Search

Cancer immunotherapy provides durable clinical benefit in only a small fraction of patients, and identifying these patients is difficult due to a lack of reliable biomarkers for prediction and evaluation of treatment response. Here, we demonstrate the first application of label-free Raman spectroscopy for elucidating biomolecular changes induced by anti–CTLA4 and anti–PD-L1 immune checkpoint inhibitors (ICI) in the tumor microenvironment (TME) of colorectal tumor xenografts. Multivariate curve resolution–alternating least squares (MCR-ALS) decomposition of Raman spectral datasets revealed early changes in lipid, nucleic acid, and collagen content following therapy. Support vector machine classifiers and random forests analysis provided excellent prediction accuracies for response to both ICIs and delineated spectral markers specific to each therapy, consistent with their differential mechanisms of action. Corroborated by proteomics analysis, our observation of biomolecular changes in the TME should catalyze detailed investigations for translating such markers and label-free Raman spectroscopy for clinical monitoring of immunotherapy response in cancer patients.Significance:This study provides first-in-class evidence that optical spectroscopy allows sensitive detection of early changes in the biomolecular composition of tumors that predict response to immunotherapy with immune checkpoint inhibitors.

Supplementary figures S1 and S2 and supplementary tables ST1 and ST2

Supplemental data regarding cecum morphology, body weights, adhesion molecule expression in spleen and thymus, spleen size, tumor and stroma cell viability, and IFN-g and VEGF serum levels after induction of dysbiosis.

SF1: Tumor growth assays for lung and HN tumors. SF2: The complete set of MCR-derived pure component spectra and tables listing their peak assignments. SF3: Representative MCR score maps for lung and HN tumor datasets. SF4: Histologic images for HN tumor dataset. TS1-4: Results of binary leave-one-mouse-out SVM analyses.

Delay in the assessment of tumor response to radiotherapy continues to pose a major challenge to quality of life for patients with nonresponsive tumors. Here, we exploited label-free Raman spectroscopic mapping to elucidate radiation-induced biomolecular changes in tumors and uncovered latent microenvironmental differences between treatment-resistant and -sensitive tumors. We used isogenic radiation-resistant and -sensitive A549 human lung cancer cells and human head and neck squamous cell carcinoma (HNSCC) cell lines (UM-SCC-47 and UM-SCC-22B, respectively) to grow tumor xenografts in athymic nude mice and demonstrated the molecular specificity and quantitative nature of Raman spectroscopic tissue assessments. Raman spectra obtained from untreated and treated tumors were subjected to chemometric analysis using multivariate curve resolution-alternating least squares (MCR-ALS) and support vector machine (SVM) to quantify biomolecular differences in the tumor microenvironment. The Raman measurements revealed significant and reliable differences in lipid and collagen content postradiation in the tumor microenvironment, with consistently greater changes observed in the radiation-sensitive tumors. In addition to accurately evaluating tumor response to therapy, the combination of Raman spectral markers potentially offers a route to predicting response in untreated tumors prior to commencing treatment. Combined with its noninvasive nature, our findings provide a rationale for in vivo studies using Raman spectroscopy, with the ultimate goal of clinical translation for patient stratification and guiding adaptation of radiotherapy during the course of treatment.Significance:These findings highlight the sensitivity of label-free Raman spectroscopy to changes induced by radiotherapy and indicate the potential to predict radiation resistance prior to commencing therapy.

The overall use of antibiotics has increased significantly in recent years. Besides fighting infections, antibiotics also alter the gut microbiota. Commensal bacteria in the gastrointestinal tract are crucial to maintain immune homeostasis, and microbial imbalance or dysbiosis affects disease susceptibility and progression. We hypothesized that antibiotic-induced dysbiosis of the gut microbiota would suppress cytokine profiles in the host, thereby leading to changes in the tumor microenvironment. The induced dysbiosis was characterized by alterations in bacterial abundance, composition, and diversity in our animal models. On the host side, antibiotic-induced dysbiosis caused elongated small intestines and ceca, and B16-F10 melanoma and Lewis lung carcinoma progressed more quickly than in control mice. Mechanistic studies revealed that this progression was mediated by suppressed TNFα levels, both locally and systemically, resulting in reduced expression of tumor endothelial adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1) and a subsequent decrease in the number of activated and effector CD8+ T cells in the tumor. However, suppression of ICAM-1 or its binding site, the alpha subunit of lymphocyte function-associated antigen-1, was not seen in the spleen or thymus during dysbiosis. TNFα supplementation in dysbiotic mice was able to increase ICAM-1 expression and leukocyte trafficking into the tumor. Overall, these results demonstrate the importance of commensal bacteria in supporting anticancer immune surveillance, define an important role of tumor endothelial cells within this process, and suggest adverse consequences of antibiotics on cancer control.Significance:Antibiotic-induced dysbiosis enhances distal tumor progression by altering host cytokine levels, resulting in suppression of tumor endothelial adhesion molecules and activated and effector CD8+ T cells in the tumor.

Endometriosis (ENDO) is a chronic estrogen-dependent gynecological condition that affects reproductive-age women, causing pelvic pain, infertility, and increased risk for ovarian cancer. Diabetes mellitus (DM) is a metabolic disease with significant morbidity and mortality and rising incidence worldwide. The occurrence of DM among ENDO patients remains understudied, despite commonalities in these conditions’ immune, inflammatory, and metabolic dysfunctions. This pilot study evaluated whether a subset of women with ENDO manifests DM co-morbidity and if so, whether DM promotes ENDO status. Archived ectopic lesions obtained at ENDO surgery from non-diabetic (ENDO-N; n = 11) and diabetic (ENDO-DM; n = 15) patients were identified by a search of an electronic health database. Retrieved samples were analyzed by immunohistochemistry for markers of proliferation (Ki67, PTEN), steroid receptor signaling (ESR, PGR) and macrophage infiltration (CD68). Immunostaining data were expressed as percentages of immune-positive cells in lesion stroma and epithelium. In lesion stroma, the percentages of nuclear immune-positive cells were higher for ESR2 and lower for PGR-T, in ENDO-DM than ENDO-N patients. The percentages of nuclear immune-positive cells for ESR1 and PTEN tended to be higher and lower, respectively, in ENDO-DM than ENDO-N groups. In lesion glandular epithelium, the percentages of nuclear immune-positive cells were higher for ESR1 and ESR2, in ENDO-DM than ENDO-N groups. ENDO-N lesions had lower percentages of stromal CD68 immune-positive cells than ENDO-DM Type 1 lesions. Findings demonstrate DM in a subset of women with ENDO, which was associated with significant changes in lesion stromal and epithelial nuclear steroid hormone receptor levels, suggestive of disease progression.

