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Placental site trophoblastic tumor (PSTT) is a rare form of gestational trophoblastic neoplasia (GTN). It most commonly occurs after a delivery but may arise after any type of pregnancy. PSTT arises after neoplastic transformation of intermediate trophoblastic cells. The most commonly reported symptoms are abnormal bleeding or amenorrhea. Due to the rarity of this disease, evidence on prognostic factors as well as optimal treatment is limited. While treatment for early-stage disease is usually limited to surgery, multimodal treatment with chemotherapy and surgery may be important for metastatic disease. Metastatic disease may be associated with minimal elevations of human chorionic gonadotropin (hCG). Here we present an unusual case of a patient with PSTT and an isolated breast metastasis who was successfully treated with surgical resection and single-agent chemotherapy., Highlights • PSTT is a rare form of GTN involving intermediate trophoblast cells. • Metastatic disease to the breast is rare. • Surgery with single agent chemotherapy is proposed for resectable metastatic PSTT.

Patients diagnosed with an endometrial cancer precursor lesion on biopsy may be found to have endometrial cancer at the time of subsequent surgery. The current study seeks to identify patients with endometrial intraepithelial neoplasia (EIN) on biopsy that may be harboring an occult carcinoma. Immunohistochemical stains for gene loss of expression (LOE) for 6 genes, PTEN, ARID1A, MSH6, MSH2, MLH1, and PMS2, were performed on 113 biopsy specimens with EIN. For the 95 patients with follow-up histology, 40 patients had cancer, 41 had EIN, and 14 had normal endometrium. PTEN LOE was found frequently in both EIN and endometrial cancer, and therefore had low positive predictive value. All specimens with ARID1A, MSH6, MSH2, MLH1, or PMS2 LOE on biopsy were subsequently found to have cancer. LOE of any gene was associated with modest sensitivity (0.78) in identifying patients with endometrial cancer who had EIN on biopsy. Further investigation is warranted to determine if gene LOE is a useful clinical tool when evaluating patients with EIN on biopsy., Highlights • PTEN, ARID1A, MSH6, MSH2, MLH1, and PMS2 were analyzed on patients with EIN. • Loss of expression was associated with the subsequent finding of endometrial cancer. • Sensitivity was 0.78 for loss of expression of any gene and the finding of cancer.

Objectives To determine characteristic features of myocardial infarction (MI) diagnosed at autopsy and establish the incidence of discrepancy. Methods Autopsy cases at a tertiary hospital with a pathologic diagnosis of acute MI were evaluated for clinicopathologic features. Modified Goldman’s classification was used to classify discrepant cases. Results Of 529 autopsy cases, 19 (3.6%) demonstrated acute/subacute MI as a pathologic diagnosis. Thrombosis was identified in a minority of cases (3/19, 15.8%). Major clinicopathologic discrepancies were identified in four (21.1%) cases. Conclusions Although acute MI is an uncommon diagnosis rendered at hospital autopsy, a notable subset of cases demonstrates diagnostic discrepancy between the clinical impression and ultimate pathologic diagnosis. Interestingly, most MI cases in this series are not related to plaque disruption and thus best classified as a type 2 MI, which is associated with imbalance between oxygen demand and supply.

