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Placental pathology in SARS-CoV-2-infected pregnancies seems rather unspecific. However, the identification of the placental lesions due to SARS-CoV-2 infection would be a significant advance in order to improve the management of these pregnancies and to identify the mechanisms involved in a possible vertical transmission. The pathological findings in placentas delivered from 198 SARS-CoV-2-positive pregnant women were investigated for the presence of lesions associated with placental SARS-CoV-2 infection. SARS-CoV-2 infection was investigated in placental tissues through immunohistochemistry, and positive cases were further confirmed by in situ hybridization. SARS-CoV-2 infection was also investigated by RT-PCR in 33 cases, including all the immunohistochemically positive cases. Nine cases were SARS-CoV-2-positive by immunohistochemistry, in situ hybridization, and RT-PCR. These placentas showed lesions characterized by villous trophoblast necrosis with intervillous space collapse and variable amounts of mixed intervillous inflammatory infiltrate and perivillous fibrinoid deposition. Such lesions ranged from focal to massively widespread in five cases, resulting in intrauterine fetal death. Two of the stillborn fetuses showed some evidence of SARS-CoV-2 positivity. The remaining 189 placentas did not show similar lesions. The strong association between trophoblastic damage and placenta SARS-CoV-2 infection suggests that this lesion is a specific marker of SARS-CoV-2 infection in placenta. Diffuse trophoblastic damage, massively affecting chorionic villous tissue, can result in fetal death associated with COVID-19 disease.

Steel syndrome (STLS) encompasses characteristic facies, dwarfness, irreducible bilateral hip and radial head dislocation, and carpal bone coalition due to COL27A1 mutations. Two consecutive pregnancies in a non-consanguineous couple were terminated because of severe fetal anomalies. Complete autopsies with microscopic exam were performed on both fetuses. Next-generation-based clinical exome sequencing was applied to the first fetus. Exome sequencing results, parental segregation, and affection of the second fetus were confirmed by Sanger sequencing. Both fetuses had signs consistent with STLS. Bilateral capitulum humeri absence explained radial head dislocation in STLS. Metaphyseal cartilage showed severe disorganization. Resting cartilage was hypercellular, organized in irregular nests limited by acellular matrix. Two variants in COL27A1 (c.2548G>A -p.Gly850Arg- and c.3249+1G> T) were found in both fetuses in compound heterozygosity with parental Mendelian segregation. This is the first report to include histology of STLS. The COL27A1 variants here described increase the number of mutations associated with STLS.

Objective: The aim of the study was to assess the diagnostic yield of 2 different next-generation sequencing (NGS) approaches: gene panel and “solo” clinical exome sequencing (solo-CES), in fetuses with structural anomalies and normal chromosomal microarray analysis (CMA), in the absence of a known familial mutation. Methodology: Gene panels encompassing from 2 to 140 genes, were applied mainly in persistent nuchal fold/fetal hydrops and in large hyperechogenic kidneys. Solo-CES, which entails sequencing the fetus alone and only interpreting the Online Mendelian Inheritance in Man genes, was performed in multisystem or recurrent structural anomalies. Results: During the study period (2015–2020), 153 NGS studies were performed in 148 structurally abnormal fetuses with a normal CMA. The overall diagnostic yield accounted for 35% (53/153) of samples and 36% (53/148) of the fetuses. Diagnostic yield with the gene panels was 31% (15/49), similar to 37% (38/104) in solo-CES. Conclusions: A monogenic disease was established as the underlying cause in 35% of selected fetal structural anomalies by gene panels and solo-CES.

Lethal congenital contracture syndrome 11 (LCCS11) is caused by homozygous or compound heterozygous variants in the GLDN gene on chromosome 15q21. GLDN encodes gliomedin, a protein required for the formation of the nodes of Ranvier and development of the human peripheral nervous system. We report a fetus with ultrasound alterations detected at 28 weeks of gestation. The fetus exhibited hydrops, short long bones, fixed limb joints, absent fetal movements, and polyhydramnios. The pregnancy was terminated and postmortem studies confirmed the prenatal findings: distal arthrogryposis, fetal growth restriction, pulmonary hypoplasia, and retrognathia. The fetus had a normal chromosomal microarray analysis. Exome sequencing revealed two novel compound heterozygous variants in the GLDN associated with LCCS11. This manuscript reports this case and performs a literature review of all published LCCS11 cases.

