Uterine Leiomyosarcoma Associated With Perivascular Epithelioid Cell Tumor: A Phenomenon of Differentiation/Dedifferentiation and Evidence Suggesting Cell-of-Origin.

Perivascular epithelioid cell tumor (PEComa) is a mesenchymal tumor thought to originate from perivascular epithelioid cells (PECs). The normal counterpart to PEC, however, has not been identified in any human organ, and the debate as to whether PEComa is related to smooth muscle tumors has persisted for many years. The current series characterizes 4 cases of uterine leiomyosarcoma (LMS) coexisting with PEComas. All cases exhibited an abrupt transition from the LMS to PEComa components. The LMS component displayed typical spindled morphology and fascicular growth pattern and was diffusely positive for desmin and smooth muscle myosin heavy chain, completely negative for HMB-45 and Melan A, and either negative or had focal/weak expression of cathepsin K and GPNMB. In contrast, the PEComa tumor cells in case 1 contained glycogen or lipid-distended cytoplasm with a foamy appearance (low grade), and in cases 2, 3, and 4, they displayed a similar morphology characterized by epithelioid cells with eosinophilic and granular cytoplasm and high-grade nuclear atypia. Different from the LMS component, the epithelioid PEComa cells in all cases were focally positive for HMB-45, and diffusely immunoreactive for cathepsin K and GPNMB. Melan A was focally positive in cases 1 and 3. Loss of fumarate hydratase expression (case 1) and RB1 expression (cases 2, 3, 4) was identified in both LMS and PEComa components, indicating that they are clonally related. In addition, both components showed an identical TP53 p.R196* somatic mutation and complete loss of p53 and ATRX expression in case 2 and complete loss of p53 expression in case 3. We hypothesize that LMSs containing smooth muscle progenitor cells may give rise to divergent, lineage-specific PEComatous lesions through differentiation or dedifferentiation. While we do not dispute the recognition of PEComas as a distinct entity, we advocate the hypothesis that modified smooth muscle cells represent the origin of a subset of PEComas, and our case series provides evidence to suggest this theory.

Transitioning From Trainee to Practicing Pathologist: A Prospective Multi-institutional Survey of the Challenges Early Career Anatomic Pathologists Encounter When Entering Independent Practice.

CONTEXT.­: Pathology training programs generally prepare graduates well for the workforce, but there may be other aspects to navigating a job that make the transition from being a trainee to a practicing pathologist challenging. OBJECTIVE.­: To identify perceived challenges of independent practice for early career pathologists and assess how these impressions evolve throughout their first year. DESIGN.­: A survey was distributed to 12 anatomic pathology fellows from 4 institutions near the end of their final training year, and 6 months and 1 year after starting their first job. The surveys queried participants' comfort level with signing out cases independently and interacting with colleagues/trainees via Likert attitude scale questions with free-text segments to elaborate on challenges experienced. RESULTS.­: The response rate to all 3 surveys was 100%. Confidence and comfort level with different aspects of independent sign-out increased incrementally over time. Main challenges encountered at 6 months included a high case load, signing out cases in areas outside of their subspecialty, time management, balancing teaching while signing out, laboratory issues, and developing relationships with clinicians. At 12 months, main challenges included time management, high case load, understaffing, laboratory issues, and signing out cases in areas outside of their subspecialty. CONCLUSIONS.­: This study identified real-time challenges faced by those adjusting to their first year of independent practice. By gaining a better understanding of the factors that make this transition challenging, we can find tailored ways to support our early career pathologists.

Ovarian non-gestational placental site trophoblastic tumor with lung metastasis: further evidence for a distinct category of trophoblastic neoplasm.

We previously described a series of cases which characterize a distinct group of primary ovarian placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT) as a non-gestational set consistent with germ cell type/origin. Here we report a new case of ovarian non-gestational PSTT. The patient was a 13 year-old young female admitted for a spontaneous pneumothorax of the left lung. The pathology of lung wedge excision specimen demonstrated metastatic PSTT and ovarian biopsy showed atypical intermediate trophoblastic proliferation which was found to be PSTT in the subsequent salpingo-oophorectomy specimen. In the ovary, the tumor was composed of singly dispersed or small clusters of predominantly mononuclear cells and rare multinucleated cells extensively infiltrating the ovarian parenchyma, tubal mucosa, and paraovarian/paratubal soft tissue. A minor component of mature cystic teratoma (less than 5% of total tumor volume) was present. Immunohistochemically, the neoplastic cells of main tumor were diffusely immunoreactive for hPL, Gata3 and AE1/AE3, and had only rare hCG-positive or p63-positive cells. The morphology and immunohistochemical results support a PSTT. Molecular genotyping revealed an identical genotype pattern between the normal lung tissue and the metastatic PSTT, indicating its non-gestational nature of germ cell type/origin. This case represents the first case of such tumor with distant (lung) metastasis. This case also provides further evidence to support our recommendation that primary ovarian non-gestational intermediate trophoblastic tumors of germ cell type/origin, including PSTT and ETT, should be formally recognized in classification systems.