// Michele Carbone 1 , David Shimizu 2 , Andrea Napolitano 1 , Mika Tanji 1 , Harvey I. Pass 3 , Haining Yang 1 , Sandra Pastorino 1 1 Thoracic Oncology Program, University of Hawaii Cancer Center, Honolulu, HI, USA 2 Department of Pathology, Queen Medical Center, Honolulu, HI, USA 3 Department of Cardiothoracic Surgery, New York University, NYU Langone Medical Center, NY, USA Correspondence to: Michele Carbone, email: mcarbone@cc.hawaii.edu Keywords: mesothelioma, lung cancer, BAP1, differential diagnosis, immunohistochemistry Received: May 20, 2016 Accepted: June 13, 2016 Published: July 18, 2016 ABSTRACT The differential diagnosis between pleural malignant mesothelioma (MM) and lung cancer is often challenging. Immunohistochemical (IHC) stains used to distinguish these malignancies include markers that are most often positive in MM and less frequently positive in carcinomas, and vice versa. However, in about 10–20% of the cases, the IHC results can be confusing and inconclusive, and novel markers are sought to increase the diagnostic accuracy. We stained 45 non-small cell lung cancer samples (32 adenocarcinomas and 13 squamous cell carcinomas) with a monoclonal antibody for BRCA1-associated protein 1 (BAP1) and also with an IHC panel we routinely use to help differentiate MM from carcinomas, which include, calretinin, Wilms Tumor 1, cytokeratin 5, podoplanin D2-40, pankeratin CAM5.2, thyroid transcription factor 1, Napsin-A, and p63. Nuclear BAP1 expression was also analyzed in 35 MM biopsies. All 45 non-small cell lung cancer biopsies stained positive for nuclear BAP1, whereas 22/35 (63%) MM biopsies lacked nuclear BAP1 staining, consistent with previous data. Lack of BAP1 nuclear staining was associated with MM (two-tailed Fisher’s Exact Test, P = 5.4 x 10 -11 ). Focal BAP1 staining was observed in a subset of samples, suggesting polyclonality. Diagnostic accuracy of other classical IHC markers was in agreement with previous studies. Our study indicated that absence of nuclear BAP1 stain helps differentiate MM from lung carcinomas. We suggest that BAP1 staining should be added to the IHC panel that is currently used to distinguish these malignancies.

ObjectiveThe aim of this study was to determine the histopathologic characteristics of patients with endometrial carcinoma with low-volume metastases (micrometastases and isolated tumor cells) compared with macrometastases.MethodsWe performed a retrospective review of patients with endometrial carcinoma.ResultsAmong 350 robotic-assisted hysterectomies for endometrial cancer, 187 (53%) underwent attempted sentinel lymph node (SLN) biopsy. At least 1 SLN was detected in 185, a 99% overall detection rate; 108 (58%) also had non-SLNs removed. Among 91 patients with SLNs and non-SLNs from the ipsilateral hemipelvis, both were negative in 74 (81%) and positive in 7 (8%), and 10 (11%) had a positive SLN with negative non-SLNs. Among 17 patients with SLNs and non-SLNs from the contralateral hemipelvis, both were negative in 12 (71%), both were positive in 3 (18%), and 2 patients (12%) had negative SLNs with contralateral positive non-SLNs. Among 79 patients with only a SLN dissection, 4 (5%) were positive; among 69 patients with only a non-SLN dissection, 14 (20%) had positive lymph nodes. Among 24 patients with metastatic SLNs, 9 (38%) had isolated tumor cells, 3 (13%) had micrometastases, and 12 (50%) had macrometastases. Among the 40 total patients with metastatic lymph nodes, low-volume metastases represented the largest metastatic deposit in one third of patients, all of which had SLN dissection. All 12 with low-volume metastases had endometrioid histology compared with less than half (46%) of those with macrometastases (P < 0.01). Grade 1 carcinoma was present in 7 (58%) of the patients with low-volume metastases compared with 4 (14%) of those with macrometastases (P < 0.01) Furthermore, significantly more patients with low-volume metastases versus macrometastases had less than 50% myometrial invasion (67% vs 4%, P < 0.001).ConclusionsLow-volume disease was present in one third of patients with nodal metastases, the largest metastatic deposit only in patients who had SLN dissection; these patients were significantly more likely to have grade 1 endometrioid carcinoma with less than 50% myometrial invasion, traditional “low-risk” features.

