Evidence of a Monoclonal Origin for Bilateral Serous Tubal Intraepithelial Neoplasia.

Serous tubal intraepithelial carcinoma (STIC) is found in 10% to 60% of cases of tuboovarian high-grade serous carcinoma (HGSC) and is presumed to be the site of origin, linking many HGSCs to the fallopian tube. Bilateral STIC is present in ∼20% of cases. Because clonal Tp53 mutations are a defining feature of HGSC, including their associated STICs, we analyzed 4 cases of bilateral serous tubal intraepithelial neoplasia (STIN), including STIC and Tp53-mutated serous tubal intraepithelial lesions (STILs), associated with HGSC to determine whether they contained the same or different p53 mutations. Extracted DNA from STINs, concurrent HGSCs and control tissues was analyzed for mutations in all exons of Tp53. Sequencing was successful in 3 of the 4 cases, and an identical Tp53 mutation was detected in the HGSC and bilateral STINs in 2 of these 3 cases. One STIN was morphologically a STIL. These findings confirm that a subset of bilateral STINs share the same Tp53 mutation, implying that at least one of the STINs is an intraepithelial metastasis from either the contralateral STIN or HGSC. This study complements others addressing the multiple origins of STIN in the setting of existing HGSC. It further underscores the fact that potential overlap in biologic behavior between STILs and STICs as well as timing and direction of metastatic spread has yet to be resolved.

Assessment of a Chemotherapy Response Score (CRS) System for Tubo-Ovarian High-Grade Serous Carcinoma (HGSC).

A chemotherapy response score (CRS) system was recently described to assess the histopathologic response and prognosis of patients with tubo-ovarian high-grade serous carcinoma (HGSC) receiving neoadjuvant chemotherapy. The current study was performed as an independent assessment of this CRS system. We retrospectively identified advanced stage HGSC patients who received neoadjuvant chemotherapy and underwent interval debulking. If available, a hemotoxylin and eosin slide from the omentum and the adnexa was selected for the study. Slides were independently scored by 13 pathologists using the 3-tiered CRS system. Reviewers then received web-based training and rescored the slides. Overall survival and progression-free survival were estimated using the Kaplan-Meier method and compared using the log-rank test. A total of 68 patients with omental (n=65) and/or adnexal (n=59) slides were included in the study. Interobserver reproducibility was moderate for omentum (κ, 0.48) and poor for adnexa (κ, 0.40), which improved for omentum (κ, 0.62) but not for adnexa (κ, 0.38) after online training. For omental slides, a consensus CRS of 1/2 was associated with a shorter median progression-free survival (10.9 mo; 95% confidence interval, 9-14) than a CRS of 3 (18.9 mo; 95% CI, 18-24; P=0.020). In summary, a 3-tiered CRS system of hemotoxylin and eosin-stained omental deposits can yield prognostic information for HGSC patients receiving neoadjuvant chemotherapy, and web-based training improved reproducibility but did not alter determination of clinical outcomes. The CRS system may allow oncologists to identify potential nonresponders and triage HGSC patients for heightened observation and/or clinical trials.

Placental Pathology in Neonatal Stroke: A Retrospective Case-Control Study.

OBJECTIVE: To assess the association of placental abnormalities with neonatal stroke. STUDY DESIGN: This retrospective case-control study at 3 academic medical centers examined placental specimens for 46 children with neonatal arterial or venous ischemic stroke and 99 control children without stroke, using a standard protocol. Between-group comparisons used χ2 and Fisher exact t test. Correlations used Spearman correlation coefficient. RESULTS: Case placentas were more likely than controls to meet criteria for ≥1 of 5 major categories of pathologic abnormality (89% vs 62%; OR, 5.1; 95% CI, 1.9-14.0; P = .0007) and for ≥2 categories (38% vs 8%; OR, 7.3; 95% CI, 2.9-19.0; P < .0001). Fetal vascular malperfusion occurred in 50% of cases and 17% of controls (OR, 4.8; 95% CI, 2.2-10.5; P = .0001). Amniotic fluid inflammation occurred in 46% of cases with arterial ischemic stroke vs 25% of controls (OR, 2.6; 95% CI, 1.1-6.1; P = .037). There was evidence of a "stress response" (meconium plus elevated nucleated red blood cells) in 24% of cases compared with 1% of controls (OR, 31; 95% CI, 3.8-247.0; P < .0001). CONCLUSIONS: Placental abnormality was more common in children with neonatal stroke compared with controls. All placental findings represent subacute-to-chronic intrauterine stressors. Placental thrombotic processes were associated with both arterial and venous stroke. Our findings provide evidence for specific mechanisms that may predispose to acute perinatal stroke. Amniotic fluid inflammation associated with neonatal arterial ischemic stroke deserves further investigation.

