The Silva pattern-based classification for HPV-associated endocervical adenocarcinoma: A single institution concordance study of trainees and gynecologic pathologists.

The Silva pattern-based classification of HPV-associated endocervical adenocarcinoma has become an integral part of the histologic assessment of these tumors. Unfortunately, the Silva system reproducibility has had mixed results in past studies, and clinical practice still favors the FIGO stage assessment in directing therapeutic interventions for patients. In our study, we aimed to assess our institution's concordance including not only gynecologic pathologists, but also pathology trainees through a series of 69 cases. The grouped total kappa concordance from all participants was 0.439 (Moderate), with an overall trainee kappa of 0.417 (moderate) and an overall pathologist kappa of 0.460 (moderate). Perfect concordance among all 10 study participants was seen in 8/69 cases (11.6 %), corresponding to 5/22 Pattern A cases (22.7 %), 0/16 Pattern B cases (0 %), and 3/31 Pattern C cases (9.7 %), with similar findings between trainees and pathologists when compared within their own cohorts. Recurrence was identified in 2 Pattern A cases, indicating a potential issue with limited excisional specimens which may not fully appreciate the true biologic aggressiveness of the lesions.

Neuropathology of Anti-Amyloid-ß Immunotherapy: A Case Report.

Host responses to anti-amyloid-ß (Aß) antibody therapy are evident in neuroimaging changes and clinical symptoms in a subset of clinical trial subjects receiving such therapy. The pathological basis for the imaging changes and clinical symptoms is not known, nor is the precise mechanism of Aß clearing. We report the autopsy findings in a 65-year-old woman who received three open label infusions of the experimental anti-Aß drug lecanemab over about one month. Four days after the last infusion, she was treated with tissue plasminogen activator for acute stroke symptoms and died several days later with multifocal hemorrhage. Neuropathological examination demonstrated histiocytic vasculitis involving blood vessels with cerebral amyloid angiopathy. Fragmentation and phagocytosis of vascular Aß were present throughout the cerebral cortex. Phagocytosis of parenchymal Aß plaques was noted. Changes suggestive of Aß and phosphorylated tau "clearing" were also noted. The findings overall suggest that anti-Aß treatment stimulated a host response to Aß, i.e., target engagement. The findings also provide evidence that amyloid-related imaging abnormalities might be indicative of an Aß phagocytic syndrome within cerebral vasculature and parenchymal brain tissue in some cases.

Borderline With Bad Behavior: An Unusual Low-grade Serous Carcinoma With Dedifferentiation From a Serous Borderline Tumor.

The pathogenesis of serous ovarian tumors has been extensively investigated, with a dualistic model dividing these cancers into 2 groups. Type I tumors, including low-grade serous carcinoma, is characteristic for concurrent presence of borderline tumors, less atypical cytology, relatively indolent biologic behavior, and molecular aberrations related to the MAPK pathway with chromosomal stability. Meanwhile, type II tumors, such as high-grade serous carcinoma, are notable for no significant association with borderline tumors, higher grade cytology, more aggressive biologic behavior, and TP53 mutations along with chromosomal instability. We describe a case of morphologic low-grade serous carcinoma with focally increased cytologic atypia arising in serous borderline tumors involving both ovaries, which demonstrated highly aggressive behavior despite several years of surgical and chemotherapeutic management. Each recurrent specimen contained more uniform higher grade morphology than what was seen in the original specimen. Immunohistochemical and molecular studies in both the original tumor and the most recent recurrence demonstrate identical mutations in the MAPK genes, but with additional mutations in the latter, notably an acquisition of a variant of possible clinical significance in the SMARCA4 gene, which is associated with dedifferentiation and aggressive biologic behavior. This case challenges our current and still evolving understanding of the pathogenesis, biologic behavior, and expected clinical outcome of low-grade serous ovarian carcinomas. It also underscores the need for further investigation into this complicated tumor.

Placental Pathology After SARS-CoV-2 Infection in the Pre-Variant of Concern, Alpha / Gamma, Delta, or Omicron Eras.