Patients with Lynch Syndrome are at an increased risk for a variety of malignancies, including ovarian cancer. Ovarian cancers associated with Lynch Syndrome are predominantly clear cell or endometrioid in histology. Lynch Syndrome is characterized by germline mutations in mismatch repair (MMR) genes. The current study aims to assess the prevalence of loss of MMR expression in patients with endometrioid and clear cell ovarian carcinoma.A retrospective review identified 90 patients with endometrioid and/or clear cell carcinomas. Slides made from tumor tissue microarray blocks were evaluated using immunohistochemical stains with antibodies against MLH1, PMS2, MSH2, and MSH6. Statistical analysis was performed.Seven of the 90 cases (7.8%) had loss of MMR expression. The mean age of patients with loss of MMR expression (47 years) was significantly younger than those with retained MMR expression (p=0.014). Loss of MMR expression was present in 20% of patients under the age of 53 with clear cell or endometrioid cancers. Genetic studies found that 3 of the 5 patients with loss of MMR expression carried mutations consistent with Lynch Syndrome; acquired hypermethylation of MLH1 was noted in one patient. Six of 7 patients (86%) whose tumors lacked MMR expression had synchronous or metachronous primary malignancies, a significantly greater prevalence than those with retained MMR expression (p0.001).Patients under the age of 53 with clear cell or endometrioid ovarian carcinomas are at a clinically significant risk for loss of MMR expression and Lynch Syndrome; routine screening with immunohistochemical staining should be considered.

Objective This study examines patients under the age of 70 with endometrial cancer and lymphatic invasion or lymph node metastases. Survival of patients with loss of tumor mismatch repair expression is compared to survival of patients with normal mismatch repair expression. Methods This is a retrospective review of patients treated from 1998–2009 for carcinoma of the endometrium. All patients with lymphatic invasion, including lymph node metastases, had immunohistochemical staining of the primary tumor for loss of expression of the mismatch repair genes MLH1, PMS2, MSH6, and MSH2. Overall survival and disease specific survival were compared using Kaplan–Meier plots. Results Sixty-six patients were identified for inclusion; 26 demonstrated loss of mismatch repair expression and 40 demonstrated normal mismatch repair expression. Overall survival and disease specific survival were significantly better in the group with defective mismatch repair expression. Subgroup analysis of FIGO stage 3C patients also showed significantly better survival in patients with deficient mismatch repair expression. Conclusion For patients with endometrial cancer and lymphatic invasion, patients demonstrating loss of mismatch repair expression in the primary tumor appear to have a significantly better survival than patients with normal mismatch repair expression. Further investigation appears warranted to examine a possible role of mismatch repair expression as a prognostic marker for high risk patients with endometrial cancer.

The stage I uterine malignant mixed mullerian tumor (MMMT) shows different potential for progression. We reason that MMMTs with high-grade carcinomatous component and positivity for HB-EGF are prone to recurrence/metastasis in the early stage. A retrospective clinical and histopathologic review with immunohistochemical staining for HB-EGF, EGFR, and integrin-α5 was performed for 62 surgically staged MMMT cases. Recurrence/metastasis (RM) is 6/18 (33%) in stage I disease. Of all the clinicopathologic variables and biomarkers analyzed for stage I MMMT, serous carcinomatous component (83% [5/6] versus 17% [1/12], P = .0015) and HB-EGF expression (100% [6/6] versus 50% [6/12], P=.0339) were significantly different between groups with RM and without RM. The presence of serous carcinoma in all stages was 83% (5/6) in stage I with RM, 8% (1/12) in stage I without RM, 20% (1/5) in stage II, 36.4% (8/22) in stage III and 64.7% (11/17) in stage IV; this was paralleled by HB-EGF expression of 100% (6/6), 50% (6/12), 40% (2/5), 50% (11/22) and 71% (12/17) with a correlation coefficient r=0.9131 (P=.027). HB-EGF and integrin-α5 were highly expressed in MMMTs bearing serous carcinoma component, compared to endometrioid and unclassifiable/miscellaneous subtypes (84.6%/47.6%/33.3%, P=.025 for HB-EGF; and 61.5%/42.9%/20.0%, P=.021 for integrin-α5). The EGFR positivity was comparable among the three subtypes (48.1%, 47.6% and 26.7%, P=.326). This study indicates that serous carcinomatous component championed by expression of HB-EGF predisposes to recurrence/metastasis in stage I MMMT. This process might involve integrin-α5 and does not seem to require overexpression of EGFR. Further study is required.