Sebaceous carcinoma (SC) is a malignant neoplasm demonstrating sebocytic differentiation, commonly in the periocular area. Sebocytic differentiation is recognized by multivesicular cytoplasmic clearing with frequent nuclear scalloping. The vesicles can be highlighted by immunohistochemical stains against the perilipin family proteins including adipophilin. Extraocular SC is uncommon but well reported, often in the setting of Muir-Torre syndrome; however, vulvar SC is exceptionally rare. The literature review yielded only 12 prior cases of vulvar SC, all of which showed invasion. Here we report 2 additional similar cases from 2 different institutions of an intraepithelial carcinoma with sebaceous differentiation. Histologic examination of multiple specimens from both patients showed similar features: a multifocal intraepithelial basaloid nodular neoplasm sparing the basal layer with occasional pagetoid spread. The tumor cells demonstrated a high nuclear to cytoplasmic ratio, mitoses, variably foamy vacuolated cytoplasm, and nuclear indentation. Multiple specimens from both patients showed evidence of sebaceous differentiation (substantiated by adipophilin positivity in a membranous vesicular pattern in case 1 and by androgen receptor and epithelial membrane antigen positivity in case 2), and squamous differentiation (substantiated by p63/p40 and weak CK 5/6 expression), as well as human papillomavirus (HPV) association (substantiated by p16 block positivity and detection of high-risk HPV by in situ hybridization). One case was a true in situ lesion without evidence of invasion, and the other case was predominantly an in situ carcinoma with prominent adnexal extension and focal superficial invasion of1 mm seen in one of multiple specimens. To our knowledge, these 2 cases are the first to show a vulvar SC/carcinoma with sebaceous differentiation that is predominantly limited to the epidermis, and the first documentation of HPV infection in vulvar sebaceous neoplasms. Vulvar intraepithelial carcinoma with sebaceous differentiation is the umbrella term we chose for this entity. Whether this is a true SC in situ that is HPV positive/driven, or a vulvar intraepithelial neoplasia with sebaceous differentiation, is not entirely clear. We emphasize the importance of looking for this morphology to avoid misclassification. Due to the rarity of cases, optimal treatment at this site has not been established.

The purpose to the study was to determine the relationship, if any, between the placental location site and antepartum complications of pregnancy. A University research librarian conducted a comprehensive literature search using the search engines PubMed and Web of Science. The search terms were “placental location” AND “pregnancy complications” OR “perinatal complications. There were no limits put on the years of the search. The search identified 110 articles. After reviewing all the abstracts, relevant full articles, and references of full articles, there were 22 articles identified specific to antepartum complications. Central + fundal locations compared to all lateral were associated with a lower risk of hypertension during pregnancy RR = 0.47, 95% CI: 0.31–0.71]. Central location compared to all lateral was also associated with lower risk of hypertension during pregnancy [RR = 0.39, 95% CI: 0.26–0.59]. Placenta locations in the lower uterine segment were associated with greater risk of antepartum hemorrhage (APH) [RR = 2.99, 95% CI: 1.16–7.75] compared to above the lower uterine segment. No differences were observed in placental locations and gestational diabetes (GDM), preterm prelabor rupture of membranes (PPROM), preterm delivery (PTD) or on a placental abruption. Central and fundal location sites and central location alone decreased the risk of hypertension during pregnancy. Low uterine segment location sites increased the risk for APH. There were no effects of placenta location sites on the development of GDM, PPROM, PTD or abruption.

Context.— Vulvar biopsy interpretation and reporting, particularly of vulvar dermatoses, can be challenging in daily practice for both surgical pathologists (SPs) and dermatopathologists (DPs). Objective.— To investigate whether prospective consensus reporting of vulvar biopsies by SPs and DPs would provide value and improve overall diagnostic concordance. Design.— Consecutive vulvar biopsies during a 6-month period were reviewed prospectively by both gynecologic SPs and DPs. Preliminary, independently generated diagnoses were recorded and then shared in consensus review (SPs+DPs). A third pathologist adjudicated cases without consensus. Multiple data elements were collected for each case: division (SP/DP), age, site, clinical history, diagnostic category, preliminary and final (consensus) diagnosis, need for adjudication, ancillary tests, and diagnostic discrepancy. Results.— Eighty-four biopsies (48 SP, 36 DP) from 70 patients were reviewed. Forty-two of 84 cases (50%) were neoplastic, 38 of 84 (45%) were reactive/inflammatory, with the remaining (5%) showing both or other features. Independent diagnoses were discrepant in 22 of 84 cases (26%), but consensus review resulted in an agreed-upon diagnosis in all cases, with adjudication required in 6 cases. Independent diagnostic agreement increased over time with a reduction in major and minor discrepancies between the first and second half of the study period. Conclusions.— Prospective review of vulvar biopsies by both SPs and DPs can improve overall reporting. Consensus review allows pathologists to gain diagnostic confidence in interpretation of inflammatory (for SPs) and neoplastic (for DPs) vulvar biopsies; therefore, intradepartmental consultation is of value, particularly in select cases.

Among SGA newborns, those5th % for GA are more likely to have adverse outcomes than those at 5-9th %. The differential morbidity and mortality may be due to abnormal placental pathology between groups. Our purpose was to compare placental pathology characteristics and composite placental pathology among SGA infants with birth weights5th % vs. 5-9th %.This study is a secondary analysis of a multicenter, retrospective cohort study. Placental pathological variables and composite placental pathology (CPP) among SGA infants5th % and 5-9th % were compared. Multivariable logistic regression was used to model the probability of an infant's birth weight being classified as5th % based on pathology characteristics.Of 11,487 live singleton births, 925 SGA infants met inclusion criteria. Placental pathology was available for review in 407 (44 %) SGA infants: 210 (51.6 %)5th % and 197 (48.4 %) 5-9th %. A decreased placental weight for GA, was more common in the5th % group compared to the 5-9th % group (p = 0.0019). No significant differences in the distribution of pathological variables or in CPP (p = 0.3) was observed between the two centile groups. A decreased placental weight was the only reliable predictor of an infant's birth weight centile group (p = 0.0018).Placental hypoplasia, reflected by a decreased placental weight for GA, was significantly more common among SGA infants5th % compared to the 5-9th %. There was no difference in placental pathological features or CPP between the two centile groups of SGA infants.