In recent years, several studies have examined the possible relationship between periodontal disease in pregnant women and preterm birth. One of the difficulties facing these studies is the heterogeneity of the clinical criteria used to define periodontitis. The aim of this cross-sectional study was to determine the degree of association between maternal periodontitis and preterm birth according to different consensus definitions of periodontal disease. In a study of 146 mothers (60 with preterm births and 86 with term deliveries) at the Sant Joan de Déu Maternal and Children's Hospital in Barcelona, a periodontal examination was carried out within 2 days of birth and the presence of periodontal disease was evaluated using the main clinical classifications published in the literature. The prevalence of periodontitis ranged from 25.4 to 52.1%, depending on the criteria used for its definition. Using the most restrictive criteria, pregnant women with periodontitis had a higher risk of preterm birth (OR: 7.49; p < 0.001) and premature rupture of membranes (OR: 2.49; p = 0.017). Premature infants born to mothers with periodontitis presented a tendency toward low weight, adjusted for gestational age (OR: 3.32; p = 0.065). Our findings suggest that the association between periodontitis and preterm birth is influenced by the definitions of periodontitis used.

Context.— Perinatal death is an increasingly important problem as the coronavirus disease 2019 (COVID-19) pandemic continues, but the mechanism of death has been unclear. Objective.— To evaluate the role of the placenta in causing stillbirth and neonatal death following maternal infection with COVID-19 and confirmed placental positivity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Design.— Case-based retrospective clinicopathologic analysis by a multinational group of 44 perinatal specialists from 12 countries of placental and autopsy pathology findings from 64 stillborns and 4 neonatal deaths having placentas testing positive for SARS-CoV-2 following delivery to mothers with COVID-19. Results.— Of the 3 findings constituting SARS-CoV-2 placentitis, all 68 placentas had increased fibrin deposition and villous trophoblast necrosis and 66 had chronic histiocytic intervillositis. Sixty-three placentas had massive perivillous fibrin deposition. Severe destructive placental disease from SARS-CoV-2 placentitis averaged 77.7% tissue involvement. Other findings included multiple intervillous thrombi (37%; 25 of 68) and chronic villitis (32%; 22 of 68). The majority (19; 63%) of the 30 autopsies revealed no significant fetal abnormalities except for intrauterine hypoxia and asphyxia. Among all 68 cases, SARS-CoV-2 was detected from a body specimen in 16 of 28 cases tested, most frequently from nasopharyngeal swabs. Four autopsied stillborns had SARS-CoV-2 identified in internal organs. Conclusions.— The pathology abnormalities composing SARS-CoV-2 placentitis cause widespread and severe placental destruction resulting in placental malperfusion and insufficiency. In these cases, intrauterine and perinatal death likely results directly from placental insufficiency and fetal hypoxic-ischemic injury. There was no evidence that SARS-CoV-2 involvement of the fetus had a role in causing these deaths.

This review gives a brief history of the development of head and neck pathology in Europe from a humble beginning in the 1930s to the explosive activities the last 15 years. During the decades before the introduction of immunohistochemistry in the 1980s, head and neck pathology grew as a subspeciality in many European countries. In the late 1940s, the Institute of Laryngology and Otology with its own pathology laboratory was founded in London, and in 1964 the World Health Organization (WHO) International Reference Centre for the Histological Classification of Salivary Tumours was established at the Bland-Sutton Institute of Pathology, also in London. International collaboration, and very much so in Europe, led to the publication of the first WHO Classification of Salivary Gland Tumours in 1972. In the 1960s, a salivary gland register was organised in Hamburg and in Cologne the microlaryngoscopy was invented enabling microscopic endoscopic examination and rather shortly afterwards a carbon dioxide laser attached to the microscope became established and laryngeal lesions could be treated by laser vaporisation. During the last three decades, the use of immunohistochemistry supplemented with cytogenetic and refined molecular techniques has greatly facilitated the pathological diagnostics of head and neck lesions and has had a huge impact on research. Collaboration between different European centres has drastically increased partly due to establishment of scientific societies such as the Head and Neck Working Group (HNWG) within the European Society of Pathology and the International Head and Neck Scientific Group (IHNSG). A very large number of European pathologists have contributed to the 2nd, 3rd and 4th WHO books, and are involved in the upcoming 5th edition. Accredited educational meetings and courses are nowadays regularly arranged in Europe. Numerous textbooks on head and neck pathology have been written and edited by European pathologists. The increased collaboration has created larger series of tumours for research and new entities, mainly defined by their genetic abnormalities, are continuously emerging from Europe, particularly regarding salivary gland neoplasms and "undifferentiated" sinonasal tumours. These findings have led to a better and more precise classification and open the possibilities for new treatment strategies. info:eu-repo/semantics/publishedVersion