OBJECTIVE The benefit of evaluating the precursor of endometrial carcinoma, endometrial hyperplasia (intraepithelial neoplasia [EIN]), for loss of mismatch repair (MMR) protein expression and Lynch syndrome has yet to be determined. The present study aims to establish the incidence and type of loss of MMR protein expression in unselected premalignant lesions of endometrial adenocarcinoma, as well as the agreement of immunohistochemical staining in pretreatment endometrial biopsy (EMB) specimens with subsequent uterine resections. METHODS A retrospective review identified 112 endometrial biopsies meeting criteria for endometrial EIN. Slides made from tissue microarray blocks were evaluated using antibodies against MLH1, PMS2, MSH2, and MSH6. Cases with a deficit in MLH1 were evaluated for gene promoter hypermethylation by polymerase chain reaction analysis. Fifty-four subsequent hysterectomy specimens were retrieved and assessed for MMR protein expression. RESULTS Of the 112 endometrial biopsies with EIN, 4.5% (5/112) exhibited loss of MMR protein expression. The majority (4/5) demonstrated a deficit of MLH1, of which all exhibited inactivation via promoter hypermethylation. A single case displayed an absence of MSH6. Age was not significantly associated with MMR deficiency. There was no significant association between MMR status in the EMB and a subsequent diagnosis of cancer. Immunohistochemical staining in all successive hysterectomy cases was concordant with the pattern observed in the EMB specimen. CONCLUSIONS Sporadic hypermethylation of MLH1 seems to be the primary mechanism underlying defective MMR protein expression in EIN. Among our cohort, only 1 patient (

Objective This study examines premenopausal and early menopause patients in a unique population with endometrial cancer and loss of mismatch repair (MMR) gene expression. The purpose is to compare clinical and pathologic differences in patients with loss of expression (LOE) to those with normal expression (NE). Methods Endometrial cancer patients under age 60 in-between 1998 and 2008 were identified from a single tumor registry. Clinical and pathologic data were abstracted from records. Staining for expression of MSH6, MSH2, MLH1, and PMS2 were performed on archived tissue blocks. Statistical analysis was performed. Results 158 patients were analyzed; 58% Asian, 34% Pacific Islander, and 8% Caucasian. 31 demonstrated LOE of at least one MMR gene; 127 retained NE. 50% Caucasian, 21.9% Asian, and 12.5% Pacific Island populations had LOE of one or more MMR genes. LOE was found to have a higher incidence of Grade III (p = 0.0013) and stage 3–4 tumors (p = 0.0079), mean depth of myometrial invasion (p = 0.0019), lymphovascular space invasion (p = 0.0020), nodal metastases (p = 0.0157), and a lower incidence of Grade I (p = 0.0020) and stage 1A tumors (p = 0.0085). LOE had a significantly lower mean BMI (p = 0.0001). 35% of patients in the NE vs zero in the LOE group had a BMI greater than 40. Conclusion Younger patients with LOE endometrial cancer appear to represent a clinically significant subgroup of patients without features characteristically found in classic type 1 endometrial cancer generally demonstrating lower BMI and tumors associated with poor prognostic characteristics. It is unclear if the distinctive ethnicity found in Hawaii has a significant impact on outcome. Further investigation is necessary to identify appropriate treatment strategies.