Metformin (MET) is increasingly implicated in reducing the incidence of multiple cancer types in patients with diabetes. However, similar effects of MET in non-diabetic women with endometrial cancer (EC) remain unknown. In a pilot study, obese non-diabetic women diagnosed with type 1, grade 1/2 EC, and consenting to participate were randomly assigned to receive MET or no MET (control (CON)) during the pre-surgical window between diagnosis and hysterectomy. Endometrial tumors obtained at surgery (MET, n = 4; CON, n = 4) were analyzed for proliferation (Ki67), apoptosis (TUNEL), and nuclear expression of ERα, PGR, PTEN, and KLF9 proteins in tumor glandular epithelial (GE) and stromal (ST) cells. The percentages of immunopositive cells for PGR and for KLF9 in GE and for PTEN in ST were higher while those for ERα in GE but not ST were lower, in tumors of MET vs. CON patients. The numbers of Ki67- and TUNEL-positive cells in tumor GE and ST did not differ between groups. In human Ishikawa endometrial cancer cells, MET treatment (60 μM) decreased cell numbers and elicited distinct temporal changes in ESR1, KLF9, PGR, PGR-B, KLF4, DKK1, and other tumor biomarker mRNA levels. In the context of reduced KLF9 expression (by siRNA targeting), MET rapidly amplified PGR, PGR-B, and KLF4 transcript levels. Our findings suggest that MET acts directly in EC cells to modify steroid receptor expression and signaling network and may constitute a preventative strategy against EC in high-risk non-diabetic women.

Type 1 diabetes mellitus and endometriosis separately affect millions of women worldwide. Reproductive-age women diagnosed with type 1 diabetes may also suffer from endometriosis, but the asymptomatic pre-clinical period of highly variable duration for each condition can lead to challenges in the timely recognition of co-morbid disease onset and misdiagnosis. While knowledge of the pathogenesis of each condition has grown substantially, co-morbid endometriosis and type 1 diabetes has not been widely considered and much less addressed. This review discusses the molecular rationale for the likelihood of their co-existence, and prospects for improvements in therapeutic strategies and reduced complications, if this paradigm is included as a significant variable in disease management.

Cancer immunotherapy provides durable clinical benefit in only a small fraction of patients, and identifying these patients is difficult due to a lack of reliable biomarkers for prediction and evaluation of treatment response. Here, we demonstrate the first application of label-free Raman spectroscopy for elucidating biomolecular changes induced by anti–CTLA4 and anti–PD-L1 immune checkpoint inhibitors (ICI) in the tumor microenvironment (TME) of colorectal tumor xenografts. Multivariate curve resolution–alternating least squares (MCR-ALS) decomposition of Raman spectral datasets revealed early changes in lipid, nucleic acid, and collagen content following therapy. Support vector machine classifiers and random forests analysis provided excellent prediction accuracies for response to both ICIs and delineated spectral markers specific to each therapy, consistent with their differential mechanisms of action. Corroborated by proteomics analysis, our observation of biomolecular changes in the TME should catalyze detailed investigations for translating such markers and label-free Raman spectroscopy for clinical monitoring of immunotherapy response in cancer patients.Significance:This study provides first-in-class evidence that optical spectroscopy allows sensitive detection of early changes in the biomolecular composition of tumors that predict response to immunotherapy with immune checkpoint inhibitors.

Advances in high-throughput sequencing have revolutionized the manner with which we can study T cell responses. We describe a woman who received a human papillomavirus (HPV) therapeutic vaccine called PepCan, and experienced complete resolution of her cervical high-grade squamous intraepithelial lesion. By performing bulk T cell receptor (TCR) β deep sequencing of peripheral blood mononuclear cells before and after 4 vaccinations, 70 putatively vaccine-specific clonotypes were identified for being significantly increased using a beta-binomial model. In order to verify the vaccine-specificity of these clonotypes, T cells with specificity to a region, HPV 16 E6 91-115, previously identified to be vaccine-induced using an interferon-γ enzyme-linked immunospot assay, were sorted and analyzed using single-cell RNA-seq and TCR sequencing. HPV specificity in 60 of the 70 clonotypes identified to be vaccine-specific was demonstrated. TCR β bulk sequencing of the cervical liquid-based cytology samples and cervical formalin-fixed paraffin-embedded samples before and after 4 vaccinations demonstrated the presence of these HPV-specific T cells in the cervix. Combining traditional and cutting-edge immunomonitoring techniques enabled us to demonstrate expansion of HPV-antigen specific T cells not only in the periphery but also in the cervix. Such an approach should be useful as a novel approach to assess vaccine-specific responses in various anatomical areas.

Team-Based Learning (TBL) has focused largely on teaching faculty to develop lessons and help learners apply content. TBL literature has overlooked providing guidance or training in quality assurance. In this study, we describe a single institution’s experience with successfully shifting to the TBL model from a traditionally didactic curriculum. A faculty peer review program (FPRP) was instituted to assure that faculty developed quality TBLs and facilitated them according to their training. The transition from didactics to TBL was facilitated by (1) TBL faculty training, (2) development of a peer review committee, and (3) implementation of the FPRP. Following the implementation of the FPRP, students combined mean scores on major shelf exams in Biochemistry increased from 76.9 to 84.1%; Cell Biology, from 77.5 to 82.5%. Their National Board of Medical Examiners Biochemistry shelf exam mean scores increased from 52.4 to 60.8%; overall percentile ranking increased from the 59th to the 85th percentile. The FPRP proved to be integral to TBL faculty development and curricular change efforts. In a survey issued only to faculty who used the TBL model, they expressed appreciation for the FPRP and identified it as a contributing factor in the successful transition to the new TBL curriculum. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40670-019-00735-z) contains supplementary material, which is available to authorized users.

Highlights • Sertoli-Leydig cell tumor and gynandroblastoma are rare ovarian sex cord-stromal tumors that warrant germline DICER1 testing. • DICER1 mutations are associated with an increased risk of various benign and malignant tumors especially during childhood. • Childhood genetic testing is controversial but provides earlier screening and diagnosis in DICER1 mutation patients., Sex cord-stromal tumors (SCSTs) are ovarian tumors that generally present with an adnexal mass and signs/symptoms of hormone excess. Gynandroblastoma is a rare subtype of SCST with a combination of female and male sex cord differentiation. These tumors typically present in premenopausal women and are diagnosed at early stages with benign clinical courses. Here, we present a rare case of recurrent gynandroblastoma in a premenopausal woman with a DICER1 germline mutation. The patient was referred to our clinic for new symptoms of hormonal imbalance with a history of ovarian juvenile granulosa cell tumor (JGCT). Evaluation revealed a 5x5cm complex right adnexal mass and rising inhibin B. Patient underwent total abdominal hysterectomy with right salpingo-oophorectomy, omentectomy and right pelvic and para-aortic lymphadenectomy. Pathology showed a right ovarian gynandroblastoma. Somatic biallelic mutations in the RNase IIIb domain of DICER1 were identified; a 23-gene germline panel confirmed a germline DICER1 pathogenic variant. Cascade testing of her children documented that both daughters inherited the pathogenic variant. Testing for DICER1 mutations has important implications for individual and familial tumor risk assessment given what we know about DICER1 mutation and increased childhood cancer risk.

