Infrapatellar fat pad adipose tissue-derived macrophages display a predominant CD11c+CD206+ phenotype and express genotypes attributable to key features of OA pathogenesis.

Objectives: In knee osteoarthritis (OA), macrophages are the most predominant immune cells that infiltrate synovial tissues and infrapatellar fat pads (IPFPs). Both M1 and M2 macrophages have been described, but their role in OA has not been fully investigated. Therefore, we investigated macrophage subpopulations in IPFPs and synovial tissues of knee OA patients and their correlation with disease severity, examined their transcriptomics, and tested for factors that influenced their polarization. Methods: Synovial tissues and IPFPs were obtained from knee OA patients undergoing total knee arthroplasty. Macrophages isolated from these joint tissues were characterized via flow cytometry. Transcriptomic profiling of each macrophage subpopulations was performed using NanoString technology. Peripheral blood monocyte-derived macrophages (MDMs) were treated with synovial fluid and synovial tissue- and IPFP-conditioned media. Synovial fluid-treated MDMs were treated with platelet-rich plasma (PRP) and its effects on macrophage polarization were observed. Results: Our findings show that CD11c+CD206+ macrophages were predominant in IPFPs and synovial tissues compared to other macrophage subpopulations (CD11c+CD206-, CD11c-CD206+, and CD11c-CD206- macrophages) of knee OA patients. The abundance of macrophages in IPFPs reflected those in synovial tissues but did not correlate with disease severity as determined from Mankin scoring of cartilage destruction. Our transcriptomics data demonstrated highly expressed genes that were related to OA pathogenesis in CD11c+CD206+ macrophages than CD11c+CD206-, CD11c-CD206+, and CD11c-CD206- macrophages. In addition, MDMs treated with synovial fluid, synovial tissue-conditioned media, or IPFP-conditioned media resulted in different polarization profiles of MDMs. IPFP-conditioned media induced increases in CD86+CD206+ MDMs, whereas synovial tissue-conditioned media induced increases in CD86+CD206- MDMs. Synovial fluid treatment (at 1:8 dilution) induced a very subtle polarization in each macrophage subpopulation. PRP was able to shift macrophage subpopulations and partially reverse the profiles of synovial fluid-treated MDMs. Conclusion: Our study provides an insight on the phenotypes and genotypes of macrophages found in IPFPs and synovial tissues of knee OA patients. We also show that the microenvironment plays a role in driving macrophages to polarize differently and shifting macrophage profiles can be reversed by PRP.

Fine needle aspiration of spindle cell lipoma-Lochkern cells as a clue for diagnosis: A case arising in the parotid gland.

Spindle cell lipoma (SCL) is a rare form of lipoma, typically occurring as a mass in the back, shoulder or posterior neck of adult males. Most cases present little diagnostic difficulty on fine needle aspiration (FNA), but can be problematic when the SCL is in an unusual location. The authors report a case in the parotid gland in a 75-year-old man. FNA was paucicellular and showed loose collections of spindle cells with mild to moderate atypia, admixed with ropy collagen fibers on a myxoid background. The nuclei showed occasional angulation, interpreted on FNA as suspicious for myoepithelial tumor or low-grade sarcoma. The subsequent excisional specimen was diagnosed as SCL. On retrospective review of the FNA, an additional finding was recognized: 'naked' nuclei with intranuclear lipid vacuoles and positive immunostaining for S100 protein, consistent with Lochkern cells of mature adipocytes. This case highlights the challenges of diagnosing SCL on cytology when no fat-containing cells are apparent on the smear, and stresses the significance of Lochkern cells as a clue for diagnosis.

Acantholytic squamous cell carcinoma mimicking epithelioid angiosarcoma: A diagnostic challenge by cytology.

