Robert A. Soslow

COX‐2 is expressed in human pulmonary, colonic, and mammary tumors

The cyclooxygenase (COX) enzyme catalyzes the formation of prostaglandins, which can affect cell proliferation and alter the response of the immune system to malignant cells. The inducible form of COX, COX‐2, has been shown to be important in carcinogenesis.

Classification of endometrial carcinoma: more than two types

Endometrial cancer is the most common gynaecological malignancy in Europe and North America. Traditional classification of endometrial carcinoma is based either on clinical and endocrine features (eg, types I and II) or on histopathological characteristics (eg, endometrioid, serous, or clear-cell adenocarcinoma). Subtypes defined by the different classification systems correlate to some extent, but there is substantial heterogeneity in biological, pathological, and molecular features within tumour types from both classification systems. In this Review we provide an overview of traditional and newer genomic classifications of endometrial cancer. We discuss how a classification system that incorporates genomic and histopathological features to define biologically and clinically relevant subsets of the disease would be useful. Such integrated classification might facilitate development of treatments tailored to specific disease subgroups and could potentially enable delivery of precision medicine to patients with endometrial cancer.

Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma.

Patients with high-grade subtypes of endometrial carcinoma (grade 3 endometrioid, serous, clear cell, or carcinosarcoma) have a relatively poor prognosis. The specific subtype may be used to guide patient management, but there is little information on the reproducibility of subtype diagnosis in cases of high-grade endometrial carcinoma. Fifty-six cases diagnosed as a high-grade subtype of endometrial carcinoma were identified from the pathology archives of Vancouver General Hospital. All slides for each case were reviewed independently by 3 pathologists, who diagnosed the specific tumor subtype(s) and assigned the percentage of each subtype for mixed tumors. Agreement between observers was categorized as follows: major disagreement: (A) no consensus for low-grade endometrioid versus high-grade carcinoma (any subtype), or (B) no consensus with respect to the predominant high-grade subtype present; minor disagreement: consensus was reached about the cell type of the predominant component of a mixed tumor, but there was disagreement about the subtype of the minor component. A tissue microarray was constructed from these cases and immunostained for p16, ER, PR, PTEN, and p53. In 35 of 56 (62.5%) cases, there was agreement between all 3 reviewers regarding the subtype diagnosis of the exclusive (in pure tumors) or predominant (in mixed tumors) high-grade component. Of these cases, there was a minor disagreement (ie, disagreement about the minor high-grade component subtype in a mixed tumor) in 4 cases (4/56, 7.1%). In 20 of 56 (35.8%) cases there was a major disagreement; in 17 (30.4%) of these cases there was no consensus about the major subtype diagnosis, whereas in 3 (5.4%) cases there was disagreement about whether a component of high-grade endometrial carcinoma was present. In the final case, all 3 reviewers diagnosed the case as low-grade endometrioid carcinoma, disagreeing with the original diagnosis of high-grade carcinoma. The most frequent areas of disagreement were serous versus clear cell (7 cases) and serous versus grade 3 endometrioid (6 cases). Immunostaining results using the 5-marker immunopanel were then used to adjudicate in the 6 cases in which there was disagreement between reviewers with respect to serous versus endometrioid carcinoma, and these supported a diagnosis of serous carcinoma in 4 of 6 cases and endometrioid carcinoma in 2 of 6 cases. Pairwise comparison between the reviewers for the 20 cases classified as showing major disagreement was as follows: reviewer 1 and reviewer 2 agreed in 5/20 cases, reviewer 1 and reviewer 3 agreed in 7/20 cases, and reviewer 2 and reviewer 3 agreed in 8/20 cases, indicating that disagreements were not because of a single reviewer holding outlier opinions. Diagnostic consensus among 3 reviewers about the exclusive or major subtype of high-grade endometrial carcinoma was reached in only 35/56 (62.5%) cases, and in 4 of these cases there was disagreement about the minor component present. This poor reproducibility did not reflect systematic bias on the part of any 1 reviewer. There is a need for molecular tools to aid in the accurate and reproducible diagnosis of high-grade endometrial carcinoma subtype.