Objectives. The goal of this study is to describe placental pathology after infection with SARS-CoV-2 before the predominance of variants of concern (pre-VOC) and during eras of predominant transmission of the Alpha & Gamma (co-circulating), Delta, and Omicron variants. Methods. We used county-level variant data to establish population-level variant proportions, SARS-CoV-2 PCR to identify cases, and IgG serology to exclude latent infections from controls and histopathologic examination to identify placental pathology. Results. We report findings in 870 placentas from pregnancies complicated by SARS-CoV-2 including 90 with infection in the Alpha/Gamma era, 60 from the Delta era and 56 from the Omicron era. Features of maternal vascular malperfusion (MVM), including decidual arteriopathy, were significantly more frequent after SARS-CoV-2 infection. The risk of these findings varied over time, with the highest rates in the Delta era. Increased COVID-19 severity and the presence of comorbidities strengthened these associations. Conclusion. MVM is a feature of SARS-CoV-2 infection in pregnancy. Lesion frequency changed with the predominant circulating virus and should be considered with new variants.

Maternal Antibody Response and Transplacental Transfer Following Severe Acute Respiratory Syndrome Coronavirus 2 Infection or Vaccination in Pregnancy.

BACKGROUND: Pregnant persons are at increased risk of severe coronavirus disease 2019 (COVID-19) and adverse obstetric outcomes. Understanding maternal antibody response, duration, and transplacental transfer after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 vaccination is important to inform public health recommendations. METHODS: This prospective observational cohort study included 351 pregnant people who had SARS-CoV-2 infection or COVID-19 vaccination during pregnancy. Immunoglobulin (Ig) G and IgM to SARS-CoV-2 S1 receptor binding domain were measured in maternal and cord blood. Antibody levels and transplacental transfer ratios were compared across (1) disease severity for those with SARS-CoV-2 infection and (2) infection versus vaccination. RESULTS: There were 252 individuals with SARS-CoV-2 infection and 99 who received COVID-19 vaccination during pregnancy. Birthing people with more severe SARS-CoV-2 infection had higher maternal and cord blood IgG levels (P = .0001, P = .0001). Median IgG transfer ratio was 0.87-1.2. Maternal and cord blood IgG were higher after vaccination than infection (P = .001, P = .001). Transfer ratio was higher after 90 days in the vaccinated group (P < .001). Modeling showed higher amplitude and half-life of maternal IgG following vaccination (P < .0001). There were no significant differences by fetal sex. CONCLUSIONS: COVID-19 vaccination in pregnancy leads to higher and longer lasting maternal IgG levels, higher cord blood IgG, and higher transfer ratio after 90 days compared with SARS-CoV-2 infection. Greater infection severity leads to higher maternal and cord blood antibodies. Maternal IgG decreases over time following both vaccination and infection, reinforcing the importance of vaccination, even after infection, and vaccine boosters for pregnant patients.

Low-level SARS-CoV-2 viremia coincident with COVID placentitis and stillbirth.

SARS-CoV-2 infection in pregnancy and COVID placentitis are associated with an increased risk of stillbirth. We sought to investigate the presence of maternal viremia in people with SARS-CoV-2 infection during pregnancy who had histologic placentitis versus those without placentitis. SARS-CoV-2 qRT-PCR was performed on plasma from 6 patients with COVID placentitis and 12 matched controls without placentitis. SARS-CoV-2 infection occurred between 4/2020-1/2021; the latency between SARS-CoV-2 diagnosis and delivery was 0-76 days. Two placentitis cases demonstrated viremia (1 stillbirth and 1 well infant), while 12/12 controls were negative. Future research may consider viremia as a possible marker of COVID placentitis.

Maternal vs Fetal Origin of Placental Intervillous Thrombi.

OBJECTIVES: To determine maternal vs fetal origin for blood in placental intervillous thrombi (IVTs). METHODS: We used comparative analysis of microsatellites (short tandem repeats [STRs]), sex chromosome fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC) for fetal (ɑ-fetoprotein [AFP]) and maternal (immunoglobulin M [IgM]) serum proteins to distinguish the origin of IVTs. Using an informatics approach, we tested the association between IVTs and fetomaternal hemorrhage (FMH). RESULTS: In 9 of 10 cases, the preponderance of evidence showed that the thrombus was mostly or entirely maternal in origin. In 1 case, the thrombus was of mixed origins. STR testing was prone to contamination by entrapped fetal villi. FISH was useful but limited only to cases with male fetuses. IgM showed stronger staining than AFP in 9 cases, supporting maternal origin. By informatics, we found no association between IVTs and FMH. CONCLUSIONS: Evidence supports a maternal origin for blood in IVTs. IHC for IgM and AFP may be clinically useful in determining maternal vs fetal contribution to IVTs.

Laboratory analysis of symptomatic and asymptomatic pregnant patients with SARS-CoV-2 infection.