Squamous cell carcinoma (SCC) is the most common malignancy of the head and neck region. Most cases present little diagnostic difficulty on fine needle aspiration (FNA), but unusual variants can be problematic. The authors report a case of the acantholytic SCC of the oral cavity in a 36-year-old male. The FNA showed hypercellularity, with malignant cells arranged in isolation, loosely cohesive groups and a linear configuration. Such cells were round to elongated, with vesicular nuclei and prominent nucleoli. Cells possessed occasional intracytoplasmic vacuoles, misinterpreted on FNA to be vasoformative features as seen in malignant endothelial cells. The cytologic diagnosis was "positive for malignancy, suggestive of angiosarcoma". A total excision was performed and by histology, the tumor was diagnosed as acantholytic SCC. The malignant cells were positive by immunostaining for AE1/AE3, p40, p63 and vimentin, but negative for CD31, CD34 and ERG. The intracytoplasmic vacuoles were PAS- and mucin-negative and negative for the above antibodies. Testing for HPV (molecular and p16 immunostaining) was negative. This case highlights the diagnostic challenges on cytology when malignant acantholytic squamous cells show intracytoplasmic vacuoles, and stresses how immunohistochemistry is important for distinguishing acantholytic SCC from other mimics.

The Usefulness of Resistant Maltodextrin and Chitosan Oligosaccharide in Management of Gut Leakage and Microbiota in Chronic Kidney Disease.

Microbiota-dysbiosis-induced gut leakage is a pathophysiologic change in chronic kidney disease (CKD), leading to the production of several uremic toxins and their absorption into the bloodstream to worsen the renal complications. We evaluate the benefits of resistant maltodextrin (RMD) and chitosan oligosaccharide (COS) supplements in cell culture and CKD-induced rats. The RMD exerted a significant anti-inflammatory effect in vitro and intestinal occludin and zonula occluden-1 up-regulation in CKD rats compared with inulin and COS. While all prebiotics slightly improved gut dysbiosis, RMD remarkably promoted the relative abundance and the combined abundance of Lactobacillus, Bifidobacteria, Akkermansia, and Roseburia in CKD rats. Supplements of RMD should be advantageous in the treatment of gut leakage and microbiota dysbiosis in CKD.

Placenta-Derived Extracellular Vesicles in Pregnancy Complications and Prospects on a Liquid Biopsy for Hemoglobin Bart's Disease.

Extracellular vesicles (EVs) are nano-scaled vesicles released from all cell types into extracellular fluids and specifically contain signature molecules of the original cells and tissues, including the placenta. Placenta-derived EVs can be detected in maternal circulation at as early as six weeks of gestation, and their release can be triggered by the oxygen level and glucose concentration. Placental-associated complications such as preeclampsia, fetal growth restriction, and gestational diabetes have alterations in placenta-derived EVs in maternal plasma, and this can be used as a liquid biopsy for the diagnosis, prediction, and monitoring of such pregnancy complications. Alpha-thalassemia major ("homozygous alpha-thalassemia-1") or hemoglobin Bart's disease is the most severe form of thalassemia disease, and this condition is lethal for the fetus. Women with Bart's hydrops fetalis demonstrate signs of placental hypoxia and placentomegaly, thereby placenta-derived EVs provide an opportunity for a non-invasive liquid biopsy of this lethal condition. In this article, we introduced clinical features and current diagnostic markers of Bart's hydrops fetalis, extensively summarize the characteristics and biology of placenta-derived EVs, and discuss the challenges and opportunities of placenta-derived EVs as part of diagnostic tests for placental complications focusing on Bart's hydrop fetalis.

Multisystem inflammatory syndrome in children (MIS-C) showing disseminated aspergillosis, cytomegalovirus reactivation and persistent SARS-COV-2: Case report with autopsy review.

Multisystem inflammatory syndrome in children (MIS-C) is an emerging phenomenon associated with SARS-COV-2 infection (COVID-19) occurring in < 1 % of infected children. MIS-C is characterized by a hyperinflammatory state with excessive cytokine release ('storm') leading to hemodynamic compromise and multiorgan failure, with a death rate of ∼2 %. Autopsy examination can play a particularly important role in helping to understand the pathogenesis of MIS-C. Yet, only five autopsy studies have been reported to date. We report a fatal case of MIS-C involving a previously healthy, 5-year-old Thai boy admitted with MIS-C, one month after exposure to SARS-COV-2. While in intensive care, he was found to have a hypertrophic cardiomyopathy, and despite immunosuppressive treatment for MIS-C, developed shock and died. Multiorgan inflammation was not found at autopsy, implying that the MIS-C had responded to treatment. However, there was disseminated aspergillosis and cytomegalovirus reactivation, attributed to the immunosuppression. SARS-COV-2 virus was also found in multiple organs. To the best of our knowledge, this is the first reported autopsy of an MIS-C patient from Asia, and the first report of aspergillosis in MIS-C. This case underscores that the risks of immunosuppression are also a concern in MIS-C. Although MIS-C is generally considered to be a post-infectious hyperimmune reaction, persistence of SARS-COV-2 is a feature in all autopsies of MIS-C patients reported to date, suggesting a possible role in the pathogenesis, at least in fatal cases.