Perceptions of Controversies and Unresolved Issues in the 2014 FIGO Staging System for Endometrial Cancer: Survey Results From Members of the International Society of Gynecological Pathologists and International Gynecologic Cancer Society.

Long-standing controversial and unresolved issues in the current "International Federation of Gynecology and Obstetrics" staging system for endometrial cancer are well-recognized by pathologists and clinicians alike and exist primarily as a result of limitations to the existing literature. To guide the design of future outcome-based studies specifically aimed at resolving such gaps, the International Society of Gynecologic Pathologists developed a survey of the current perceptions of pathologists (n = 172) and clinicians (n= 135) from the International Society of Gynecological Pathologists and from the International Gynecologic Cancer Society on areas for potential refinement of the current International Federation of Gynecology and Obstetrics staging system. The highest priority issues for pathologists and clinicians alike were the need to determine whether stage IIIA patients (ovarian/fallopian tube involvement) can be reliably separated into favorable versus unfavorable outcome groups to avoid over-treatment of the former group and to determine whether stage IIIC patients (lymph node metastases) can be separated into favorable versus unfavorable outcome groups based on the size of lymph node metastases. The majority of pathologists and clinicians viewed lymphovascular space invasion as an independent prognostic variable and favored incorporating lymphovascular space invasion into staging, though the level of support did not meet the threshold of 75% in support that we used to define a formal consensus. While pathologists did agree on the prognostic value of reporting the extent of lymphovascular space invasion, there was no consensus on the diagnostic criteria to distinguish focal versus substantial involvement. The majority of pathologists and clinicians viewed that a universally accepted protocol for sentinel lymph node ultra-staging is lacking. Both survey groups conveyed a slight preference for incorporating tumor histotype and molecular classification into staging but the support was short of the 75% threshold for formal consensus. Collectively, this survey permits the International Society of Gynecological Pathologists to develop a pathologist and clinician-driven long-term strategy for prioritizing and designing outcome-based studies specifically targeted to resolving controversial and unresolved issues in the International Federation of Gynecology and Obstetrics staging of endometrial cancer.

Pathology Residency Curricula.

OBJECTIVES: To perform a systematic review of the published literature on pathology graduate medical education, with a focus on novel educational curricula. METHODS: We systematically searched the PubMed and Embase databases for relevant articles published between 2000 and 2021. RESULTS: We analyzed 612 articles and selected 19 peer-reviewed, full-length, English language articles published between 2003 and 2021 describing unique curricula for final review. Details on the general characteristics, conceptualization, design, implementation, and assessment were collected and discussed. CONCLUSIONS: This systematic review highlights a recent increase in published curricular endeavors specifically addressing topics of educational need that are otherwise not commonly taught in traditional residency training. Curricula are diverse in their teaching methods, implementation, and originating institutions. The lack of meaningful evaluated outcomes and available curricular materials may hinder wider use of such curricula; these should be considered by future pathology educators undertaking their design.

Practical Scientific Writing and Publishing in Anatomic Pathology.

OBJECTIVES: To develop a structured, introductory curriculum in scientific writing and publishing for residents in anatomic pathology. METHODS: We assessed the need for this curriculum by using an online questionnaire sent to anatomic pathology residents in our program and tailored content to address areas of least familiarity. The curriculum consisted of 4 virtual lectures delivered by select experts in the field. Curriculum evaluation was assessed through a postcurriculum questionnaire. RESULTS: In total, 27 of 31 (87%) residents responded to the initial questionnaire. The major educational need was identified in the following topics: "responsibilities of a corresponding author"; "selecting a journal for publication"; "editor's approach to evaluating a manuscript"; "correspondence with editors and reviewers"; and "open access, cost and increasing exposure to manuscript." Eight residents participated in at least 3 of 4 lectures and completed the pre- and postcurriculum survey. The postcurriculum survey demonstrated statistically significant interval increases in familiarity with 7 of 18 topics, and the leading increases were noted in topics of most significant educational need. CONCLUSIONS: Development of novel curricula is vital to the ever-changing landscape of pathology resident education. This study proposes a generalizable algorithmic approach to assessing new areas of educational need and effectively addressing them through targeted curricula.

