significant association between ER and GPR30 (P<0.05). The coexpression of PR and ER did not influence GPR30 expression, yet coexpression of GPR30 and ER was linked to PR positivity. Unlike ER, which varied inversely with HER-2/neu and tumor size, GPR30 positively associated with HER-2/neu and tumor size. In addition, GPR30 showed a positive association with metastasis (P=0.014; odds ratio, 1.9). CONCLUSIONS: GPR30 and ER exhibited distinct patterns of association with breast tumor progression variables, including HER-2/neu, tumor size, and metastatic disease. Thus, these results support the hypothesis that GPR30 and ER have an independent influence on estrogen responsiveness in breast carcinoma.

Fibroadenoma With Pleomorphic Stromal Giant Cells: It's Not as Bad as It Looks!

Clinically relevant histological categorization of fibroepithelial lesions can be a daunting task, especially in a core needle biopsy. Assessment of stromal nuclear atypia, including nuclear pleomorphism and mitotic activity, is a key morphological feature employed to classify fibroepithelial lesions. We describe a case of fibroadenoma with markedly atypical nuclear features in the stromal cells that led to misclassification as phyllodes tumor in the core needle biopsy. Excision showed a fibroadenoma containing pleomorphic stromal giant cells, with occasional mitotic figures, including atypical forms. Aforementioned nuclear findings in a fibroepithelial lesion raise a legitimate question of phyllodes tumor. Knowledge of this pitfall may help avoid overtreatment of an otherwise benign fibroepithelial lesion.