Classification of stillbirth by the International Classification of Diseases for Perinatal Mortality using a sequential approach: A 20-year retrospective study from Thailand.

AIM: The International Classification of Diseases for Perinatal Mortality (ICD-PM) is a system for recording causes of perinatal death. In this system, placental pathology is considered a "maternal condition" and this category does not cover the spectrum of placental pathology that can impact on perinatal death. The aim of the study was to apply a wider spectrum of placental pathology as a separate parameter for classifying death in the ICD-PM. METHODS: All autopsy reports at a single institution over a 20-year period (2001-2020) were reviewed. Causes of stillbirth were analyzed in a sequential manner: step 1, clinical history and laboratory results; step 2, placenta; and step 3, autopsy; and classified at each step according to the ICD-PM. RESULTS: The review identified 330 cases, including 126 antepartum and 204 intrapartum deaths. Step 1 identified a cause in 176 (86%) intrapartum deaths and 64 (51%) antepartum deaths. The addition of placental pathology (step 2) changed the cause of death in 12% of cases, with causes now identified in 190 (93%) intrapartum and 89 (71%) antepartum deaths. Adding step 3 did not identify any additional causes of death. CONCLUSION: The accuracy of the ICD-PM classification is dependent on the data available. Placental pathology made a significant difference in assigning causes of death in our series, stressing the importance of placental examination. Determination of the cause of death based on clinical history and laboratory data alone may be inaccurate, and less useful for comparative studies and planning prenatal care.

Excessive Subchorionic Fibrinoid Deposition as a Component of Massive Perivillous Fibrin Deposition: A Case With Maternal Immune Thrombocytopenia.

Maternal floor infarction (MFI) and massive perivillous fibrin deposition (MPFD) are overlapping placental disorders of unknown etiology, associated with adverse obstetric outcome, and a significant risk of recurrence. We describe a 31-year-old mother with asymptomatic thrombocytopenia throughout pregnancy and a positive lupus anticoagulant. She delivered a normal female neonate at term, whose weight was small for gestational age, with a placenta weighing less than the 10th percentile. Placental examination showed MPFD together with excessive subchorionic fibrinoid deposition. The placenta showed diffuse C4d deposition and an immune-mediated reaction was postulated for the pathogenesis of the placental changes. We suggest that excessive subchorionic fibrinoid deposition may be part of the morphologic spectrum of MFI/MPFD.

Placental Findings Contributing to Perinatal Death: A 15-Year Retrospective Review from a Teaching Hospital in Thailand.

Introduction: The placenta is infrequently examined in developing countries. This study examined the role of placental pathology in perinatal deaths at Chulalongkorn University Hospital, Bangkok. Methods: Included were singleton intrauterine deaths after gestational week 20 and live-born infants up to 1 week old, over a 15-year period. Placental lesions were classified as: inflammatory-immune, maternal stromal-vascular, fetal stromal-vascular, umbilical cord complications and other. Results: 208 such cases had the placenta available. A placental cause of death was found in 96 (46%), non-placental causes in 28% and the cause of death was unknown in 26%. Of those 96 placentas, 44% were categorized as inflammatory-immune, 30% maternal stromal-vascular, 13% fetal stromal-vascular, 7% umbilical cord complications and 6% other. Conclusions: Placental causes of death were less common than in many Western studies, but inflammatory-immune processes more common. These differences may relate to how cases were accrued, and/or local socioeconomic factors, and warrant further study.

Combined Placental Maternal Floor Infarction and Cytomegalovirus Placentitis: A Case Report.