Inter-pathologist and pathology report agreement for ovarian tumor characteristics in the Nurses' Health Studies.

BACKGROUND: Grade and histotype of ovarian carcinomas are often used as surrogates of molecular subtypes. We examined factors affecting pathologists' reproducibility in two prospective studies. METHODS: Two pathologists independently reviewed slides from 459 incident ovarian cancers in the Nurses' Health Study (NHS) and NHSII. We described agreement on tumor characteristics using percent agreement and Cohen's standard kappa (κ) coefficients. We used logistic regression, with disagreement as the outcome, to evaluate the contribution of case and tumor characteristics to agreement. RESULTS: Inter-rater agreement was 95% (κ = 0.81) for carcinoma versus borderline, 89% (κ = 0.58) for grade and 85% (κ = 0.71) for histotype. Inter-rater grading disagreement was higher for non-serous histotypes (OR = 4.66, 95% CI 2.09-10.36) and lower for cancers with bizarre atypia (OR = 0.13, 95% CI 0.04-0.38). Agreement with original pathology reports was 94% (κ = 0.73) for carcinoma versus borderline, 78% (κ = 0.60) for histotype, and 79% (κ = 0.24) for grade. Grading disagreement was significantly lower for tumors with 'solid, pseudoendometrioid or transitional' (SET) architecture (OR = 0.08, 95%CI 0.01-0.84). Date of original diagnosis, hospital type, number of slides available for review, tumor stage, and slide quality were not related to agreement. CONCLUSION: Overall, inter-rater agreement for tumor type and grade for archival tissue specimens was good. Agreement between the consensus review and original pathology reports was lower. Factors contributing to grading disagreement included non-serous histotype, absence of bizarre atypia, and absence of SET architecture.

Serous tubal intraepithelial neoplasia: the concept and its application.

In recent years it has become clear that many extra-uterine (pelvic) high-grade serous carcinomas (serous carcinomas) are preceded by a precursor lesion in the distal fallopian tube. Precursors range from small self-limited 'p53 signatures' to expansile serous tubal intraepithelial neoplasms that include both serous tubal epithelial proliferations (or lesions) of uncertain significance and serous tubal intraepithelial carcinomas. These precursors can be considered from three perspectives. The first is biologic underpinnings, which are multifactorial, and include the intersection of DNA damage with Tp53 mutations and disturbances in transcriptional regulation that increase with age. The second perspective is the morphologic discovery and classification of intraepithelial neoplasms that are intercepted early in their natural history, either incidentally or in risk-reduction surgeries for germline mutations. For the practicing pathologist, as well as the investigators, a distinction between a primary intraepithelial neoplasm and an intramucosal carcinoma must be made to avoid misinterpreting (or underestimating) the significance of these proliferations. The third perspective is the application of this information to intervention, devising strategies that will actually lower the ovarian cancer death rate by opportunistic salpingectomy, widespread comprehensive genetic screening and early detection. Central to this issue are the questions of (1) whether some STICs are metastatic, (2) whether lower-grade epithelial proliferations can invade prior to evolving into intraepithelial carcinoma, or (3) metastasize and become malignant elsewhere ('precursor escape'). An important caveat is the persistent and unsettling reality that many high-grade serous carcinomas are not associated with an obvious point of initiation in the fallopian tube. The pathologist sits squarely in the midst of all of these issues, and has a pivotal role in managing expectations for stemming the death rate from this lethal disease.

Frequency of "incidental" serous tubal intraepithelial carcinoma (STIC) in women without a history of or genetic risk factor for high-grade serous carcinoma: A six-year study.