Objective: the aim of our study was to assess the contribution of quantitative fluorescent polymerase chain reaction (QF-PCR) and pathology studies in the diagnosis of diandric triploidies/partial hydatidiform moles. Methods: this study included all fet al triploidies diagnosed by QF-PCR in chorionic villi or amniotic fluid in the 2 centers of BCNatal in which a maternal saliva sample was used to establish its parental origin. Pathology studies were performed in products of conception and concordance between a partial hydatidiform mole diagnosis and the finding of a diandric triploidy was assessed. Results: among 46 fetal triploidies, found in 13 ongoing pregnancies and in 33 miscarriages, there were 26 (56%) diandric triploidies. Concordant molecular (diandric triploidy) and pathology results (partial mole) were achieved in 14 cases (54%), while in 6 cases (23%) pathology studies were normal, and in the remaining 6 cases (23%) pathology studies could not be performed because miscarriage was managed medically. Conclusions: diandric triploidy is associated with partial hydatidiform mole and its diagnosis is crucial to prevent the development of persistent trophoblastic disease. QF-PCR analysis in chorionic villi or amniotic fluid provides a more accurate diagnosis of the parental origin of triploidy than the classical pathology studies.

Background Oral premalignant lesions (OPML) are frequently extensive and multifocal leading high morbidity for patients. Although oral squamous carcinoma (OSCC) in non-smoker patients is increasing, little is known about OPML and the carcinogenesis process in these patients. The aims of the study were to insight and compare the clinicopathological and molecular characteristics of OPML of non-smoker and smoker patients from which one or multiple OSCC have developed. Methods Eighty-one patients showing extensive and/or multifocal OPML were included in the survey. HPV and EBV were investigated by PCR and in situ hybridization respectively. Cytogenetic studies were performed by microarray in sequential progressive 30 lesions; p53 expression was investigated by immunohistochemistry. Results The patients were 41 males and 40 females, ages ranging from 32 to 93 years (median 64); 43 (53%) were smokers. Non-smokers were more frequently female with a median age of 68, whereas smokers were men with a median age of 60 (P = 0.005). HPV and EBV were negative in all cases. The most consistent and earliest cytogenetic alterations in both non-smokers and smokers were loss of heterozygosity (LOH) and losses of locus harboring tumor suppressor genes. Progression to high-grade dysplasia and OSCC showed progressive addition of LOH, tumor suppressor losses, and oncogenic gains. Conclusion Non-smoker patients are mostly elderly female and show oral carcinogenic pathways and outcomes similar to smoker patients.

The involvement of human papillomavirus (HPV) in laryngeal and hypopharyngeal lymphoepithelial carcinoma was investigated in a series of ten cases (seven laryngeal and three hypopharyngeal), retrieved from the files of three tertiary hospitals in the 2000-2017 period, through polymerase chain reaction with SPF10 primers and INNO-LiPA HPV Genotyping Extra II (Innogenetics). Epstein-Barr virus (EBV) was tested in all cases with in situ hybridization INFORM EBER Probe (Ventana Medical Systems). p16 and p53 expression were immunohistochemically analyzed. Calculated annual incidence was 0.013/100,000, and prevalence was 0.2% of laryngeal and hypopharyngeal carcinomas. All cases were EBV negative. HPV was detected in five cases, three of which also overexpressed p16. HPV16 was detected in four cases, and HPV58 in one case. Five cases were HPV negative, only one of these five overexpressed p16. No recurrence was observed in nine cases during follow-up. The 5-year disease-specific-survival rate was 100%. Mean overall survival was 87 months. Lymphoepithelial carcinoma of the larynx and hypopharynx are not related to EBV. Simultaneous HPV+/p16+ is consistent with HPV causation in a fraction of laryngeal and hypopharyngeal lymphoepithelial carcinomas.