BackgroundMaternal floor infarction (MFI) and massive perivillous fibrin deposition (MPFD) are uncommon, related placental conditions secondary to trophoblastic cell damage. The etiology is unknown but MPFD/MFI is associated with adverse obstetric outcome and a significant risk of recurrence. Case report: We report a case of MPFD/MFI associated with cytomegalovirus (CMV) placentitis. A 27-year-old mother delivered a stillborn male fetus with a postmortem diagnosis of congenital CMV. The placenta showed a lymphohistiocytic villitis with isolated CMV inclusions, in combination with MFI. The villitis had features intermediate between CMV placentitis and villitis of unknown etiology (VUE). Conclusion: VUE is considered to be a maternal anti-fetal immune reaction resembling allograft rejection. We postulate that the viral infection in our case may have triggered this immune response, given that CMV antigens are known to cross react with some human antigens, in particular HLA. The subsequent trophoblastic cell damage could then lead to MFI/MFPD.

Massive Perivillous Fibrin Deposition Associated With Placental Syphilis: A Case Report.

Massive perivillous fibrin deposition (MPFD) and the related entity of maternal floor infarction (MFI) are uncommon placental disorders of unknown etiology, associated with adverse obstetric outcome and a significant risk of recurrence. We describe a 19-year-old mother with untreated syphilis who delivered a male neonate with low birth weight, skin desquamation, and pneumonia. Placenta examination showed the expected changes for syphilis but unexpectedly, also showed MPFD. To our knowledge, this is the first report of MPFD associated with placental syphilis, thus expanding the list of etiologies that may be related to MPFD/MFI. It is postulated that the syphilis infection in our case led to a hypercoaguable state, eventually resulting in MPFD. In the right clinical setting, syphilis might be considered in the differential diagnosis when MPFD/MFI is observed on placental examination. The recurrence risk of MFPD/MFI associated with infections is believed to be lower than idiopathic cases and, by extrapolation, this lower risk should apply to syphilis as well.

Pleomorphic adenoma with bizarre myoepithelial cells: A diagnostic challenge on cytologic smear.

The diagnosis on fine needle aspiration of salivary gland tumors with a myoepithelial component is challenging because myoepithelial cells can have a wide cytomorphologic spectrum. The authors report a case of a pleomorphic adenoma of the parotid gland that expands the spectrum of appearances that myoepithelial cells can show with this tumor. A 55-year-old female was found to have a right parotid gland mass. FNA showed hypercellularity, with loosely cohesive fragments of spindle-shaped myoepithelial cells admixed with small nests of epithelial cells. Interspersed may occasional bizarre cells possessing severely pleomorphic nuclei with hyperchromasia. The cytologic diagnosis was "suspicious for carcinoma ex pleomorphic adenoma." A total parotidectomy was performed with complete resection of the tumor that was confirmed to be a pleomorphic adenoma. The pleomorphic cells noted on FNA were scattered throughout the tumor, and were positive by immunostaining for keratin, S-100 protein and p63, identifying them as myoepithelial cells. These cells did not show mitotic activity and were negative for Ki67. The pleomorphic adenoma showed extensive degenerative changes including central cyst formation, stromal hyalinization and hemosiderin deposition. On the basis of the combined light microscopic and immunohistochemical findings, there was no evidence to support a malignant change in the pleomorphic adenoma. It was concluded the pleomorphic myoepithelial cells were a degenerative change, reminiscent of what is seen in "ancient" schwannoma and some uterine leiomyomata. Our case expands the spectrum of appearances that can be seen in myoepithelial cells in the salivary gland.

Cardiac Findings in Fetal and Pediatric Autopsies: A 15-Year Retrospective Review.

INTRODUCTION: Congenital heart defects (CHDs) carry significant morbidity and mortality in pediatric patients. This study determined the spectrum of CHDs based on fetal and pediatric autopsies. METHODS: Autopsy reports over a 15-year period were reviewed. Postmortem findings were correlated with echocardiography records. RESULTS: From 608 autopsies, 119 cases with CHDs were identified (11% of fetal, 53% of neonatal, 18% of infant, and 4.5% of childhood autopsies). Persistent left superior vena cava was the most common individual defect. 41% of cases had extracardiac malformations. 18.5% of cases had chromosomal abnormalities. Prenatal echocardiography was available in 52 cases, showing 85% correlation with autopsy findings. Defects missed by echocardiography were generally of mild severity. CONCLUSION: Postmortem examination is important to delineate the anatomy of CHDs, and recognize extracardiac malformations for identification of possible genetic syndromes. This information can be used for parental counseling and for assessment of accuracy of pre-mortem imaging studies.