The revised Bethesda guidelines for Lynch syndrome recommend microsatellite instability (MSI) testing all colorectal cancers in patients diagnosed before age 50 years and colorectal cancers diagnosed in patients between ages 50 and 59 years with particular pathology features. Our aim was to identify pathology and other features that independently predict high MSI (MSI-H).Archival tissue from 1098 population-based colorectal cancers diagnosed before age 60 years was tested for MSI. Pathology features, site, and age at diagnosis were obtained. Multiple logistic regression was performed to determine the predictive value of each feature, as measured by an odds ratio (OR), from which a scoring system (MsPath) was developed to estimate the probability a colorectal cancer is MSI-H.Fifteen percent of tumors (162) were MSI-H. Independent predictors were tumor-infiltrating lymphocytes (OR, 9.1; 95% confidence interval [CI], 5.9-14.1), proximal subsite (OR, 4.7; 95% CI, 3.1-7.3), mucinous histology (OR, 2.8; 95% CI, 1.7-4.8), poor differentiation (OR, 1.9; 95% CI, 1.2-3.1), Crohn's-like reaction (OR, 1.9; 95% CI, 1.2-2.9), and diagnosis before age 50 years (OR, 1.9; 95% CI, 1.3-2.9). MsPath scoreor=1.0 had a sensitivity of 93% and a specificity of 55% for MSI-H.The probability an individual colorectal cancer is MSI-H is predicted well by the MsPath score. There is little value in testing for DNA mismatch repair loss in tumors, or for germline mismatch repair mutations, for colorectal cancers diagnosed in patients before age 60 years with an MSPath score1 (approximately 50%). Pathology can identify almost all MSI-H colorectal cancers diagnosed before age 60 years.

Objectives To determine the impact of implementing p16 Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions (LAST) guidelines, we compared p16 use and follow-up data before and after implementation of the guidelines. Methods We reviewed all cervical biopsy specimens diagnosed by two pathologists before and after implementation of the LAST guidelines and calculated the rate of and reason for p16 use across all biopsy specimens, high-grade squamous intraepithelial lesion (HSIL) detection, and follow-up. Results In total, 1,829 and 1,623 cervical biopsy specimens were reviewed in periods A and B, respectively. Overall p16 use increased from 2.8% to 6.2% ( P < .001). Recommendations 2 and 4 increased from 0.16% and 0% of all cervical biopsy specimens in period A to 1.4% and 1.9% in period B, respectively ( P < .0001). p16+ HSIL increased from 1.4% to 2.3% ( P < .05). The positive predictive value of p16+ HSIL increased from 48% to 76% ( P < .05). Conclusions Implementation of the p16 LAST guidelines resulted in a significant increase in p16 use and a significant increase in the positive predictive value of p16+ HSIL.

Objective. This retrospective review was undertaken to evaluate survival in patients with T1 squamous cell carcinoma of the vulva treated with radical local excision and sentinel node dissection. Methods. Patients with T1 cancers underwent pre-operative lymphoscintigraphy and sentinel lymph node dissection using technetium sulfur colloid and isosulfan blue dye. The primary tumor was removed with radical local excision. Patients with negative sentinel nodes did not receive any additional treatment. Survival was calculated using life table analysis. Results. There were 21 patients who underwent 27 sentinel node dissections. Three patients were found to have positive sentinel nodes. At a median follow-up of 4.6 years, two patients have died of cancer, and three patients have died of intercurrent illness. None of the patients with negative sentinel nodes has died of cancer. There were no groin or distant recurrences in patients with negative sentinel nodes. Three-year disease-free survival for all patients and for patients with negative sentinel nodes were 90% and 100% respectively. Conclusion. The survival for patients with early vulvar cancer treated with sentinel node dissection and radical local excision appears excellent.