BACKGROUND: Inflammatory biomarkers have been used to portend disease severity in nonpregnant individuals with SARS-CoV-2 infection. However, currently, limited data are available, and with mixed results, to elucidate which inflammatory biomarkers may be most associated with clinical phenotype in pregnant patients. OBJECTIVE: We aimed to compare laboratory findings among pregnant patients with SARS-CoV-2 infection by symptom status and disease severity. STUDY DESIGN: We retrospectively evaluated pregnant patients with positive SARS-CoV-2 infection, confirmed through polymerase chain reaction testing, at an urban academic US hospital between March 2020 and October 2020, performed for reported symptoms or universal screening on admission. In our hospital, all patients with SARS-CoV-2 infection were recommended to have baseline laboratory testing, including leukocyte, neutrophil, and lymphocyte counts; aspartate aminotransferase and alanine aminotransferase; high-sensitivity C-reactive protein; procalcitonin; lactate dehydrogenase; D-dimer; and ferritin. We performed multivariable logistic regression to evaluate peak laboratory abnormalities significantly associated with symptomatic SARS-CoV-2 infection and disease severity with gestational age at diagnosis, maternal age, and obesity as covariates. The sensitivity and specificity of laboratory abnormalities were calculated to identify symptomatic vs asymptomatic infection and severe to critical disease vs mild to moderate disease. RESULTS: We identified 175 pregnant patients with SARS-CoV-2 infection, of whom 100 (57%) were symptomatic; 17 (17%) of those who were symptomatic had a severe to critical disease. Laboratory data were available for 128 patients, of whom 67 (52%) were symptomatic. Compared with asymptomatic individuals, symptomatic individuals were more likely to exhibit elevated high-sensitivity C-reactive protein levels after adjusting for gestational age (adjusted odds ratio, 5.67; 95% confidence interval, 1.42-22.52; sensitivity, 81%; specificity, 43%). In symptomatic individuals, transaminitis (adjusted odds ratio, 5.67; 95% confidence interval, 1.27-25.43), elevated procalcitonin levels (adjusted odds ratio, 16.60; 95% confidence interval, 2.61-105.46), and elevated lactate dehydrogenase levels (adjusted odds ratio, 17.55; 95% confidence interval, 2.51-122.78) were independently associated with severe to critical disease rather than mild to moderate disease after adjusting for maternal age and obesity. For differentiating disease severity, sensitivity rates for transaminitis, procalcitonin elevation, and lactate dehydrogenase elevation were 47%, 87%, and 53%, respectively, whereas the specificity rates were 89%, 63%, and 90%, respectively. CONCLUSION: Inflammatory biomarkers in pregnant patients with SARS-CoV-2 infection exhibited vast heterogeneity, poor discriminative ability, and thereby limited clinical utility. Larger registry studies should evaluate which inflammatory biomarkers may be most useful for risk stratification and prognostication of pregnant patients with SARS-CoV-2 infection, taking into account the physiology of pregnancy.

A Framework for Maintaining a Fully Operational Autopsy Service at a Large Academic Teaching Institution During a Global Pandemic.

The COVID-19 pandemic created new challenges in health care, and pathology departments have led with innovations in testing and education. While the medical community and public showed great interest in gross and histologic findings in COVID-affected patients, paradoxically many autopsy services nationwide closed due to uncertainties surrounding the proximity to infected patient tissue, shortages in personal protective equipment, and pressures to discontinue perceived nonessential hospital operations. These disruptions furthermore negatively impacted pathology trainee education. The autopsy division at Northwestern Memorial Hospital, with the belief that a fully functioning autopsy service is especially crucial at this time, adopted a framework for continuing at full capacity for both clinical care and education. New operations were modeled on national protocols by the Centers for Disease Control and Prevention and the College of American Pathologists, and the service continually adjusted policies to reflect rapidly changing guidelines and feedback from trainees and staff. Between January and December 2020, we performed 182 adult autopsies including 45 COVID-19 autopsies. Twelve residents, 4 staff, and 5 attendings rotated through the service. In exit interviews, participants expressed: (1) improved comfort managing both COVID-related and general autopsies; (2) sense of personal safety on service (despite the increased risk of exposure); (3) belief that both COVID-related and general autopsies contributed to their personal education and to the medical community. There have been zero known autopsy-related COVID-19 infections to date. We hope that our innovative autopsy service restructuring can serve as a framework for other academic programs during the current and in future pandemics.