Aim To investigate microbial profiles in placentas from a population of East African mothers with and without adverse pregnancy outcomes and with regard to their periodontal status. Material and methods Thirty-six placentas from pregnant women from Tanzania were classified into three groups according to both pregnancy outcome and the mother's periodontal health. The microbial composition in each group was then compared using 16S rRNA metagenomics. Additionally, placenta specimens were analyzed histologically for chorioamnionitis by a single pathologist blinded to the clinical data. Results The greatest differences were observed in the group of mothers with periodontitis. The microbial load was low in all three groups of mothers. Periodontitis had a notable influence on the structure of the placental microbiota. Three phyla and 44 genera were associated with periodontitis, whereas only the Tenericutes phylum was associated with the adverse pregnancy variable. Streptococcaceae and Mycoplasmataceae families were associated with both periodontitis and adverse pregnancy outcomes. Finally, although the differences for chorioamnionitis were not significant, this intra-amniotic infection was more frequent in the placentas from mothers with periodontitis. Conclusions Our findings suggest that bacteria from the oral cavity may involve the feto-placental unit, and that periodontitis may be a modulating factor of the microbial community present in this niche.

The exposure to a fetal inflammatory response (FIR) is often followed by a postnatal systemic inflammation, increasing the risk of perinatal brain injury. We profiled the transcriptome and proteome in neonatal dried blood spots from extremely preterm newborns (< 28 weeks of gestation), affected and unaffected by FIR. The observed molecular changes confirm the activation of the innate immune system in FIR‐affected neonates and reveal an impairment of their adaptive immunity., The fetal inflammatory response (FIR) increases the risk of perinatal brain injury, particularly in extremely low gestational age newborns (ELGANs

The malignant transformation of endometriosis is very uncommon. Whereas 75% of tumors arising from endometriosis arise in the ovary, location in extra-genital organs is rare and mesenchymal neoplasms are exceptional. A 47 year-old woman who underwent hysterectomy with bilateral salpingo-ooforectomy due to endometriosis 13 years before presented with abdominal pain. The magnetic resonance imaging (MRI) showed a 9.7×7.5 cm solid-cystic supravesical mass and a recto-vaginal tumor, as well as endometriotic nodules in the sigma, right parametrium and peritoneum that had significantly increased in size over a six months period. The patient underwent surgical resection of the masses. The histological study showed a low-grade endometrial stromal sarcoma (ESS) arising from endometriosis located at recotovaginal septum and affecting colonic wall and multiple peritoneal and pelvic implants. The patient received radiotherapy and aromatase inhibitors and is free of disease after a follow up of 2 years. Only 15 cases of ESS arising in endometriosis of the bowel have been reported. Tumor dissemination at diagnosis is unusual but does not imply a poor prognosis, as only one patient has died due to progression of the tumor. ESS should be included in the differential diagnosis of mesenchymal neoplasms in the intestine.

BACKGROUND Cervico-mediastinal hemangiomas in adulthood are rare and slow-growing vascular tumors. The optimal treatment for giant hemangiomas is controversial. In asymptomatic cases, clinical observation is generally recommended. METHODS We report the transoral resection of a pharyngolaryngeal hemangioma (diameters of 44 × 56 × 39 mm) with tracheal involvement and mediastinal extension. Clinically, the patient had throat foreign body sensation, severe dyspnea and stridor. The hemangioma was first embolized by injecting ethylene-vinyl alcohol copolymer (Onyx) transorally, and then the obstructive aspect of the tumor was resected with a bipolar and ultrasonic clamp (ThunderBeat®, Olympus). RESULTS Two months after surgery, nasal fiberendoscopy showed complete disappearance of the vascular mass at the larynx and hypopharynx, with a normal mobility of the larynx. CONCLUSION In symptomatic patients, surgical reduction of large pharyngolaryngeal hemangiomas may be feasible by direct embolization and transoral ultrasonic resection. Both may provide an almost bloodless surgical field. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1239-1242, 2017.