β-Catenin and E-Cadherin Expression Patterns in High-Grade Endometrial Carcinoma Are Associated with Histological Subtype

Both β-catenin and E-cadherin are epithelial cell adhesion molecules. In addition, β-catenin is an important element of the Wnt signal transduction pathway, which has been implicated in embryogenesis and carcinogenesis, including the development of endometrial and ovarian endometrioid carcinomas. We hypothesized that the expression pattern of these two adhesion molecules may depend upon the histological subtype of endometrial carcinomas. Therefore, we compared the immunohistochemical expression of β-catenin and E-cadherin in a set of uterine adenocarcinomas matched for high histologic grade, that is, poorly differentiated (International Federation of Gynecology and Obstetrics [FIGO] Grade III) uterine endometrioid carcinomas and uterine serous carcinomas. Seventeen FIGO Grade III endometrioid adenocarcinomas and 17 serous carcinomas were evaluated histologically and immunohistochemically with commercially available monoclonal antibodies against β-catenin and E-cadherin. Nuclear expression of β-catenin was observed in 8 of 17 (47%) endometrioid adenocarcinomas but in none of the serous carcinomas (P = .003). Moderate or strong E-cadherin expression was identified in 7 of 17 (41%) serous carcinomas as opposed to in only 1 of 17 (6%) endometrioid adenocarcinomas (P = .02). The majority of endometrioid adenocarcinomas showed strong β-catenin expression coupled with weak E-cadherin expression; serous carcinomas did not exhibit a comparable trend. Our results indicate that the expression of β-catenin and E-cadherin in high-grade endometrial cancers is strongly associated with histological subtype. These data provide further support for the distinct molecular profiles of endometrioid adenocarcinoma and serous carcinoma. Notably, differences in cell adhesion molecule expression could account for variations in patterns of tumor dissemination. The immunohistochemical staining pattern may also be useful for diagnostic purposes.

Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma

Women with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome have a high risk for endometrial cancer (EC) and frequently present with a gynaecological cancer as their first or sentinel malignancy. Identification of these patients is important given their personal and family risk for synchronous and metachronous tumours. Modalities to detect ECs for the possibility of HNPCC include microsatellite instability assay, immunohistochemistry for DNA mismatch repair proteins, MLH1 promoter hypermethylation assay and mutational analysis of DNA mismatch repair genes. The revised Bethesda guidelines provide screening criteria for HNPCC in colorectal cancers (CRCs). However, there are currently no such screening recommendations for women with endometrial carcinoma. While age and family history are useful screening criteria, their sensitivity has been shown to be low for detection of HNPCC in EC. Expansion of these criteria to include tumour morphology (presence of tumour infiltrating lymphocytes and tumour heterogeneity including dedifferentiated/undifferentiated ECs) and topography (lower uterine segment localisation) as well as presence of synchronous ovarian clear cell carcinomas may significantly enhance the detection of patients with EC at risk for HNPCC. Consideration should be given to incorporating these screening criteria into a revision of the Bethesda guidelines for detecting EC patients at highest risk for HNPCC.

A comparative analysis of 57 serous borderline tumors with and without a noninvasive micropapillary component.