A Postmortem Portrait of the Coronavirus Disease 2019 (COVID-19) Pandemic: A Large Multi-institutional Autopsy Survey Study.

CONTEXT.­: This study represents the largest compilation to date of clinical and postmortem data from decedents with coronavirus disease 2019 (COVID-19). It will augment previously published small series of autopsy case reports, refine clinicopathologic considerations, and improve the accuracy of future vital statistical reporting. OBJECTIVE.­: To accurately reflect the preexisting diseases and pathologic conditions of decedents with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection through autopsy. DESIGN.­: Comprehensive data from 135 autopsy evaluations of COVID-19-positive decedents is presented, including histologic assessment. Postmortem examinations were performed by 36 pathologists at 19 medical centers or forensic institutions in the United States and Brazil. Data from each autopsy were collected through the online submission of multiple-choice and open-ended survey responses. RESULTS.­: Patients dying of or with COVID-19 had an average of 8.89 pathologic conditions documented at autopsy, spanning a combination of prior chronic disease and acute conditions acquired during hospitalization. Virtually all decedents were cited as having more than 1 preexisting condition, encompassing an average of 2.88 such diseases each. Clinical conditions during terminal hospitalization were cited 395 times for the 135 autopsied decedents and predominantly encompassed acute failure of multiple organ systems and/or impaired coagulation. Myocarditis was rarely cited. CONCLUSIONS.­: Cause-of-death statements in both autopsy reports and death certificates may not encompass the severity or spectrum of comorbid conditions in those dying of or with COVID-19. If supported by additional research, this finding may have implications for public health decisions and reporting moving forward through the pandemic.

Placental pathology in COVID-19.

OBJECTIVES: To describe histopathologic findings in the placentas of women with COVID-19 during pregnancy. METHODS: Pregnant women with COVID-19 delivering between March 18, 2020 and May 5, 2020 were identified. Placentas were examined and compared to historical controls and women with placental evaluation for a history of melanoma. RESULTS: 16 placentas from patients with SARS-CoV-2 were examined (15 with live birth in the 3rd trimester 1 delivered in the 2nd trimester after intrauterine fetal demise). Compared to controls, third trimester placentas were significantly more likely to show at least one feature of maternal vascular malperfusion (MVM), including abnormal or injured maternal vessels, as well as delayed villous maturation, chorangiosis, and intervillous thrombi. Rates of acute and chronic inflammation were not increased. The placenta from the patient with intrauterine fetal demise showed villous edema and a retroplacental hematoma. CONCLUSIONS: Relative to controls, COVID-19 placentas show increased prevalence of features of maternal vascular malperfusion (MVM), a pattern of placental injury reflecting abnormalities in oxygenation within the intervillous space associated with adverse perinatal outcomes. Only 1 COVID-19 patient was hypertensive despite the association of MVM with hypertensive disorders and preeclampsia. These changes may reflect a systemic inflammatory or hypercoagulable state influencing placental physiology.

Placental Pathology in COVID-19.

OBJECTIVES: To describe histopathologic findings in the placentas of women with coronavirus disease 2019 (COVID-19) during pregnancy. METHODS: Pregnant women with COVID-19 delivering between March 18, 2020, and May 5, 2020, were identified. Placentas were examined and compared to historical controls and women with placental evaluation for a history of melanoma. RESULTS: Sixteen placentas from patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were examined (15 with live birth in the third trimester, 1 delivered in the second trimester after intrauterine fetal demise). Compared to controls, third trimester placentas were significantly more likely to show at least one feature of maternal vascular malperfusion (MVM), particularly abnormal or injured maternal vessels, and intervillous thrombi. Rates of acute and chronic inflammation were not increased.The placenta from the patient with intrauterine fetal demise showed villous edema and a retroplacental hematoma. CONCLUSIONS: Relative to controls, COVID-19 placentas show increased prevalence of decidual arteriopathy and other features of MVM, a pattern of placental injury reflecting abnormalities in oxygenation within the intervillous space associated with adverse perinatal outcomes. Only 1 COVID-19 patient was hypertensive despite the association of MVM with hypertensive disorders and preeclampsia. These changes may reflect a systemic inflammatory or hypercoagulable state influencing placental physiology.

Mucinous Ovarian Tumors.