OBJECTIVES: To describe placental histopathological findings in a large cohort of pregnancies complicated by pre-eclampsia (PE) and/or small-for-gestational age (SGA), and to investigate their association with fetoplacental Doppler parameters. METHODS: This was a prospective observational study of normotensive pregnancies with SGA (defined as birth weight < 10(th) centile) (n = 184), PE pregnancies with a normally grown fetus (n = 102), pregnancies with both PE and SGA (n = 120) and uncomplicated pregnancies (n = 202). Uterine (UtA), umbilical (UA) and fetal middle cerebral (MCA) artery pulsatility indices (PI) were assessed. The cerebroplacental ratio (CPR) was calculated by dividing MCA-PI by UA-PI. Doppler parameters were considered abnormal when UtA-PI or UA-PI was > 95(th) centile or MCA-PI or CPR was < 5(th) centile. Placental lesions were categorized as vascular (maternal or fetal side), immunoinflammatory or other, according to the 2014 Amsterdam Placental Workshop Group Consensus Statement. Comparison between the study groups was performed using univariate and multiple regression analysis, and logistic regression was used to determine the relationship between abnormal Doppler parameters and placental lesions. RESULTS: Maternal-side vascular lesions were significantly more common in PE pregnancies with SGA than in the other groups (PE + SGA, 73% vs PE, 46% vs SGA, 38% vs controls, 31%; P = 0.01) and included mainly two types of lesion: developmental (PE + SGA, 13% vs PE, 5% vs SGA, 3% vs controls, 1.5%; P < 0.001) and malperfusion (PE + SGA, 70% vs PE, 39% vs SGA, 32% vs controls, 25%; P = 0.001). In contrast, the incidence of fetal-side developmental lesions was significantly higher in normotensive SGA pregnancies than in controls and PE pregnancies (PE + SGA, 0% vs PE, 3% vs SGA, 8% vs controls, 2%; P = 0.001). All cases displayed a lower prevalence of infectious lesions than did controls, with the highest prevalence of immune lesions observed in pregnancies with both PE and SGA (PE + SGA, 18% vs PE, 8% vs SGA, 10% vs controls, 9%; P = 0.001). All fetoplacental Doppler parameters evaluated were associated with maternal-side vascular lesions, mainly malperfusion (mean UtA-PI: odds ratio (OR), 2.45 (95% CI, 1.51-3.97); UA-PI: OR, 2.05 (95% CI, 1.02-4.47); MCA-PI: OR, 2.75 (95% CI, 1.40-5.42); CPR: OR, 1.75 (95% CI, 1.04-2.95)). This association was evident mainly in the normotensive SGA group, being non-significant in controls or PE pregnancies without SGA. No significant associations were observed between fetoplacental Doppler parameters and other placental lesions in any of the study groups. CONCLUSIONS: PE and SGA are associated with different patterns of placental histopathological lesions in accordance with the clinical manifestation of the placental disorder (maternal vs fetal). Fetoplacental Doppler findings show an association with placental malperfusion lesions on the maternal side, supporting the use of abnormal Doppler as a surrogate for placental insufficiency. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVE: To perform a comprehensive assessment of the placental aging process in small term fetuses classified as being small-for-gestational age (SGA) or having fetal growth restriction (FGR) through analysis of senescence and apoptosis markers. METHODS: This was a prospective nested case-control study of singleton pregnancies delivered at term, including 21 control pregnancies with normally grown fetuses and 36 with a small fetus classified as SGA (birth weight between the 3(rd) and 9(th) percentiles and normal fetoplacental Doppler; n = 18) or FGR (birth weight < 3(rd) percentile and/or abnormal cerebroplacental ratio and/or uterine artery Doppler; n = 18). Telomerase activity, telomere length (quantified by comparing the amount of amplification product for the telomere sequence (T) to that of a single copy of the gene 36B4 (S)) and RNA expression of senescence (Sirtuins 1, 3 and 6) and apoptosis (p53, p21, BAX and Caspases 3 and 9) markers (analyzed using the 2(- Ct) method) were determined in placental samples collected at birth and compared between the three groups. RESULTS: Compared to pregnancies with a normally grown fetus, both SGA and FGR pregnancies presented signs of accelerated placental aging, including lower telomerase activity (mean ± SD, 12.8 ± 6.6% in controls vs 7.98 ± 4.2% in SGA vs 7.79 ± 4.6% in FGR; P = 0.008), shorter telomeres (mean ± SD T/S ratio, 1.20 ± 0.6 in controls vs 1.08 ± 0.9 in SGA vs 0.66 ± 0.5 in FGR; P = 0.047) and reduced Sirtuin-1 RNA expression (mean ± SD 2(- Ct) , 1.55 ± 0.8 in controls vs 0.91 ± 0.8 in SGA vs 0.63 ± 0.5 in FGR; P = 0.001) together with increased p53 RNA expression (median (interquartile range) 2(- Ct) , 1.07 (0.3-3.3) in controls vs 5.39 (0.6-15) in SGA vs 3.75 (0.9-7.8) in FGR; P = 0.040). FGR cases presented signs of apoptosis, with increased Caspase-3 RNA levels (median (interquartile range) 2(- Ct) , 0.94 (0.7-1.7) in controls vs 3.98 (0.9-31) in FGR; P = 0.031) and Caspase-9 RNA levels (median (interquartile range) 2(- Ct) , 1.21 (0.6-4.0) in controls vs 3.87 (1.5-9.0) in FGR; P = 0.037) compared with controls. In addition, Sirtuin-1 RNA expression, telomerase activity, telomere length and Caspase-3 activity showed significant linear trends across groups as severity of the condition increased. CONCLUSIONS: Accelerated placental aging was observed in both clinical forms of late-onset fetal smallness (SGA and FGR), supporting a common pathophysiology and challenging the concept of SGA fetuses being constitutionally small. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