Immune checkpoint inhibitors have revolutionized cancer treatment. However, there are currently no methods for noninvasively and nondestructively evaluating tumor response to immune checkpoint inhibitors. We used diffuse reflectance spectroscopy to monitor in vivo tumor microenvironmental changes in response to immune checkpoint inhibitors in a CT26 murine colorectal cancer model. Mice growing CT26 tumor xenografts were treated with either anti-PD-L1, anti-CTLA-4, a combination of both inhibitors, or isotype control on 3 separate days. Monotherapy with either anti-PD-L1 or anti-CTLA-4 led to a large increase in tumor vascular oxygenation within the first 6 days. Reoxygenation in anti-CTLA-4-treated tumors was due to a combination of increased oxygenated hemoglobin and decreased deoxygenated hemoglobin, pointing to a possible change in tumor oxygen consumption following treatment. Within the anti-PD-L1-treated tumors, reoxygenation was primarily due to an increase in oxygenated hemoglobin with the minimal change in deoxygenated hemoglobin, indicative of a likely increase in tumor perfusion. The tumors in the combined treatment group did not show any significant changes in tumor oxygenation following therapy. These studies demonstrate the sensitivity of diffuse reflectance spectroscopy to tumor microenvironmental changes following immunotherapy and the potential of such non-invasive techniques to determine early tumor response to immune checkpoint inhibitors.

In this review, we highlight the benign and premalignant lesions of the endometrium that the pathologist may encounter in daily practice. We begin by detailing our current understanding of excess estrogen in the progression of endometrial neoplasia. We outline the currently accepted terminology to be used when evaluating proliferative endometrial lesions, while highlighting their key features. Attention is then turned to the molecular underpinnings of neoplastic progression and how this can be exploited with immunohistochemical stains when appropriate. Finally, we discuss types of metaplasia and their associations, including so-called papillary proliferations of the endometrium.

Endometrial clear cell carcinoma (ECCC) is an uncommon histotype without unique identified molecular alterations. Recently, The Cancer Genome Atlas molecular subtypes have been reported in ECCC. ECCC cases were collected from 11 institutions with diagnoses confirmed by morphologic review and immunohistochemistry. DNA mismatch repair (MMR) proteins, p53 expression, and ARID1A expression was assessed by immunohistochemistry on tissue microarrays. Targeted next-generation sequencing was completed for POLE, TP53, KRAS, and PIK3CA. Pathogenicity of mutations was determined using MutationTaster and PolyPhen databases. For p53, immunohistochemistry and sequencing were complimentarily used to assess the p53 status. Of 57 cases, 46 were considered prototypical ECCC by morphology and immunohistochemical profile (Napsin A-positive and ER-negative). Three cases were excluded because of insufficient sample for complete immunohistochemical analysis, and 6 had failed sequencing, resulting in 37 cases. Of the 37 remaining cases, 6/37 (16%) had predicted pathogenic mutations in the exonuclease domain of POLE with an allelic frequency >10%; however, no hot-spot mutations were identified. No cases were MMR-deficient. The gene most commonly affected was TP53 (59%, 22/37), followed by KRAS (13%, 2/15) and PIK3CA (13%, 2/15). The current study is the largest molecular analysis of pure ECCC reported to date. When strict classification criteria are applied, MMR-deficient and POLE mutated subtypes are not represented. Further consensus on what represents a deleterious POLE mutations is needed. The findings support separately studying histologically/immunohistochemically defined ECCC to identify characteristic molecular alterations in future studies.

The crosstalk between the microbiota and the host is crucial to maintaining immune homeostasis. A growing body of evidence shows that microbial imbalance affects cancer susceptibility and progression. A common significant influence on the microbiota in the gastrointestinal (GI) tract is the use of antibiotics. Oral antibiotics severely alter the bacteria in the GI tract by destroying beneficial bacteria alongside pathogenic ones — producing a state of microbial imbalance called dysbiosis. The overall use of antibiotics has increased by more than 30% in recent years, and moreover, many cancer patients are prescribed antibiotics during treatment, as infection is frequently a complication. We hypothesized that antibiotic-induced dysbiosis of the gut microbiota would suppress cytokine profiles in the host, thereby causing stromal immune surveillance suppression. We found that antibiotics as well as tumorigenesis caused changes in the bacterial abundance, composition, or diversity in the GI tract. On the host side, we found that antibiotic-induced dysbiosis caused the small intestine and cecum to enlarge and elongate, yet the colon was not affected. Moreover, B16-F10 melanoma and Lewis Lung carcinoma progressed more quickly during dysbiosis. Mechanistically, tumor progression was mediated by suppressed TNF-α levels, both locally and systemically. In contrast, IFN-γ and VEGF did not change significantly during dysbiosis. The suppressed levels of TNF-α, a pleiotropic regulator of intercellular adhesion molecule-1 (ICAM-1), resulted in reduced expression of tumor endothelial cell associated ICAM-1, and a subsequent decrease in the number of activated and effector CD8+ T-cells in the tumor. However, suppression of ICAM-1 or its binding site, the alpha subunit of lymphocyte function-associated antigen-1 (LFA-1), was not seen in established vasculature during dysbiosis as assessed in the spleen or the thymus. While dysbiosis enhanced tumor growth in ICAM-1+/+ and immunocompetent mice, it did not affect tumor growth in ICAM-1-/- or T-cell deficient mice, highlighting the influence and impact of dysbiosis on T-cell trafficking and extravasation. TNF-α supplementation in dysbiotic mice was able to overcome the dysbiosis-induced suppression as evident by increased ICAM-1 expression, leukocyte trafficking and tumor growth inhibition. Overall, these results demonstrate the importance of commensal bacteria in supporting immune surveillance and expand our understanding of the crosstalk between the gut microbiome and the stroma in distal non-GI tract tumors. Moreover, this knowledge has the potential to influence clinical decision-making when treating patients for solid cancers with dysbiosis-inducing antibiotics and may further inform concurrent and (neo-)adjuvant treatments to overcome the adverse effects of the antibiotics. Citation Format: Samir V. Jenkins, Michael S. Robeson, Eric R. Siegel, Charles M. Quick, Robert J. Griffin, Martin J. Cannon, Kieng B. Vang, Ruud P. Dings. T-cell trafficking and extravasation is suppressed in distal tumors during gastrointestinal tract dysbiosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3529.