Electron Microscopy Can Still Have a Role in the Diagnosis of Selected Inborn Errors of Metabolism.

Many anatomic pathology laboratories no longer have electron microscopy facilities. A retrospective review of autopsies was performed to identify cases of inborn errors of metabolism (IEM) and determine the contribution of electron microscopy in making the diagnosis in those cases. Over a period of 17 years, there were 900 perinatal and pediatric autopsies. There were 7 cases (1%) of IEM, including 4 cases of Pompe disease, 1 case of I-cell disease, 1 case of bile acid synthesis defect, and 1 case of mitochondrial disease (Leigh syndrome). Electron microscopy was important in the diagnosis of I-cell disease and Pompe disease in our series. This technique enabled a prenatal diagnosis to be made from a chorionic villus biopsy in 2 cases with a positive family history. In less developed countries where upfront genetic testing may be too expensive and may need international referral, electron microscopy can still be useful for diagnosis of IEM, providing an affordable alternative with a more rapid turnaround time compared to gene mutation analysis or enzyme assay. Results can be used both for patient management and as a screen for which cases might benefit from genetic testing.

Paediatric oral pathology in Thailand: a 15-year retrospective review from a medical teaching hospital.

OBJECTIVES: To determine whether the spectrum of oral pathology in children seen at a medical institution differs from studies derived from dental facilities. METHODS: Oral biopsy records from paediatric patients (<16 years of age) were retrieved from the pathology archives at Chulalongkorn University Hospital over a period of 15 years. Lesions were categorised as inflammatory/reactive, tumour/tumour-like or cystic. RESULTS: Two-hundred and thirty biopsies were identified. Most lesions were inflammatory/reactive (62%), followed by tumour/tumour-like (35%) and cystic (3%). The largest proportion of lesions was found in the 12-16 years' age group. Mucocele was the most common lesion (38%), followed by hemangioma (8.3%), irritation fibroma (6%) and nevus (6%). The predominance of mucocele is similar to that in reports from other countries. The proportion of malignant tumours (5%) was higher than in other studies (<1-2%). In contrast, odontogenic cysts and odontogenic tumours were rare (3% and <1%, respectively), compared with published studies (7-35% and 2-21%, respectively). CONCLUSIONS: This study from a medical institution shows a somewhat different spectrum of paediatric oral pathology compared with that reported from dental institutions. While some of the lesions may not be treated by dentists, they still need to be aware of these lesions because affected patients can still present initially to a dentist.

Pulmonary Neuroendocrine Cell Hyperplasia in Hemoglobin Bart-induced Hydrops Fetalis: A model for Chronic Intrauterine Hypoxia.

The pulmonary neuroendocrine system includes pulmonary neuroendocrine cells (PNECs) and neuroepithelial bodies (NEBs) that are distributed throughout respiratory epithelium and regulate lung growth and maturation antenatally. Abnormalities in this system have been linked to many hypoxia-associated pediatric pulmonary disorders. Hemoglobin (Hb) Bart disease is a severe form of α-thalassemia resulting in marked intrauterine hypoxia with hydrops fetalis (HF) and usually death in utero. Affected fetuses can serve as a naturally occurring human model for the effects of intrauterine hypoxia, and we postulated that these effects should include changes in the pulmonary neuroendocrine system. Bombesin immunostaining was used to assess PNECs and NEBs in stillborn fetuses with Hb Bart HF ( n = 16) and with HF from other causes ( n = 14) in comparison to non-HF controls. Hb Bart HF showed a significant increase in the proportion of PNECs in respiratory epithelium ( P = .002), mean number of NEB nuclei ( P = .03), and mean size of NEBs ( P = .002), compared to normal non-HF controls. Significant differences were not observed between HF due to other causes and non-HF controls with normal lungs. Non-HF controls with pulmonary hypoplasia showed significant increases in PNECs compared to HF cases not due to Hb Bart HF, implying HF alone does not cause such increases. In contrast, no significant differences were noted between non-HF controls with pulmonary hypoplasia and Hb Bart cases. Hb Bart HF may provide a useful model for studying the pulmonary neuroendocrine system under chronic intrauterine hypoxia.