BACKGROUND Indications of transoral laser microsurgery (TLM) are conditioned by the risk of local relapse. OBJECTIVE To evaluate prognostic factors of local relapse and local control with TLM (LC-TLM). METHODS Local relapse and LC-TLM were evaluated in 1119 patients. Logistic regression and CHAID decision tree analysis were performed. RESULTS Local relapse correlated to previous radiotherapy failure (8.45, CI 95%: 2.64-27.03; P

The purpose of this study was to describe the fetal/neonatal cytomegalovirus (CMV) status according to chorionicity and outcome in twin pregnancies diagnosed with CMV.An opportunistic diagnosis of CMV infection was performed in a tertiary referral center. All cases diagnosed in twin pregnancies (2006-2011) were included. Prenatal diagnosis was performed by CMV-DNA in the amniotic fluid (AF) of both fetuses only on the evidence of sonographic findings in either one or both twins. Neonatal screening was selectively assessed in symptomatic newborns, preterm, and infants born to HIV-infected mothers. Congenital infection was considered in the presence of CMV-DNA in AF, fetal tissues or newborn urine within the first 2 weeks of life, and symptomatic disease with clinical findings at birth or autopsy.A total of six twin pregnancies with congenital CMV infection were diagnosed, five dichorionic and one monochorionic diamniotic. Only one sibling was infected among dichorionic pregnancies, two diagnosed prenatally, and three after birth. In the monochorionic pregnancy, the diagnosis was performed prenatally and the two fetuses were infected and severely damaged.Congenital CMV infection in twins might be related, among other factors, to chorionicity, and in DC twins a non-concordant infection can be expected.

We studied the expression of p16INK4a in a series of HPV-negative laryngeal squamous cell carcinomas and assessed its association with prognosis. Forty-five patients with laryngeal carcinoma were included in the study. Clinicopathological features and prognosis were reviewed. p16INK4a protein expression was analysed through immunohistochemistry. We analysed messenger RNA (mRNA) in 25 cases through quantitative reverse transcription polymerase chain reaction. HPV status was assessed by PCR using three different protocols based on MY09/11 and GP5/6 primers. Four out of 45 (9 %) cases overexpressed p16INK4a protein and showed a tendency to worse survival that was significant for stages I–III (log-rank p value = 0.001). Expression of p16INK4a mRNA was high in 12 out of 25 (48 %) cases using an arbitrary cut-off level. All tumours were HPV negative with all three detection methods. A CDKN2A mutation was found in eight cases. One case with a missense and one with a frameshift mutation showed p16INK4a protein expression by immunohistochemistry. Six out of seven (86 %) mutated but only 6 out of 18 (33 %) non-mutated cases presented p16INK4a mRNA overexpression (p = 0.03). Our findings suggest that p16INK4a overexpression, both at protein and mRNA levels, may reflect CDKN2A genetic alterations in HPV-negative laryngeal squamous cell carcinomas.