Uterine leiomyosarcomas (uLMS) are aggressive tumors arising from the smooth muscle layer of the uterus. We analyzed 83 uLMS sample genetics, including 56 from Yale and 27 from The Cancer Genome Atlas (TCGA). Among them, a total of 55 Yale samples including two patient-derived xenografts (PDXs) and 27 TCGA samples have whole-exome sequencing (WES) data; 10 Yale and 27 TCGA samples have RNA-sequencing (RNA-Seq) data; and 11 Yale and 10 TCGA samples have whole-genome sequencing (WGS) data. We found recurrent somatic mutations in TP53, MED12, and PTEN genes. Top somatic mutated genes included TP53, ATRX, PTEN, and MEN1 genes. Somatic copy number variation (CNV) analysis identified 8 copy-number gains, including 5p15.33 (TERT), 8q24.21 (C-MYC), and 17p11.2 (MYOCD, MAP2K4) amplifications and 29 copy-number losses. Fusions involving tumor suppressors or oncogenes were deetected, with most fusions disrupting RB1, TP53, and ATRX/DAXX, and one fusion (ACTG2-ALK) being potentially targetable. WGS results demonstrated that 76% (16 of 21) of the samples harbored chromoplexy and/or chromothripsis. Clinically actionable mutational signatures of homologous-recombination DNA-repair deficiency (HRD) and microsatellite instability (MSI) were identified in 25% (12 of 48) and 2% (1 of 48) of fresh frozen uLMS, respectively. Finally, we found olaparib (PARPi; P = 0.002), GS-626510 (C-MYC/BETi; P < 0.000001 and P = 0.0005), and copanlisib (PIK3CAi; P = 0.0001) monotherapy to significantly inhibit uLMS-PDXs harboring derangements in C-MYC and PTEN/PIK3CA/AKT genes (LEY11) and/or HRD signatures (LEY16) compared to vehicle-treated mice. These findings define the genetic landscape of uLMS and suggest that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs.

Cannabidiol (CBD) is a biologically active, non-psychotropic component of Cannabis sativa whose popularity has grown exponentially in recent years. Besides a wealth of potential health benefits, ingestion of CBD poses risks for a number of side effects, of which hepatotoxicity and CBD/herb-drug interactions are of particular concern. Here, we investigated the interaction potential between the cannabidiol-rich cannabis extract (CRCE) and methylsulfonylmethane (MSM), a popular dietary supplement, in the mouse model. For this purpose, 8-week-old male C57BL6/J mice received MSM-containing water (80 mg/100 mL) ad libitum for 17 days. During the last three days of treatment, mice received three doses of CRCE administered in sesame oil via oral gavage (123 mg/kg/day). Administration of MSM alone did not result in any evidence of liver toxicity and did not induce expression of mouse cytochrome P450 (CYP) enzymes. Administration of CRCE did produce significant (p &lt, 0.05) increases in Cyp1a2, Cyp2b10, Cyp2c29, Cyp3a4, Cyp3a11, Cyp2c65, and Cyp2c66 messenger RNA, however, this effect was not amplified by MSM/CRCE co-treatment. Similarly, no evidence of liver toxicity was observed in MSM/CRCE dosed mice. In conclusion, short-term MSM/CRCE co-administration did not demonstrate any evidence of hepatotoxicity in the mouse model.

Beta-catenin (BC) mutations are associated with a high risk of recurrence in otherwise low-grade, early-stage uterine endometrioid adenocarcinomas. Recent literature suggests nuclear BC expression by immunohistochemistry is highly sensitive and specific for BC mutations. The significance of BC expression in endometrioid intraepithelial neoplasia (EIN/atypical hyperplasia) and its relationship to altered differentiation patterns in EIN has yet to be fully explored. Cases meeting current diagnostic criteria for EIN based on H&E examination were obtained from 2 institutions (years 1999-2014). Patterns of altered differentiation (eg, tubal, squamous morular metaplasia, mucinous, secretory) were noted. Representative blocks were stained for BC, and expression patterns recorded. Follow-up and demographic data was obtained from the electronic medical record. Ninety-six cases were included (84 biopsies, 12 hysterectomies). BC nuclear expression was identified in 41 cases (42.7%), with 33 of 41 demonstrating foci of nonmorular BC staining. BC staining in any component of EIN was not significantly associated with the presence of carcinoma on subsequent hysterectomy (P=0.79). When restricting to nonmorular BC, the results were the same (P=0.56). Cases with tubal differentiation were significantly less likely to demonstrate nonmorular BC than cases with no specific pattern of differentiation (P

The combination of radiotherapy and immunotherapy may generate synergistic anti-tumor host immune responses and promote abscopal effects. Spatial fractionation of a radiation dose has been found to promote unique physiological responses of tumors, which might promote synergy with immunotherapy. To determine whether spatial fractionation may augment immune activity, whole-tumor or spatial fractionation grid radiation treatment (GRID) alone or in combination with antibodies against immune checkpoints PD1 and CTLA-4 were tested in an immunocompetent mouse model using a triple negative breast tumor (4T1). Tumor growth delay, immuno-histochemistry and flow cytometry were used to characterize the effects of each treatment type. Whole-beam radiation with immune checkpoint inhibition significantly restrained tumor growth in the irradiated tumor, but not abscopal tumors, compared to either of these treatments alone. In mice that received spatially fractionated irradiation, evidence of abscopal immune responses were observed in contralateral tumors with markedly enhanced infiltration of both antigen-presenting cells and activated T cells, which were preceded by increased systemic IFNγ production and led to eventual tumor growth delay. These studies suggest that systemic immune activation may be triggered by employing GRID to a primary tumor lesion, promoting anti-tumor immune responses outside the treatment field. Interestingly, PD-L1 was found to be upregulated in abscopal tumors from GRID-treated mice. Combined radio-immunotherapy therapy is becoming a validated and novel approach in the treatment of cancer. With the potential increased benefit of GRID to augment both local and metastatic disease responses, further exploration of GRID treatment as a part of current standards of care is warranted.