The literature concerning serous borderline tumors with a noninvasive micropapillary component suggests an association with invasive implants. We compared the clinicopathologic features of micropapillary serous borderline tumors (MSBTs) with typical SBTs to determine the following: 1) the importance of focal micropapillary architecture in an otherwise typical SBT, 2) the behavior of low-stage MSBTs, 3) whether high-stage MSBTs are inherently more aggressive than high-stage SBTs, and 4) whether invasive implants are prevalent in an MSBT cohort without referral selection bias. The 57 borderline tumors studied were diagnosed at a university hospital between 1981 and 1998; they included 14 MSBTs, 35 SBTs, and 8 SBTs with focal micropapillary features. None of the specimens were referrals for expert pathologic consultation, thus distinguishing our study group from most of those previously reported. Neither MSBTs nor SBTs were associated with invasive implants at diagnosis (0 of 14 and 0 of 43, respectively). They also did not differ with respect to overall stage at diagnosis, but MSBTs were more frequently bilateral than SBTs (71% versus 23%, p = 0.001). There was an increased risk of recurrence in MSBT versus SBT (3 of 14 versus 1 of 43, p = 0.035), but this was stage related; there was no difference between groups when evaluating recurrence in stage I disease (0 of 8 versus 0 of 27). There was no difference in recurrence or stage at diagnosis between SBTs with focal micropapillary features and other SBTs. There was 100% survival in all groups. We conclude that high-stage MSBTs with noninvasive implants should be considered a subtype of SBTs with an increased risk of recurrence. Stage I MSBTs demonstrate clinical features that are similar to low-stage SBTs. Focal micropapillary architecture (<5 mm) has no bearing on outcome. MSBTs in the general population are not strongly associated with invasive implants.

MECHANISM OF HEALING FOLLOWING THE SNODGRASS REPAIR

PURPOSE It has been suggested that healing after tubularized incised plate urethroplasty occurs through re-epithelialization with normal tissue ingrowth or by secondary intent through scarring. We investigated healing in tubularized incised plate urethroplasty. MATERIALS AND METHODS Hypospadias was created in 5 dogs by incising the ventral urethra, allowed to heal for 21 days and subsequently repaired. During hypospadias creation a tattoo was made longitudinally in the midline dorsal urethral plate. The tattoo was bisected during repair, thus creating 2 distinct lines marking the edges of the incision. A neourethra was tubularized and closed in 2 layers. At 21 days the phallus was harvested, inspected and embedded for histology. RESULTS The dorsal urethral plate incision contained 2 distinct lines in all samples representing the area of separation between the native and ingrowing urethras. The distance between these lines was 0.9 +/- 0.1 mm. Proximal urethral lumen diameter (3. 3 +/- 0.1 mm.) was not significantly different from that of the neourethral lumen (3.1 +/- 0.1 mm.). Histologically all repairs had intact squamous epithelium. There was normal appearing subepithelial architecture with scant perivascular lymphocytic infiltrates between the tattoos. In contrast, the area around the sutures showed a desmoplastic (fibroblastic) reaction with an inflammatory, primarily neutrophilic response. CONCLUSIONS Healing of the incision in the dorsal urethral plate during tubularized incised plate urethroplasty occurs by re-epithelialization with normal tissue ingrowth. In contrast, the sutured closure heals with a desmoplastic and inflammatory response.

Histotype-genotype correlation in 36 high-grade endometrial carcinomas.

Endometrioid, serous, and clear cell carcinomas are the major types of endometrial carcinoma. Histologic distinction between these different tumor types can be difficult in high-grade cases, in which significant interobserver diagnostic disagreement exists. Endometrioid and clear cell carcinomas frequently harbor ARID1A and/or PTEN mutations. Serous carcinoma acquires TP53 mutations/inactivation at onset, with a significant subset harboring an additional mutation in PPP2R1A. This study examines the correlation between tumor histotype and genotype in 36 previously genotyped high-grade endometrial carcinomas. This included 23 endometrioid/clear cell genotype and 13 serous genotype tumors. Eight subspecialty pathologists reviewed representative online slides and rendered diagnoses before and after receiving p53, p16, and estrogen receptor immunostaining results. &kgr; statistics for histotype-genotype concordance were calculated. The average &kgr; values for histotype-genotype concordance was 0.55 (range, 0.30 to 0.67) on the basis of morphologic evaluation alone and it improved to 0.68 (range, 0.54 to 0.81) after immunophenotype consideration (P<0.001). Genotype-incompatible diagnoses were rendered by at least 2 pathologists in 12 of 36 cases (33%) (3 cases by 2/8 pathologists, 2 by 3/8, 2 by 4/8, 3 by 6/8, 1 by 7/8, and 1 case by 8/8 pathologists). Six of the 12 were endometrioid/clear cell genotype tumors, and the other 6 were serous genotype tumors. The histopathologic features associated with histotype-genotype–discordant cases were reviewed, and specific diagnostic recommendations were made to improve concordance. This study found that although the majority of morphologic diagnoses are genotype concordant, genotype-incompatible diagnoses are made in a significant subset of cases. Judicious use and interpretation of p53 immunohistochemistry in selected scenarios can improve histotype-genotype concordance.