Objective To investigate whether signs of placental underperfusion (PUP), defined as any maternal and/or fetal vascular pathology, confer an increased risk of neonatal morbidity in late-onset small-for-gestational-age (SGA) fetuses with normal umbilical artery (UA) Doppler indices. Methods A cohort of 126 SGA singleton fetuses with normal UA Doppler indices that were delivered after 34 weeks' gestation was studied. For each case, the placenta was evaluated histologically for signs of PUP using a hierarchical and standardized classification system. Neonatal morbidity was assessed according to the score calculated from the morbidity assessment index for newborns (MAIN), a validated outcome scale. The independent association between PUP and neonatal morbidity was evaluated using multivariable median regression analysis. Results In 84 (66.7%) placentae, 97 placental histological findings that qualified as signs of PUP were observed. These PUP cases had a significantly higher incidence of emergency Cesarean section for non-reassuring fetal status (44.1% vs 21.4%, respectively; P = 0.013) and neonatal metabolic acidosis at birth (33.3% vs 14.3%, respectively; P = 0.023), than did those without PUP. The median MAIN score differed significantly between those with PUP and those without (89 vs 0, respectively; P = 0.025). This difference remained significant after adjustment for potential confounders. The proportion of cases with scores indicative of mild to severe morbidity was also significantly higher in the PUP group (31% vs 14.3%, respectively; P = 0.043). Conclusion In late-onset SGA fetuses with normal UA Doppler indices, signs of PUP imply a higher neonatal morbidity. These findings allow the phenotypic profiling of fetal growth restriction among the general population of late-onset SGA. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.

Among the variants of squamous cell carcinoma (SCC) of the head and neck arising in mucosal surfaces, examples with sebaceous differentiation are exceedingly rare. We present a new case of SCC with sebaceous differentiation, developing in the larynx of a 64 year-old male, cigarette smoker and alcohol drinker. The tumor extended transglottically, metastasized to cervical lymph nodes, and killed the patient after 12 months. Comparing this case with four previously reported cases of SCC with sebaceous differentiation, two arising in the larynx and the other two in the adjacent pharynx, all five patients mostly shared the following features: appearance of the tumor in the seventh decade of life, heavy tobacco smoking, alcohol intake in three, surgery as mainstay treatment, tumor size between 2 and 4.7 cm, and regional lymph node metastases in four of them. Out of the four patients with a follow up of 12 months, two died of disease, one was alive with disease, and only one was alive without disease. One patient was lost for follow up. In conclusion, mucosal SCC with sebaceous differentiation is a very rare variant of SCC that when arising in the larynx and anatomically adjacent parts of the pharynx behaves aggressively and bears a dismal prognosis. The recognition of new cases of this entity requires special awareness of its phenotypic features and may be important for further assessment of its behavior.

Hidradenoma papilliferum (HP) is probably the commonest benign neoplasm involving the anogenital mammary-like glands (AMLGs). Diagnosis may require differentiation from Bartholin cysts/abscesses, l...

Cervico-mediastinal hemangiomas in adulthood are rare and slow-growing vascular tumors. The optimal treatment for giant hemangiomas is controversial. In asymptomatic cases, clinical observation is generally recommended.We report the transoral resection of a pharyngolaryngeal hemangioma (diameters of 44 × 56 × 39 mm) with tracheal involvement and mediastinal extension. Clinically, the patient had throat foreign body sensation, severe dyspnea and stridor. The hemangioma was first embolized by injecting ethylene-vinyl alcohol copolymer (Onyx) transorally, and then the obstructive aspect of the tumor was resected with a bipolar and ultrasonic clamp (ThunderBeat®, Olympus).Two months after surgery, nasal fiberendoscopy showed complete disappearance of the vascular mass at the larynx and hypopharynx, with a normal mobility of the larynx.In symptomatic patients, surgical reduction of large pharyngolaryngeal hemangiomas may be feasible by direct embolization and transoral ultrasonic resection. Both may provide an almost bloodless surgical field. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1239-1242, 2017.

High-grade neuroendocrine carcinomas (HGNECs) of the head and neck have the morphological appearance of undifferentiated carcinomas and could be histologically similar to human papillomavirus (HPV)-associated non-keratinizing squamous cell carcinomas of the head and neck. The aim of the study is to characterize histologically, immunohistochemically, and virologically these unusual neoplasms. Nineteen HGNECs of the head and neck (1 oropharyngeal, 5 sinonasal, 7 of the larynx, and 6 of the parotid gland) were reviewed and analyzed with a immunohistochemical panel, with special emphasis on cell cycle proteins. The tumors were tested for HPV by in situ hybridization (GenPoint HPV, Dako) and PCR (SPF10-DEIA-LiPA25). Merkel cell polyomavirus was studied using the antibody CM2B4. Fifteen HGNEC were of small cell and 4 of large cell type. Most of the tumors (14/19, 73.7 %), including all the pure small cell carcinomas, showed a strong and diffuse positive staining for p16. Eleven of them (78.5 %) had Rb loss and a low or absent cyclin D1 expression. All cases were negative for HPV and polyomavirus. Most patients were smokers, diagnosed at advanced stages of the disease, and had a poor outcome, with a 5-year survival of 18 %. In conclusion, HGNECs of the head and neck are infrequently related to HPV infection, but usually show strong, diffuse positive p16 immunostaining due to Rb pathway dysregulation. Awareness of this immunohistochemical pattern of expression may avoid a potential diagnostic pitfall with HPV-associated non-keratinizing squamous cell carcinomas, which have a better prognosis.