To evaluate placental abnormalities in pregnancies affected by diabetes compared to unaffected pregnancies from a single academic center.This is a retrospective cohort study of women with singleton gestations delivered at the University of Arkansas for Medical Sciences from 2007 to 2016. Pathologic examination of placentas from pregestational and gestational diabetic pregnancies were compared to placentas from patients without diabetes using 12 histologic elements. Maternal and neonatal outcomes were extracted from the medical record and compared between groups. Findings were adjusted for hypertensive disorders of pregnancy. Placental lesions were also correlated with diabetic control.Pathology reports of 590 placentas along with corresponding medical records were reviewed. The diabetic group (Accelerated villous maturation was found to be more frequent in pregnancies complicated by pregestational diabetes, even after controlling for hypertension. In pregnancies complicated by gestational diabetes, the placental findings were not significant after controlling for hypertension. In contrast with prior studies, there was no increase in thrombotic lesions of the placenta in patients with diabetes.

Cannabidiol (CBD) is the major non-psychotropic phytocannabinoid present in Cannabis sativa. In 2018, Congress designated certain C. sativa plant material as “hemp”, thus removing it from the DEA’s list of controlled substances. As a result, CBD-containing hemp extracts and other CBD products are now widely available and heavily marketed, yet their FDA regulatory status is still hotly debated. The goal of this study was to investigate the effects of a cannabidiol-rich cannabis extract (CRCE) on the gut microbiome and associated histomorphological and molecular changes in the mouse gut mucosa. Male C57BL6/J mice were gavaged with either 0, 61.5, 184.5, or 615 mg/kg/bw of CRCE in sesame oil for 2 weeks (Mon-Fri). Substantial CRCE-induced increases in the relative abundance of A. muciniphila, a bacterial species currently accepted as probiotic, was observed in fecal samples at all doses. This was paralleled by decreases in the relative abundance of other gut bacterial species. Coincident with the observed changes in gut ecology were multiple pro-inflammatory responses, including increased expression of cytokines and chemokines – Il1ß, Cxcl1, and Cxcl2 in the colon tissue. Furthermore, dramatic increases in the relative abundance of A. muciniphila significantly decreased expression of Muc2 – a gene intimately associated with gut integrity. Taken together, these findings raise concerns about the safety of long-term CBD usage and underline the need for additional well-designed studies into its tolerability and efficacy.

Patient: Female, 26-year-old Final Diagnosis: Adenocarcinoma with signet-ring cell features Symptoms: 32 week gestation with new onset chest pain and shortness of breath Medication: — Clinical Procedure: — Specialty: Obstetrics and Gynecology Objective: Rare co-existance of disease or pathology Background: Cancer in pregnancy is extremely rare, and gastric cancers are rarer still. Diagnosis is difficult in pregnancy due to overlapping symptoms with pregnancy such as nausea, pain, anemia, and fatigue. Case Report: A 26-year-old G1 woman at 32 weeks gestation with a past medical history of systemic lupus erythematosus presented with new-onset chest pain and shortness of breath. Computed tomography of the chest, electrocardiogram, and echocardiogram were normal. Laboratory evaluation revealed thrombocytopenia, proteinuria of 480 milligrams, and normal complement. She delivered on hospital day 3 due to worsening chest pain. During cesarean delivery, the patient became hypotensive and hypoxic and required intensive care unit admission after a cesarean hysterectomy. On postoperative day 2 she had a pulmonary embolus and was started on therapeutic anticoagulation. She clinically improved until postoperative day 4, when she was found unresponsive with pulseless electrical activity. After 38 minutes of Advanced Cardiac Life Support, death was pronounced. An autopsy was performed and the cause of death found to be complications of multi-organ system involvement of adenocarcinoma with signet ring cell features. Lymphangitic carcinomatosis was noted throughout the lungs. Conclusions: This patient had adenocarcinoma with signet ring cell features and associated lymphangitic carcinomatosis, which led to her postpartum death. Lymphangitic carcinomatosis is associated with an exceedingly poor prognosis, especially in pregnancy.

To review what is currently known about placental mesenchymal dysplasia (PMD) including imaging techniques for diagnosis and differentiation from a molar pregnancy, genetics, maternal/fetal effects, and management.A literature search by research librarians at 2 universities was undertaken using the search engines PubMed and Web of Science. The search terms used were "etiology" OR "cause" OR "risk" OR "risks" OR "epidemiology" OR "diagnosis" OR "therapy" OR "prognosis" OR "management" AND "placental mesenchymal dysplasia" OR "placenta" AND "mesenchymal dysplasia." No limit was put on the number of years searched.The etiology of PMD remains uncertain, although there are a number of theories on causation. An elevated maternal serum α-fetoprotein level, slightly elevated human chorionic gonadotropin level, normal karyotype, multicystic lesions on ultrasound, and varying degrees of flow within cysts using color Doppler (stained-glass appearance) are helpful in making the diagnosis. On pathologic examination of the placenta, PMD is differentiated from molar pregnancy by the absence of trophoblastic hyperplasia. Fetal complications of PMD include hematologic disorders, Beckwith-Wiedemann syndrome, liver tumors, fetal growth restriction, preterm delivery, and intrauterine fetal demise. Maternal complications include gestational hypertension, preeclampsia, HELLP (hemolysis, elevated liver function tests, low platelets) syndrome, and eclampsia.Accurate diagnosis of PMD is imperative for appropriate management and surveillance to minimize adverse maternal and fetal outcomes.The importance of a correct diagnosis of PMD is important because it can be misdiagnosed as a partial molar pregnancy or a complete mole with coexisting normal fetus, and this can result in inappropriate management.