Objective The purpose of this study was to determine the prevalence of incidentally discovered serous tubal intraepithelial carcinoma in women without a genetic risk for or history of high grade serous carcinoma (HGSC) in the gynecologic tract. METHODS: All pathology reports at our institution that included bilateral salpingectomies from January 2006-December 2011 were examined in women >50years old in which the entire tube or the distal one-third was examined histologically with the complete (proximal and distal fallopian tube) or modified (distal one third of the tube) SEE-FIM protocol. Cases were divided into: Group 1, a history of or known risk factors (BRCA1 or BRCA2 mutations) for HGSC and Group 2, those without these attributes for whom a STIC would be unexpected (incidental). Women undergoing unspecified "risk-reducing" procedures were included in Group 1. RESULTS: Of 4051 identified total, 2268 had complete examination of the distal fallopian tube and were age 50 or above. Of these, 1747 were in group 2. Two STICs were identified (0.1%), one associated with a grade 2 endometrial endometrioid adenocarcinoma and one with a low-grade ovarian serous carcinoma in the setting of a serous borderline tumor. CONCLUSIONS: Incidental STICs in women over age 50 are uncommon. However, the significance of lesser tubal atypias (0.3% in this study), risk of STIC in women with no epithelial pathology and the risk imposed by coexisting endometrioid neoplasia are unclear and require further study.

Quantitative computed tomography assessment of bronchiolitis obliterans syndrome after lung transplantation.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is a clinical manifestation of chronic allograft rejection following lung transplantation. We examined the quantitative measurements of the proximal airway and vessels and pathologic correlations in subjects with BOS. METHODS: Patients who received a lung transplant at the Brigham and Women's Hospital between December 1, 2002 and December 31, 2010 were included in this study. We characterized the quantitative CT measures of proximal airways and vessels and pathological changes. RESULTS: Ninety-four (46.1%) of the 204 subjects were included in the study. There was a significant increase in the airway vessel ratio in subjects who developed progressive BOS compared to controls and non-progressors. There was a significant increase in airway lumen area and decrease in vessel cross-sectional area in patients with BOS compared to controls. Patients with BOS had a significant increase in proximal airway fibrosis compared to controls. CONCLUSIONS: BOS is characterized by central airway dilation and vascular remodeling, the degree of which is correlated to decrements in lung function. Our data suggest that progressive BOS is a pathologic process that affects both the central and distal airways.

p16ink4 and cytokeratin 7 immunostaining in predicting HSIL outcome for low-grade squamous intraepithelial lesions: a case series, literature review and commentary.

p16ink4 and cytokeratin 7 (CK7) have been proposed to identify low-grade squamous intraepithelial lesions (LSIL) at greater or lesser risk for an outcome of high-grade squamous intraepithelial lesion (HSIL). We correlated CK7 and p16ink4 staining in LSILs with outcome on follow-up and placed this information in the context of prior reports. Cervical LSIL biopsies with at least 1-year follow-up information were immunostained for CK7 and p16ink4. Follow-up outcomes included no SIL, LSIL (persistence) or HSIL (CIN2+). In all, 109 LSILs were studied and 18.3% stained positive for CK7. Ninety-one percent of CK7-negative LSILs regressed, 4.5% persisted, and 4.5% had an HSIL outcome, versus 60, 20, and 20% of CK7-positive LSILs, respectively (P=0.036). p16ink4 status did not significantly associate with outcome. Review of the literature revealed a highly variable rate of both positive p16ink4 immunoreactivity in LSIL and CIN2+ outcome for p16-positive LSIL but a consistently high negative predictive value (>90%) in the case of no/low p16 expression. Inter-observer reproducibility for the diagnosis of CIN2 in the literature ranged from poor to good, with unanimous agreement on the diagnosis of CIN2 occurring in less than 25% of cases. As with high-risk human papillomavirus testing, the most clinically useful result of p16ink4 staining is a negative test, implying no lesion or CIN1 and conferring a low risk of HSIL outcome. HSIL outcomes ('progression') are highly variable and are subject to wide differences in inter-observer interpretation for CIN2. This argues against the wisdom of relying on p16ink4 to both predict CIN2+ or upgrade CIN1 to CIN2. It also begs the question of whether CIN2 should be replaced by an alternate and less pejorative term (SIL of intermediate grade) for lesions that are not reproducibly classified as LSIL or HSIL, with an appropriate management scheme.

Risk Factors for Occult Uterine Sarcoma Among Women Undergoing Minimally Invasive Gynecologic Surgery.