To explore in women with late-onset preeclampsia (PE) the association between maternal levels of angiogenic/antiangiogenic factors in the first trimester of pregnancy and histological findings attributable to placental underperfusion (PUP).A nested case-control cohort study was conducted in 73 women with pregnancies complicated by late-onset PE (34 weeks at delivery) matched with controls. First trimester uterine artery Doppler (UtA); maternal levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were retrieved. Placentas were histologically evaluated using a hierarchical and standardized classification system. One-way ANOVA with linear polynomial contrast or linear-by-linear association test was performed to test the hypothesis of a linear association across study groups (controls, PE without PUP and PE with PUP).In 54 (74%) placentas, 89 placental histological findings qualifying for PUP were found. Across study groups, significant values were observed in maternal levels of decreased PlGF (MoM values: 1.53, 1.41 and 1.37; p 0.001), increased sFlt-1 (MoM values: 3.11, 3.11 and 3.22; p = 0.002), increased sFlt-1/PlGF ratio (MoM values: 2.3, 2.3 and 2.44; p 0.001), abnormal UtA Doppler (MoM values: 1, 1.26 and 1.32; p 0.001), and worse perinatal outcomes in terms of gestational age at delivery, cesarean section for not reassuring fetal status, birth weight and neonatal acidosis.In late-onset PE an imbalance of circulating angiogenic and anti-angiogenic factors already present at 8-10 weeks of pregnancy was associated with histological findings reflecting placental insufficiency. An early first trimester screening by angiogenic factors might help to identify patients with placental involvement among late-onset PE cases.In late-onset preeclampsia, first-trimester uterine Doppler and circulating levels of angiogenic/antiangiogenic factors are associated with placental underperfusion.

Conde L, Vilaseca I, Alos L, Bernal-Sprekelsen M, Cardesa A & Nadal A (2012) Histopathology Methylthioadenosine phosphorylase inactivation depends on gene deletion in laryngeal squamous cell carcinoma Aims: Methylthioadenosine phosphorylase (MTAP) is an essential enzyme for the methionine and adenosine salvage pathway in normal cells, frequently inactivated in many different human cancers. MTAP status could be important for tumour cell sensitivity to adjuvant chemotherapy. To our knowledge, there have been no reports to date on MTAP status in laryngeal carcinoma. Methods and results: A series of 31 laryngeal squamous cell carcinomas was investigated for MTAP mRNA expression using reverse transcription and quantitative polymerase chain reaction (qPCR), as well as for MTAP gene deletion and/or promoter hypermethylation using qPCR and methylation-specific PCR, respectively. Low MTAP mRNA expression was found in 32% of cases, and was associated with MTAP gene deletion (in 70%; P

Objective To evaluate the value of maternal IgM to cytomegalovirus (CMV) as a predictive factor of fetal infection in fetuses with sonographic markers. Methods Observational study (2006–2011) including a consecutive series of 19 fetuses with sonographic markers of fetal infection and confirmed infection by positive CMV-DNA in amniotic fluid or fetal blood. We evaluated the status of maternal CMV IgM at the time of sonographic suspicion. Results During this 6-year study period, CMV infection was diagnosed in 19 fetuses from 18 pregnancies, including 16 singletons, both twins of a monochorionic diamniotic pregnancy and one twin of a dichorionic pregnancy. Sonographic suspicion was established on the basis of one or more of the following: brain abnormalities (14), fetal hydrops (4), hyperechogenic bowel (4), pericardial effusion (1), cardiomegaly (1), oligoanhydramnios (4), and placentomegaly (2). Maternal IgG antibodies were positive in all cases but maternal IgM antibodies were negative in 56% of pregnancies. Five of the 10 pregnancies with negative maternal IgM were diagnosed in the second trimester and five in the third trimester. Conclusion In around half of fetuses with confirmed CMV infection ascertained by sonographic markers, maternal IgM antibodies are negative and should therefore not be used as a diagnostic parameter. © 2012 John Wiley & Sons, Ltd.