Context Progesterone (P) resistance is a hallmark of endometriosis, but the underlying mechanism(s) for loss of P sensitivity leading to lesion establishment remains poorly understood. Objective To evaluate the association between Notch-1 signaling activation and P resistance in the progression of endometriosis. Design Case control study; archived formalin-fixed, paraffin-embedded tissues. Setting University hospitals (United States, Taiwan). Patients Women with endometriosis; human endometrial stromal cell line (HESC). Intervention Eutopic endometria (EU) and ectopic lesions (ECs) were collected from surgically diagnosed patients. Archived tissue sections of EU and ECs were identified. HESCs were treated with N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) and valproic acid (VPA) to, respectively, suppress and induce Notch-1 activation. Outcome Measures Tissues were analyzed for Notch Intra-Cellular Domain 1 (NICD1) and progesterone receptor (PGR) protein expression by immunohistochemistry and for transcript levels of NICD1 target genes HES1, PGR, and PGR-B by quantitative reverse transcription polymerase chain reaction. DAPT- or VPA-treated HESCs with and without P cotreatment were evaluated for cell numbers and for PGR, HES1, and PGR target gene DKK1 transcript levels. Results Nuclear-localized stromal NICD1 protein levels were inversely associated with those of total PGR in EU and ECs. Stromal ECs displayed higher HES1 and lower total PGR and PGR-B transcript levels than EU. In HESCs, DAPT reduction of NICD1 decreased cell numbers and increased PGR transcript and nuclear PGR protein levels and, with P cotreatment, maintained P sensitivity. Conversely, VPA induction of NICD1 decreased PGR transcript levels and, with P cotreatment, abrogated P-induced DKK1 and maintained HES1 transcript levels. Conclusions Aberrant Notch-1 activation is associated with decreased PGR that contributes to P resistance in endometriosis., Notch-1 activation is associated with loss of progesterone receptor expression in ectopic lesions of endometriotic patients and with loss of progesterone sensitivity in endometrial stromal cells.

Background Primary adenocarcinoma of the anal canal is a rare and aggressive gastrointestinal disease with unclear pathogenesis. Because of its rarity, no clear clinical practice guideline has been defined and a targeted therapeutic armamentarium has yet to be developed. The present article aimed at addressing this information gap by in-depth characterising the anal glandular neoplasms at the histologic, immunologic, genomic and epidemiologic levels. Methods In this multi-institutional study, we first examined the histological features displayed by each collected tumour (n = 74) and analysed their etiological relationship with human papillomavirus (HPV) infection. The intratumoural immune cell subsets (CD4, CD8, Foxp3), the expression of immune checkpoints (PD-1, PD-L1), the defect in mismatch repair proteins and the mutation analysis of multiple clinically relevant genes in the gastrointestinal cancer setting were also determined. Finally, the prognostic significance of each clinicopathological variable was assessed. Results Phenotypic analysis revealed two region-specific subtypes of anal canal adenocarcinoma. The significant differences in the HPV status, density of tumour-infiltrating lymphocytes, expression of immune checkpoints and mutational profile of several targetable genes further supported the separation of these latter neoplasms into two distinct entities. Importantly, anal gland/transitional-type cancers, which poorly respond to standard treatments, displayed less mutations in downstream effectors of the EGFR signalling pathway (i.e., KRAS and NRAS) and demonstrated a significantly higher expression of the immune inhibitory ligand-receptor pair PD-1/PD-L1 compared to their counterparts arising from the colorectal mucosa. Conclusions Taken together, the findings reported in the present article reveal, for the first time, that glandular neoplasms of the anal canal arise by HPV-dependent or independent pathways. These etiological differences leads to both individual immune profiles and mutational landscapes that can be targeted for therapeutic benefits.

Mesonephric adenocarcinoma most commonly arises in the cervix and is presumed to be derived from normal or hyperplastic mesonephric remnants. It is characterized by recurrent KRAS mutations and lack of PIK3CA/PTEN alterations. Adenocarcinomas of the uterine corpus and ovary characterized by morphologic and immunophenotypic similarities to mesonephric adenocarcinoma have been reported. The pathogenesis of these tumors, which have been designated "mesonephric-like adenocarcinomas" is unknown, and it has been debated whether these represent mesonephric adenocarcinomas that arise in the endometrium/ovary or endometrioid adenocarcinomas that closely mimic mesonephric adenocarcinoma. The relationship at the molecular level between mesonephric adenocarcinomas and mesonephric-like adenocarcinomas is unknown. The aim of this study was to examine the molecular alterations in mesonephric-like adenocarcinomas to identify driver mutations and potential therapeutically targetable mutations, and to determine the relationship between mesonephric-like adenocarcinomas and mesonephric adenocarcinomas using targeted next-generation sequencing. Seven mesonephric-like adenocarcinomas (4 ovarian, 3 uterine corpus) underwent targeted next-generation sequencing to detect mutations, copy number variations and structural variants in exonic regions of 300 cancer genes, and 113 selected intronic regions across 35 genes. All 7 tumors (100%) harbored canonical activating KRAS mutations (4 G12D, 3 G12V). PIK3CA activating mutations were identified in 3 of 7 (43%) cases. There were no alterations in PTEN, ARID1A, or TP53 in any of the tumors. In copy number analysis, 5 of 7 (71%) tumors exhibited 1q gain, which was accompanied by 1p loss in 2 cases. In addition, 4 of 7 (57%) tumors had chromosome 10 gain, which was accompanied by gain of chromosome 12 in 3 cases. Mesonephric-like adenocarcinomas, similar to mesonephric adenocarcinomas, are characterized by recurrent KRAS mutations, gain of 1q, lack of PTEN mutations, and gains of chromosomes 10 and 12. PIK3CA mutations, which have not previously been identified in mesonephric adenocarcinoma, were found in 3 of 7 (43%) mesonephric-like adenocarcinomas in our study. Mesonephric-like adenocarcinomas exhibit strikingly similar molecular aberrations to mesonephric adenocarcinomas, but also frequently harbor PIK3CA mutations, demonstrating biological overlap with carcinomas of both mesonephric and Mullerian (endometrioid) differentiation. Given the previously documented association with endometriosis (ovarian neoplasms) and the prominent endometrial involvement (uterine corpus neoplasms), we believe these are best regarded as of Mullerian origin and representing adenocarcinomas which differentiate along mesonephric lines; as such, we propose the term mesonephric-like Mullerian adenocarcinoma.