STUDY OBJECTIVE: To determine factors that can identify a population at increased risk for uterine leiomyosarcoma. DESIGN: Retrospective case-control study (Canadian Task Force classification II-2). SETTING: University teaching hospitals. PATIENTS: Seventy-two women who underwent minimally invasive gynecologic surgery for presumed leiomyoma. Patients diagnosed with leiomyosarcoma (cases) were matched with up to 4 controls on age, year of surgery, and surgeon specialty. INTERVENTION: Cases were identified through the pathology database, and the diagnosis of leiomyosarcoma or leiomyoma was confirmed by gynecologic pathologists. The cumulative risk of leiomyosarcoma was calculated, and factors predictive of elevated risk for leiomyosarcoma were investigated using conditional logistic regression. MEASUREMENTS AND MAIN RESULTS: Fifteen patients with the diagnosis of inadvertently morcellated leiomyosarcoma were identified and matched with 57 controls. The cumulative risk of diagnosing uterine leiomyosarcoma on pathology after performing minimally invasive gynecologic surgery with morcellation was 0.19% (95% confidence interval [CI], 0.06%-0.56%). The presence of a hematocrit value < 30% (adjusted odds ratio [aOR], 20; 95% CI, 1.08-100; p = .05) was independently associated with the diagnosis of uterine leiomyosarcoma on multivariate analysis. Increased myoma size (aOR, 9.73; 95% CI, 0.75-1.26; p = .08) and presence of a solitary myoma (aOR, 3.85; 95% CI, 0.65-25; p = .14) were associated with a greater risk of uterine leiomyosarcoma; however, the difference was not statistically significant. CONCLUSION: Anemia and myoma size >7 cm may be associated with occult leiomyosarcoma; however, these criteria are not sufficiently discriminatory to allow for preoperative identification of patients with uterine sarcoma. Future large multicenter studies are needed to further investigate these findings and the discovery of innovative ways to detect uterine leiomyosarcoma are urgently needed.

The value of re-exploration in patients with inadvertently morcellated uterine sarcoma.

OBJECTIVE: To describe the role of immediate re-exploration in patients with inadvertently morcellated uterine leiomyosarcoma (ULMS) and smooth muscle tumors of uncertain malignant potential (STUMP). METHODS: All patients with ULMS/STUMP who were managed or referred to the participating institutions from January 2005 to January 2012 following minimally invasive gynecology surgery with morcellation were detected through the pathology database. The diagnosis was confirmed by gynecologic-pathologists following post-surgery pathology review. RESULTS: Twenty-one patients with the diagnosis of ULMS (N = 15) and STUMP (N = 6) after morcellation were identified. The median age of occurrence was 46 years (range, 25-58 years). Median follow-up duration was 27 months (range, 1.8-93.1 months). None of the 21 patients had documented evidence of extra-uterine disease at the time of original surgery. Ultimately 12 patients were immediately re-explored to complete staging. The median time to the staging surgery was 33 days (range 15-118 days). Two (28.5%) out of seven patients with presumed stage I ULMS and one (25%) out of four patients with presumed stage I STUMP had significant findings of disseminated intraperitoneal disease detected at immediate surgical re-exploration. One of the 8 patients with confined early ULMS and STUMP at the second surgery had intraperitoneal recurrence, while the remaining 7 patients have had no recurrence and remain disease free. CONCLUSION: Surgical re-exploration is likely to show findings of disseminated peritoneal sarcomatosis in a significant number of patients diagnosed with ULMS after a morcellation procedure. Findings from re-exploration can contribute to the knowledge of natural history of morcellated ULMS/STUMP and allow for accurate prognostication.

Fetal Renal DNA Methylation and Developmental Programming of Stress-Induced Hypertension in Growth-Restricted Male Mice.