Hemoglobin Bart hydrops fetalis: A model for studying vascular changes in placental hypoxia.

INTRODUCTION: Placental ischemia can be pre-placental (maternal), placental or post-placental (fetal), with corresponding changes in villous vasculature. Hydrops fetalis (HF) resulting from hemoglobin (Hb) Bart disease can serve as a model for intrauterine hypoxia, and placentas from such cases show a distinctive peripheral villous stromal myofibroblastic hypercellularity (PVSH). We hypothesized that Hb Bart disease, which results in profound fetal hypoxia, would lead to placental hypoxia on a post-placental basis. METHODS: We assessed villous vasculature using computerized morphometry, comparing placentas in 14 Hb Bart HF cases to 18 non-Hb Bart HF cases. Morphometric parameters were matched as closely as possible to those reported in the literature for comparison purposes. RESULTS: Villous vessels of Hb Bart HF showed significantly increased numbers of vessels (p = 0.001), longer vascular perimeter (p = 0.002), thickening of vascular endothelial layer (p = 0.038) and higher shape coefficient (p = 0.042) indicating a more branching pattern of vessels. In addition, placental villi of Hb Bart HF containing PVSH showed a longer vascular perimeter (p = 0.008) and narrower lumen (p = 0.002), with a higher shape coefficient (p = 0.03), in comparison to villi lacking PVSH. DISCUSSION: Contrary to expectations, the overall pattern of vascular changes in Hb Bart HF suggested multifactorial hypoxia: pre-placental, on the basis of the marked placentomegaly, compromising blood flow from uterine distention; placental, from hydropic villi causing a generalized diminished intervillous space; and post-placental from the greatly reduced capacity of Hb Bart to extract oxygen from the intervillous space. Standardized vascular morphometry will facilitate comparison between different conditions, for a better understanding of placental hypoxia.

Maternal Floor Infarction/Massive Perivillous Fibrin Deposition Associated with Hypercoiling of a Single-Artery Umbilical Cord: A Case Report.

Maternal floor infarction is a rare and idiopathic placental disorder associated with adverse obstetric outcomes and a high rate of recurrence in subsequent pregnancies. The pathogenesis of maternal floor infarction is unclear but has been linked to diverse underlying maternal conditions, including gestational hypertension/preeclampsia, immune-mediated diseases, and thrombophilia. Few reports link maternal floor infarction to fetoplacental conditions. We report a 34-week, macerated, growth-restricted male fetus for which the placenta showed maternal floor infarction. The umbilical cord showed excessive coiling and a single umbilical artery. These cord changes are postulated to have resulted in increased placental villous resistance and decreased fetal blood flow, creating a hydrostatic pressure gradient between the villous stroma and the intervillous space. The pressure changes could then lead to trophoblast damage and fibrinoid deposition, contributing to the maternal floor infarction in this case.

Thyroid Paraganglioma: "Naked" Nuclei as a Clue to Diagnosis on Imprint Cytology.

A cytologic diagnosis of paraganglioma of the thyroid is difficult to make because the thyroid gland is an unusual location for such a tumor and the cytologic findings overlap with other benign and malignant thyroid tumors. We report the case of a 28-year-old female presenting with a solitary mass of the right thyroid gland. A diagnosis of paraganglioma was made on the resected specimen. At the time of tumor resection, imprint cytology was performed. The imprint was hypercellular with cohesive sheets of round cells showing anisokaryosis and anisocytosis. Moreover, there was a second cell type consisting of oval nuclei with dispersed nuclear chromatin present within the sheets and separate as "naked" nuclei. By immunohistochemistry, the cohesive round cells were positive for chromogranin A, indicating chief cells. The naked nuclei were positive for S-100 protein, indicating sustentacular cells. To the best our knowledge, this is the first case report describing naked nuclei as a cytologic feature of paraganglioma. Identification of sustentacular cells provides a clue for the cytologic diagnosis of paraganglioma.