Diabetes (DM) is a disease with significant morbidity and mortality and is a major public health problem worldwide. Endometriosis (ENDO) is a chronic estrogen-dependent gynecological condition that affects ~10% of reproductive-age women, causes debilitating pain and infertility, and carries an increased risk for ovarian cancer. Little is known about the co-morbidity of endometriosis and diabetes (Type 1, T1DM; Type 2, T2DM), despite both conditions sharing similar pathophysiology including chronic inflammation triggered by overactivation of the immune response. To evaluate if ENDO is promoted in women diagnosed with DM, we analyzed the expression of key molecular ENDO markers in endometriosis with no associated ovarian lesions collected from non-diabetic and diabetic patients at ENDO surgery. Formalin-fixed, paraffin-embedded sections, identified from analyses of TRINETX data set and retrieved from the Pathology Department, represented women with ENDO alone (n=10; mean age of 42 yo), ENDO/T1DM (n=6; mean age of 28 yo), and ENDO/T2DM (n=7, mean age of 42 yo). Body mass indices (kg/m2) were comparable for women with T1DM (mean of 44.8) and T2DM (mean of 42.5) and higher than for ENDO alone women (mean of 30.8). Endometriotic lesions were analyzed by immunohistochemistry for markers of cellular proliferation (Ki67, PTEN, NICD1) and steroid hormone receptor expression (ESR1, ESR2, PGR-Total, PGR-B) in the epithelial and stromal compartments. We found that immunoreactive ESR1 in lesion epithelial glands (cytoplasm and nuclei) were higher in ENDO/T1DM and ENDO/T2DM than in ENDO alone (P

Distinguishing hyalinized stroma from osteoid production by a heterologous osteosarcomatous component can be challenging in gynecologic tract carcinosarcomas. As heterologous components in a carcinosarcoma may have prognostic and therapeutic implications, it is important that these are recognized. This study examines interobserver reproducibility among gynecologic pathologists in the diagnosis of osteosarcomatous components, and its correlation with expression of the novel antibody SATB2 (marker of osteoblastic differentiation) in these osteosarcomatous foci. Digital HE images from 20 gynecologic tract carcinosarcomas were reviewed by 22 gynecologic pathologists with a request to determine the presence or absence of an osteosarcomatous component. The 20 preselected cases included areas of classic heterologous osteosarcoma (malignant cells producing osteoid; n=10) and osteosarcoma mimics (malignant cells with admixed nonosteoid matrix; n=10). Interobserver agreement was evaluated and SATB2 scored on all 20 cases and compared with the original diagnoses. Moderate agreement (Fleiss' κ=0.483) was identified for the 22 raters scoring the 20 cases with a median sensitivity of 7/10 and a median specificity of 9/10 for the diagnosis of osteosarcoma. SATB2 showed 100% sensitivity (10/10) and 60% (6/10) specificity in discriminating classic osteosarcoma from osteosarcoma mimics. Utilizing negative SATB2 as a surrogate marker to exclude osteosarcoma, 73% (16/22) of the reviewers would have downgraded at least 1 case to not contain an osteosarcomatous component (range, 1-6 cases, median 1 case). Gynecologic pathologists demonstrate only a moderate level of agreement in the diagnosis of heterologous osteosarcoma based on morphologic grounds. In such instances, a negative SATB2 staining may assist in increasing accuracy in the diagnosis of an osteosarcomatous component.

Endometrial adenocarcinoma is the most common malignancy of the gynaecologic tract, and therefore one of the most commonly encountered surgical pathology specimens. Accurate diagnosis, grading and staging are necessary to direct therapy for this common disease. Evaluation of these cases is usually straightforward. Some cases, however, may be complicated by a variety of issues such as difficulty assessing depth of invasion; difficulty assessing cervical involvement; possibility of synchronous ovarian primaries; evaluation of lymphovascular space invasion; difficulties with FIGO grade (especially in the company of altered differentiation); and subtle patterns of myoinvasion. The purpose of this review is to emphasize these problematic areas and offer straightforward guidelines to apply when these situations are encountered. Proper recognition of these diagnostic challenges will hopefully improve grading and staging accuracy, and subsequently therapy, for the multitudes of women affected by this disease.

Aetiologically linked to HPV infection, malignancies of the anal canal have substantially increased in incidence over the last 20 years. Although most anal squamous cell carcinomas (SCCs) respond well to chemoradiotherapy, about 30% of patients experience a poor outcome, for undetermined reasons. Despite cumulative efforts for discovering independent predictors of overall survival, both nodal status and tumour size are still the only reliable factors predicting patient outcome. Recent efforts have revealed that the biology of HPV-related lesions in the cervix is strongly linked to the originally infected cell population. To address the hypothesis that topography also influences both gene expression profile and behaviour of anal (pre)neoplastic lesions, we correlated both proteomic signatures and clinicopathological features of tumours arising from two distinct portions of the anal canal: the lower part (squamous zone) and the more proximal anal transitional zone. Although microdissected cancer cells appeared indistinguishable by morphology (squamous phenotype), unsupervised clustering analysis of the whole proteome significantly highlighted the heterogeneity that exists within anal canal tumours. More importantly, two region-specific subtypes of SCC were revealed. The expression profile (sensitivity/specificity) of several selected biomarkers (keratin filaments) further confirmed the subclassification of anal (pre)cancers based on their cellular origin. Less commonly detected compared to their counterparts located in the squamous mucosa, SCCs originating in the transitional zone more frequently displayed a poor or basaloid differentiation, and were significantly correlated with reduced disease-free and overall survivals. Taken together, we present direct evidence that anal canal SCC comprises two distinct entities with different cells of origin, proteomic signatures, and survival rates. This study forms the basis for a dualistic classification of anal carcinoma, with implications for management, outcome expectations, and possibly therapy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Objective To review what is currently known about placental mesenchymal dysplasia (PMD) including imaging techniques for diagnosis and differentiation from a molar pregnancy, genetics, maternal/fetal effects, and management. Evidence acquisition A literature search by research librarians at 2 universities was undertaken using the search engines PubMed and Web of Science. The search terms used were "etiology" OR "cause" OR "risk" OR "risks" OR "epidemiology" OR "diagnosis" OR "therapy" OR "prognosis" OR "management" AND "placental mesenchymal dysplasia" OR "placenta" AND "mesenchymal dysplasia." No limit was put on the number of years searched. Results The etiology of PMD remains uncertain, although there are a number of theories on causation. An elevated maternal serum α-fetoprotein level, slightly elevated human chorionic gonadotropin level, normal karyotype, multicystic lesions on ultrasound, and varying degrees of flow within cysts using color Doppler (stained-glass appearance) are helpful in making the diagnosis. On pathologic examination of the placenta, PMD is differentiated from molar pregnancy by the absence of trophoblastic hyperplasia. Fetal complications of PMD include hematologic disorders, Beckwith-Wiedemann syndrome, liver tumors, fetal growth restriction, preterm delivery, and intrauterine fetal demise. Maternal complications include gestational hypertension, preeclampsia, HELLP (hemolysis, elevated liver function tests, low platelets) syndrome, and eclampsia. Conclusions Accurate diagnosis of PMD is imperative for appropriate management and surveillance to minimize adverse maternal and fetal outcomes. Relevance The importance of a correct diagnosis of PMD is important because it can be misdiagnosed as a partial molar pregnancy or a complete mole with coexisting normal fetus, and this can result in inappropriate management.