Keratin Granulomas in the Peritoneum on Frozen Section: A Case Report with Multiple Suspects and the Search for the Culprit.

Keratin granulomas in the peritoneum are a rare finding with multiple etiologies and can be especially challenging for both the pathologist and the surgeon when these lesions are grossly visible. We report a case of a unique frozen section diagnostic scenario of evaluation of keratin granulomas in the peritoneum of a 47-year-old woman in the setting of multiple potential culprits: endometrial endometrioid adenocarcinoma following fertility sparing treatment, and a concurrent dermoid cyst. We discuss the various etiologies of keratin granulomas in the peritoneum, mechanism of their formation, diagnostic significance, as well as implications of fertility sparing treatments. To the best of our knowledge, this is the only case of keratin granulomas in the peritoneum with multiple distinct potential pathologic culprits as well the only case following fertility sparing treatment.

TP53 Mutation and Extraneural Metastasis of Glioblastoma: Insights From an Institutional Experience and Comprehensive Literature Review.

Extraneural metastases of glioblastoma (GBM), although rare, are becoming an increasingly recognized occurrence. Currently, the biological mechanism underlying this rare occurrence is not understood. To explore the potential genomic drivers of extraneural metastasis in GBM, we present the molecular features of 4 extraneural metastatic GBMs, along with a comprehensive review and analysis of previously reported cases that had available molecular characterization. In addition to our 4 cases, 42 patients from 35 publications are reviewed. To compare the molecular profiles between GBM cases with extraneural metastasis and the general GBM population, genomic data from GBM samples in The Cancer Genome Atlas (TCGA) database were also analyzed. We found that 64.5% (20/31) of the cases with extraneural metastasis that were tested for TP53 changes had at least 1 TP53 pathogenic variant detected in either 1 or both primary and metastatic tumors. In contrast, TP53 mutation was significantly less frequent in the unselected GBM from TCGA (22.6%, 56/248) (P=0.000). In addition, O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was more common in unselected TCGA GBM cases (48.6%, 170/350) than in cases with extraneural metastasis (31.8%, 7/22), although not statistically significant. Although isocitrate dehydrogenase (IDH) mutation is a rare occurrence in high-grade astrocytomas, IDH-mutant grade 4 astrocytomas are at least as likely to metastasize as IDH wild-type GBMs; 3 metastatic cases definitively harbored an IDH1 (p.R132H) mutation in our analysis. Our findings not only provide potential biomarkers for earlier screening of extraneural metastasis, but could also suggest clues to understanding biological mechanisms underlying GBM metastasis, and for the development of therapeutic modalities.

The "Far Left" of the Morphologic Spectrum of Ovarian High-grade Serous Carcinoma: Case Report of a Purely Noninvasive High-grade Serous Carcinoma Mimicking an Ovarian Serous Borderline Tumor.

High-grade serous carcinoma has a variety of different growth patterns, but is typically easily recognizable to pathologists and rarely confused with serous borderline tumors. We report a case of a 71-yr-old woman with a unilateral 5.1 cm ovarian cyst with small papillary projections on contrast-enhanced magnetic resonance imaging of the pelvis. Histologic examination showed a noninvasive papillary neoplasm with hierarchical branching and epithelial proliferation, and thus, at low magnification, bearing a striking resemblance to a serous borderline tumor. However, a more careful examination demonstrated high-grade cytologic features, nuclear pleomorphism, and abundant mitotic activity, suggestive of high-grade serous carcinoma. The morphology and immunohistochemical profile of this lesion is consistent with a rare, purely noninvasive growth pattern of high-grade serous carcinoma. This lesion represents the "far left" of the high-grade ovarian serous carcinoma morphologic spectrum and can mimic a serous borderline tumor.

Giant Cell Carcinosarcoma of the Parotid Gland With a PLAG 1 Translocation in Association With a Pleomorphic Adenoma With HMGA2 Translocation.