Fetal growth restriction (FGR) is associated with developmental programming of adult onset hypertension, which may be related to differences in nephron development. Prior studies showed that maternal nutrient restriction is associated with reduced nephrogenesis in rodents, especially in male progeny. We hypothesized that maternal genetic risk for FGR may similarly affect fetal kidney development, leading to adult onset hypertension. We employed an angiotensinogen (AGT) gene titration transgenic (TG) construct with 3 copies of the mouse AGT gene that mimics a common human genotype (AGT A[-6]G) associated with FGR. We investigated whether FGR in 2-copy (wild type, [WT]) progeny from 3-copy TG dams leads to developmental programming differences in kidney development and adult blood pressure compared with age- and sex-matched controls. Progeny were tested in the late fetal period (e17.5), neonatal period (2 weeks of age), and as young adults (12 weeks). We measured weights, tested for renal oxidative stress, compared renal DNA methylation profiles, counted the number of glomeruli, and measured adult blood pressure ± stress. Progeny from TG dams were growth restricted with evidence of renal oxidative stress, males showed fetal renal DNA hypermethylation, they had fewer glomeruli, and they developed stress-induced hypertension as adults. Their female siblings did not share this pathology and instead resembled progeny from WT dams. Surprisingly, glomerular counts in the neonatal period were not different between sexes or maternal genotypes. In turn, we suspect that differences in fetal renal DNA methylation may affect the long-term viability of glomeruli, rather than reducing nephrogenesis.

Peutz-Jeghers Syndrome: Pathobiology, Pathologic Manifestations, and Suggestions for Recommending Genetic Testing in Pathology Reports.

Peutz-Jeghers syndrome (PJS), in most cases, is attributed to mutation in STK11/LKB1 and is clinically characterized by gastrointestinal hamartomatous polyposis, mucocutaneous pigmentation, and predisposition to certain neoplasms. There are currently no recommended gynecologic screening or clinical surveillance guidelines beyond those recommended for the general population; however, cervical cytology samples must be examined with a high level of suspicion for cervical adenocarcinoma. It is considered prudent to note the established association with PJS and recommend referral for genetic counseling. Complete surgical excision after a diagnosis of atypical lobular endocervical glandular hyperplasia is recommended.

Evidence for a dualistic model of high-grade serous carcinoma: BRCA mutation status, histology, and tubal intraepithelial carcinoma.

Most early adnexal carcinomas detected in asymptomatic women with germline BRCA mutations (BRCA) present as serous tubal intraepithelial carcinomas (STIC). However, STICs are found in only ∼40% of symptomatic high-grade serous carcinomas (HGSCs) and less frequently in pseudoendometrioid variants of HGSC. Consecutive cases of untreated HGSC from BRCA and BRCA women with detailed fallopian tube examination (SEE-FIM protocol) were compared. STIC status (+/-) was determined, and tumors were classified morphologically as SET ("SET", >50% solid, pseudoendometrioid, or transitional) or classic predominate ("Classic"). SET tumors trended toward a higher frequency in BRCA versus BRCA women (50% vs. 28%, P=0.11), had a significantly younger mean age than those with classic HGSC in BRCA women (mean 56.2 vs. 64.8 y, P=0.04), and displayed a better clinical outcome in both groups combined (P=0.024). STIC was significantly more frequent in tumors from the BRCA cohort (66% vs. 31%, P=0.017) and specifically the BRCA tumors with classic morphology (83%) versus those with SET morphology (22%, P=0.003). Overall, several covariables-histology, BRCA status, age, coexisting STIC, and response to therapy-define 2 categories of HGSC with differences in precursor (STIC) frequency, morphology, and outcome. We introduce a dualistic HGSC model that could shed light on the differences in frequency of STIC between symptomatic and asymptomatic women with HGSC. This model emphasizes the need for further study of HGSC precursors to determine their relevance to the prevention of this lethal malignancy.

Cyclophosphamide-associated cardiotoxicity in a child after stem cell transplantation for ß-thalassemia major: case report and review of the literature.

We present a clinicopathologic study of the youngest reported child with lethal cyclophosphamide-induced cardiotoxicity after hematopoietic stem cell transplantation for ß-thalassemia major and the 1st pediatric report of the use of extracorporeal membrane oxygenation as a therapeutic modality to bridge the patient to myocardial recovery. Despite improvement in myocardial function while on extracorporeal membrane oxygenation, at autopsy 11 days after the onset of cardiac dysfunction, epicardial hemorrhage and extensive myocardial hemorrhagic infarction were revealed. Histopathologic and ultrastructural examination of the myocardium revealed extensive coagulative necrosis of cardiomyocytes, endothelial damage, fibrin thrombi, and subendothelial and interstitial fibrin. We review the literature on cyclophosphamide-induced cardiotoxicity and describe its clinicopathologic characteristics. Our findings point to endothelial damage leading to thrombotic microangiopathy and ischemic tissue injury as the most likely pathogenesis.