Ovarian mucinous tumors range from benign cystadenomas to borderline tumors to frankly malignant adenocarcinomas, and may display either intestinal-type morphology or, less frequently, endocervical-type differentiation. The latter category has been the subject of recent controversy owing to its morphologic overlap with so-called "seromucinous" ovarian tumors, a group that shares more molecular features with endometrioid tumors than it does with either serous or mucinous ovarian neoplasias. Endocervical-type differentiation in ovarian mucinous tumors may also represent an endocervical metastasis. Distinction of primary ovarian mucinous tumors from gastrointestinal metastases can be difficult, as the morphology of intestinal-type ovarian mucinous primaries sometimes differs only subtly if at all from gastrointestinal metastases.

PD-L1 Expression and Tumor-infiltrating Lymphocytes in Uterine Smooth Muscle Tumors: Implications for Immunotherapy.

Immunotherapies targeting the PD-1/PD-L1 checkpoint axis are of growing interest for the treatment of mesenchymal neoplasms. However, PD-L1 expression and tumor-associated lymphocytes have not been well-investigated in uterine smooth muscle tumors. Forty-nine uterine smooth muscle tumors (23 leiomyosarcomas, 8 smooth muscle tumors of uncertain malignant potential [STUMP], 7 atypical leiomyomas, and 11 benign leiomyomas) were evaluated for tumoral and tumor-associated immune PD-L1 expression and tumor-associated T-cell infiltration. ALK immunohistochemistry was performed to exclude inflammatory myofibroblastic tumors. Tumor PD-L1 expression was seen in 70% of leiomyosarcomas and 14% of atypical leiomyomas; no cases of STUMP or benign leiomyoma demonstrated tumoral PD-L1. PD-L1 positivity was seen in tumor-associated immune cells in 78% of leiomyosarcomas, 25% of STUMP, no cases of atypical leiomyomas, and 9% of benign leiomyomas. Of the 23 leiomyosarcomas, 15 (65%) had a combined positive score ≥1, while of the 26 other uterine smooth muscle tumors, only 2 (8%) had a combined positive score ≥1. Tumor-associated CD8+ cells were highest among leiomyosarcomas (mean: 87/high-power fields vs. 17/high-power fields for nonleiomyosarcomas), and were significantly associated with PD-L1 expression. One PD-L1, CD8-enriched leiomyosarcoma showed an ALK overexpression suggesting possible classification as inflammatory myofibroblastic tumor, but otherwise lacked morphologic features of this entity. Leiomyosarcomas demonstrate significantly higher PD-L1 expression and cytotoxic T-cell infiltration when compared with other uterine smooth muscle tumors. These data suggest the possibility that treatment with targeted immunotherapy may be appropriate in a selected population of patients with leiomyosarcoma and, potentially, in related tumors bearing ALK rearrangements.

Recurrent Non Immune Fetal Hydrops Associated With IPEX Syndrome.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is a clinical syndrome associated with mutations in FOXP3 and consequent abnormalities of T regulatory cells. Affected males typically die in infancy or early childhood from a variety of autoimmune conditions. Reports of recurrent pregnancy loss of male fetuses in these families have been accompanied by descriptions of nonimmune fetal hydrops, with or without additional fetal anomalies. Here, we report an additional family affected by IPEX with a novel mutation leading to recurrent second trimester fetal hydrops and intrauterine fetal demise with associated fetal anomalies. This report underscores how careful genetic and pathologic analysis of even midtrimester fetuses can provide important information impacting an entire family. It also further substantiates the use of broad, symptom-targeted genetic screening panels in cases of recurrent pregnancy loss even in the absence of a remarkable pedigree.

A New Era in Pathology Consultation: The MyPathologist Electronic Consultation Tool.

Pathologists and laboratory scientists provide valuable guidance on laboratory utilization, test ordering, interpretation, and quality control provided that clinical staff can easily access the laboratory team. To encourage consultation between clinicians with laboratory scientists and pathologists, we developed an easily accessible electronic tool termed "MyPathologist," placed on the homepage of our electronic health record system. Over its 2-year pilot, utilization of this consultation tool climbed as we continued to publicize it and incorporated education into housestaff onboarding and electronic health record training. Physician satisfaction with the tool was high. Additionally, this became the primary source of consults to our residency call service. Evaluation of MyPathologist questions received during its pilot period showed that more than half the questions were of significant educational value to the residents, often focusing on results interpretation, appropriate test ordering, and quality control. MyPathologist is a novel electronic tool for pathology consultation within our electronic health record and also represents an avenue for educating residents, improving utilization of the laboratory, and improving patient care.