OBJECTIVES: Carcinosarcomas of the salivary gland are rare neoplasms and have been described arising de novo or in association with pleomorphic adenoma (PA). PLAG1 and HMGA2 translocations are known to occur in PAs and carcinomas ex PA but are mutually exclusive. METHODS: We report a case of a carcinosarcoma in the parotid gland of a 77-year-old man with unusual anaplastic sarcomatoid giant cell morphology. RESULTS: Microscopically, a small separate PA was found adjacent to the carcinosarcoma. By conventional notion, the PA and carcinosarcoma would be considered related, as carcinosarcomas are well known to arise from PAs (carcinosarcoma ex PA). However, fluorescence in situ hybridization (FISH) assay demonstrated PLAG1 translocation in the carcinosarcoma and HMGA2 translocation in the separate PA. CONCLUSIONS: These findings support that the carcinosarcoma likely originated from another PA with a PLAG1 translocation or de novo but not from the coexisting PA harboring a different translocation. To our knowledge, the case is the first to demonstrate PLAG1 translocation by FISH in a sarcomatous component of any parotid gland tumor, which may help better classify these tumors. In addition, multiple PAs are commonly found in the salivary gland, and to our knowledge, our case is the first to demonstrate that the same parotid gland can host PAs and PA-related tumors with different translocations.

Practice Paradigms Before and After Introduction of the Diagnosis-Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP): an Institutional Experience.

The recently adopted terminology of "Noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) reflects the indolent behavior of these tumors. In contrast to conventional papillary thyroid carcinomas, NIFTP can be managed conservatively. The purpose of this study was to investigate changes in surgical and pathologic practice patterns at our institution since the introduction of the NIFTP diagnosis in 2016. A retrospective analysis of all thyroid specimens received in our laboratory between January 2015 and April 2017 was performed. The final cohort consisted of 1508 thyroidectomy specimens from 1508 patients (1153 (76.5%) women and 355 (23.5%) men), of which 1011 (67%) were total thyroidectomies and 497 (33%) were partial thyroidectomies. There were 558 (69.2%) total thyroidectomies and 248 (30.8%) partial thyroidectomies performed prior to introduction of the NIFTP diagnosis and 453 (64.5%) and 249 (35.5%) total and partial thyroidectomies, respectively, after the change in nomenclature. Within a year following the initial use of this diagnosis, 67 NIFTP cases were identified (9.5% of all thyroidectomies), whereas compared with the year preceding it, malignant diagnoses decreased from 54.5 (439) to 44.6% (313), and the benign category remained unchanged from 44.5 (367) to 45.9% (322). For the entirely submitted 67 NIFTP cases, the mean number of blocks submitted was 14.7 (0.98 blocks/g); for malignant lesions 17.7 (0.92 blocks/g); and for benign lesions 16.6 (0.75 blocks/g). The results of our study suggest that NIFTP are encountered in almost 10% of thyroidectomies at our institution with expected shifts in cytology and surgical pathology diagnoses as a result of the change in nomenclature. During this time period, significant shifts towards less aggressive surgical management were not observed. All 67 NIFTP nodules were submitted entirely with no significant difference in the number of cassettes submitted for NIFTP nodules as compared with follicular variant papillary thyroid carcinoma (PTC), classic variant PTC, or follicular adenoma.

Targeting the Tcf4 G13ANDE17 binding site to selectively disrupt ß-catenin/T-cell factor protein-protein interactions.

Selective disruption of protein-protein interactions by small molecules is important for probing the structure and dynamic aspects of cellular network. It can also provide new therapeutic targets. ß-Catenin of the canonical Wnt signaling pathway uses the same positively charged groove to bind with T-cell factor (Tcf), cadherin, and adenomatous polysis coli (APC). The extravagant formation of ß-catenin/Tcf interactions drives the initiation and progression of many cancers and fibroses, while ß-catenin/cadherin and ß-catenin/APC interactions are essential for cell-cell adhesion and ß-catenin degradation. In this study, a selective binding site that can differentiate ß-catenin/Tcf, ß-catenin/cadherin, and ß-catenin/APC interactions was identified by alanine scanning and biochemical assays. A new peptidomimetic strategy that incorporates SiteMap and multiple-copy simultaneous search was used to design selective small-molecule inhibitors for ß-catenin/Tcf interactions. A potent inhibitor was discovered to bind with ß-catenin and completely disrupt ß-catenin/Tcf interactions. It also exhibits dual selectivity for ß-catenin/Tcf over ß-catenin/cadherin and ß-catenin/APC interactions in both biochemical and cell-based assays. This study provides a proof of concept for designing selective inhibitors for ß-catenin/Tcf interactions.