Impact of incorporating an algorithm that utilizes sentinel lymph node mapping during minimally invasive procedures on the detection of stage IIIC endometrial cancer

OBJECTIVE To determine whether the frequency of cases diagnosed with stage IIIC endometrial cancer is affected by the incorporation of a modified surgical lymph node assessment. METHODS Since 2008, we have increasingly utilized a modified nodal assessment using an algorithm that incorporates SLN mapping. For this analysis, we identified all cases of newly diagnosed endometrial cancers undergoing a minimally invasive staging procedure not requiring conversion to laparotomy from 1/1/08 to 12/31/10. Procedures were categorized as standard, modified, and hysterectomy only. Differences were based on time period: 2008 (Y1), 2009 (Y2), and 2010 (Y3). Appropriate statistical tests were used. RESULTS We identified a total of 507 cases. The distribution of cases was 143 (Y1), 190 (Y2), and 174 (Y3). Tumor grade (P=0.05) and high-risk histologies (P=0.8) did not differ during the 3 time periods. A standard staging procedure was performed in the following cases: Y1 (93/143; 65%), Y2 (66/166; 35%), and Y3 (40/164; 23%) (P<0.001). Median operative times were as follows: Y1 (218 min), Y2 (198 min), and Y3 (176.5 min) (P<0.001). The median numbers of total lymph nodes removed among cases with at least 1 node retrieved were: Y1 (20); Y2 (10); Y3 (7) (P<0.001). Cases diagnosed as stage IIIC were as follows: Y1 (10/143; 7%), Y2 (15/166; 7.9%), and Y3 (13/164; 7.5%) (P=1.0). CONCLUSIONS The incorporation of a modified staging approach utilizing the SLN mapping algorithm reduces the need for standard lymphadenectomy and does not appear to adversely affect the rate of stage IIIC detection.

High grade undifferentiated uterine sarcoma: Surgery, treatment, and survival outcomes

OBJECTIVES High grade undifferentiated uterine sarcomas (HGUS) are rare, aggressive malignancies. Data regarding management are limited. We aimed to describe disease stage, response to treatment, and survival outcomes among patients with HGUS at our institution. METHODS We identified all patients with HGUS who received treatment at our institution from 1/2000 to 3/2011. Demographics, surgical procedures, disease stage, treatment response, and survival outcomes were abstracted from the medical records. RESULTS Twenty-one patients were identified. FIGO 2008 stage distribution was: I-7 (33%), II-1 (5%), III-2 (10%), IV-11 (52%). Eighteen of 21 patients (86%) undergoing primary surgical resection achieved a complete gross resection; however, progression within the abdominal cavity was identified in 11 patients (61%) by the time they underwent postoperative imaging. Of 13 patients who received first-line chemotherapy for measurable disease, the overall response rate was 62%. Responses were observed in patients treated with gemcitabine/docetaxel (6 of 8) and doxorubicin-based regimens (2 of 5). Progression-free and overall survivals for the entire cohort were 7.3 months and 11.8 months, respectively. In 14 patients with measurable disease at the time of treatment, 1-year survival was 35.7% versus 80% in 5 patients without measurable disease at time of treatment (P=0.112). Nine patients received second- or additional chemotherapy for progressive disease, with response rate of 19%. Time to progression was short among responders. CONCLUSIONS HGUS represents a distinct histologic subtype of uterine sarcoma with poor outcomes regardless of stage at diagnosis. A majority rapidly develops distant metastases despite surgical resection. Gemcitabine-docetaxel and doxorubicin-based treatment achieved objective, but short-lived, responses in patients with measurable disease.