Objective. The current study was undertaken to determine if DNA ploidy is a useful prognostic variable for predicting recurrence in stage I endometrial cancer. For cancer of the endometrium, survival following recurrence may depend on a number of factors, including the pattern of recurrence and the response to second line treatment. Previous studies have demonstrated a worse survival for patients with DNA aneuploid tumors. It remains unclear, however, whether this is necessarily due to a higher risk of recurrence. This study was undertaken to assess DNA ploidy and risk of recurrence in patients with stage I endometrial cancer. Methods. This is a retrospective study of surgically treated patients with stages IB and IC endometrial cancer treated from 1992 to 2000. All patients underwent definitive surgery, including staging lymphadenectomy. None of the patients received postoperative treatment. DNA ploidy was determined using flow cytometry and image analysis. Grade, lymph-vascular space invasion, stage (stage IB versus IC), and DNA ploidy were analyzed with regard to recurrence and survival. Results. There were 100 patients with stages IB and IC endometrial cancer in this analysis. There were 17 recurrences (17%) and 10 patients that died of cancer (10%). Grade 3 and the presence of lymph-vascular space invasion were associated with increased risk of recurrence; DNA aneuploidy and stage were not. Grade, lymph-vascular space invasion, and DNA ploidy were associated with survival. These findings indicate that DNA aneuploidy does not increase the risk of disease recurrence but is associated with overall survival. Conclusion. Although the recurrence risk is not higher for patients with surgical stage I endometrial cancer and aneuploid tumors, overall mortality remains higher.

PURPOSE: Between 1995 and 1999, we observed an increasing number of nodes being recovered from colorectal specimens. Patients with colorectal cancer were studied to determine whether increasing the number of negative nodes recovered would better stage the patient and more accurately predict disease-free survival. METHODS: All patients undergoing colorectal resection with curative intent between 1995 and 1999 at a tertiary referral hospital were retrospectively reviewed. Tumor stage, grade, number of nodes recovered, and the association of these factors with disease-free survival was analyzed. RESULTS: Three hundred forty-five patients with M0 disease undergoing surgical resection of carcinoma of the colon or rectum were studied. There was no statistically significant difference in tumor stage or grade during the study period. A statistically significant increase in the mean number of nodes recovered was observed during the study period. Node-positive patients did substantially worse than node-negative individuals. When compared with a national cancer registry (OncoPool), we observed a significantly greater number of nodes sampled in our study population and a statistically significant improved disease-free survival between our node-negative patients and that of the national cancer registry population. CONCLUSION: The extent of the pathologic assessment of the nodal status of colorectal cancer patients as determined by the number of nodes examined affects disease-free survival. The need for quality control for uniform pathologic assessments is critical.

Objective. The aim of this study was to evaluate the findings when pathologic ultrastaging techniques are applied in conjunction with sentinel node dissection in patients with vulvar cancer. Methods. Patients with squamous cell cancer of the vulva underwent intraoperative lymphoscintigraphy following intradermal injection of 99mTc-labeled sulfur colloid at the site of the primary tumor. Isosulfan blue dye was also injected at the tumor site to facilitate identification of the sentinel node in the groin. Following removal, the sentinel node was then bisected and examined in the standard manner using hematoxylin and eosin staining. Negative nodes were subjected to additional ultrastaging evaluation with serial sectioning and immunohistochemical staining. Results. Nine patients with 10 primary tumors underwent radical local excision of the primary tumor and sentinel node dissection of the groin. Sentinel nodes were identified and removed in all patients. One node was positive by conventional staining; the remainder were all negative. Of these negative nodes, 2 were found to be positive for micrometastases on serial sectioning and immunohistochemical staining. Therefore 2 of 3 positive nodes were not detected using conventional histologic techniques. Conclusion. Sentinel node dissection appears to be technically feasible in patients with vulvar cancer. Pathologic ultrastaging combined with sentinel node dissection appears to be highly sensitive for detecting subclinical micrometastases in the regional lymphatics. This technique potentially provides a more accurate assessment with less surgical morbidity than conventional inguinalfemoral lymphadenectomy.

Tailgut cysts, also known as retrorectal cystic hamartomas and mucus-secreting cysts, are rare benign congenital lesions that are thought to be derived from remnants of the embryonic postanal gut, which incompletely regresses during development. They are composed of uni- or multilocular cysts lined by a variety of epithelia, and occur mostly in middle-aged women at …