Emily E. Meserve

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.

Outcome of unexpected adnexal neoplasia discovered during risk reduction salpingo-oophorectomy in women with germ-line BRCA1 or BRCA2 mutations

OBJECTIVE This study computed the risk of clinically silent adnexal neoplasia in women with germ-line BRCA1 or BRCA2 mutations (BRCA(m+)) and determined recurrence risk. METHODS We analyzed risk reduction salpingo-oophorectomies (RRSOs) from 349 BRCA(m+) women processed by the SEE-FIM protocol and addressed recurrence rates for 29 neoplasms from three institutions. RESULTS Nineteen neoplasms (5.4%) were identified at one institution, 9.2% of BRCA1 and 3.4% of BRCA2 mutation-positive women. Fourteen had a high-grade tubal intraepithelial neoplasm (HGTIN, 74%). Mean age (54.4) was higher than the BRCA(m+) cohort without neoplasia (47.8) and frequency increased with age (p < 0.001). Twenty-nine BRCA(m+) patients with neoplasia from three institutions were followed for a median of 5 years (1-8 years.). One of 11 with HGTIN alone (9%) recurred at 4 years, in contrast to 3 of 18 with invasion or involvement of other sites (16.7%). All but two are currently alive. Among the 29 patients in the three institution cohort, mean ages for HGTIN and advanced disease were 49.2 and 57.7 (p = 0.027). CONCLUSIONS Adnexal neoplasia is present in 5-6% of RRSOs, is more common in women with BRCA1 mutations, and recurs in 9% of women with HGTIN alone. The lag in time from diagnosis of the HGTIN to pelvic recurrence (4 years) and differences in mean age between HGTIN and advanced disease (8.5 years) suggest an interval of several years from the onset of HGTIN until pelvic cancer develops. However, some neoplasms occur in the absence of HGTIN.

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.

Cervical Squamous Neoplasia

Abstract This chapter has been extensively revised to address several important issues in the field of cervical neoplasia. These include new information about the origin of cervical squamous neoplasia and its impact on our perceptions of lesion development. This leads in to a discussion of the conundrum of lesion grading, specifically the laboratory management of lesions that fall between cervical intraepithelial neoplasia grade 1 (CIN1) and grade 3 (CIN3). Strategies for managing this problem are offered, and the concept of squamous intraepithelial lesion (SIL) of intermediate (or indeterminate) grade is unveiled. The underpinning of this concept is the absence of any biomarker that can be depended upon to segregate low-grade squamous intraepithelial lesion (LSIL) from high-grade squamous intraepithelial lesion (HSIL) in light of the widespread variations in interpretation between observers and the lack of compelling information to support p16 as either a marker of HSIL or a predictor thereof. Other important topics include new approaches to superficially invasive squamous carcinoma, new management schemes, and the promise of vaccination programs. Finally, the concept of prophylactic ablation of the squamocolumnar junction (SCJ) is addressed as another possible approach to cervical cancer risk reduction in vulnerable populations.

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.

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.

Benign Conditions of the Ovary

Abstract The primary purposes of this chapter are to both acquaint the reader with the myriad of pathologic findings that will be encountered in the benign ovary and provide a detailed description of pathologic conditions, including altered ovarian cortical and follicular biology (polycystic ovary syndrome [PCOS]), endometriosis, infections, and infertility. Potential mimics of neoplasia, such as tangentially sectioned follicles, stromal or hilar cell hyperplasias, and atypias in endometriosis, are also discussed.

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.

Pulmonary Clinicopathological Correlation after Allogeneic Hematopoietic Stem Cell Transplantation: An Autopsy Series

Pulmonary complications are a significant cause of morbidity, mortality, and resource utilization after hematopoietic stem cell transplantation (HSCT). The objective of this study was to compare antemortem clinical suspicion of pulmonary complications and postmortem findings in a modern HSCT cohort. All patients who underwent allogeneic HSCT at our institution (n = 1854) between January 1, 2000 and June 30, 2010 were reviewed and patients who died of any cause greater than 1 year after HSCT and had an unrestricted autopsy available for analysis were included. Presence of pulmonary graft-versus-host disease (GVHD) was assessed by a pathologist blinded to the autopsy report, as previously described by Yousem (1995). A total of 35 (1.9%) patients had autopsies available for review. Airway disease, vascular disease, and interstitial disease were all clinically under-recognized compared with the pathological findings on autopsy. Varying degrees of pathological changes were detected, including 10 (28.6%) patients having bronchiolitis obliterans (BO) and 12 (34.3%) patients having pulmonary veno-occlusive disease (PVOD). Pulmonary manifestations of chronic GVHD, particularly BO and PVOD, were clinically under-recognized in our cohort. Our results suggest that PVOD, which has traditionally been considered a rare complication, may be clinically and histologically under-recognized.

Gestational Diseases and the Placenta

Abstract The purpose of this chapter is to integrate the most common clinical scenarios faced in obstetric practice with pathologic examination of the placenta. Because much of the pathology has been covered descriptively in Chapters 31 and 32 Chapter 31 Chapter 32 , the principal intent of this chapter is to discuss pathologic conditions as they present clinically focusing on pathologic conditions that lead to premature birth, induction of labor, and peripartum and postpartum hemorrhage. Only previously uncovered pathologic aspects of clinical disorders are discussed in more detail. The penultimate section of this chapter briefly addresses pathologic aspects of twin gestations, and the final section of this chapter addresses four discrete clinicopathologic entities, termed constellation disorders (amniotic fluid infection, maternal vascular malperfusion, fetal vascular malperfusion, and chronic abruption) with suggested pathologic reporting of these conditions.