Thyroid Fine Needle Aspiration, the Bethesda System, and the BRAFV600E Mutation in Papillary Thyroid Carcinoma: Association and Prediction for Biopsy.

INTRODUCTION: BRAFV600E mutations have been associated with papillary thyroid carcinoma (PTC) histological types including tall-cell and classical, peritumoral infiltration, and nuclear signs, whereas cytological features such as plump cells and sickle nuclei have also been associated with favorable thyroid fine needle aspiration (FNA) results for this tumor. BRAF and RAS are considered early driver mutations that contribute to the development of BRAF-like PTCs and RAS-like PTCs. Our aim was to assess the possible association between all Bethesda System cytological features and thyroid FNAs for PTC and their potential predictive value for future BRAFV600E-related biopsies. METHODS: Our study analyzed 63 cases of PTCs operated on at our hospital over a 5-year period between 2005 and 2017 that had previously undergone FNA and had been classified by the Bethesda System. BRAFV600E was identified by pyrosequencing paraffin-embedded tissues and comparing the cytological signs with the Bethesda System. In addition, a statistical and predictive study of the diagnostic factors "non-follicular," "non-round nuclei," and "non-clear chromatin" was performed to discriminate BRAF-like signs from other hypothetical RAS-like follicular signs. RESULTS: BRAFV600E was detected in 43/63 cases (68.2%). Histological types were significant (p < 0.001), with the classical variant being the most prevalent 31/63 (49.2%) and independent by multivariate analysis odds ratio of 10.58 [2.67; 41.97]. Follicular cytological signs are negatively associated with BRAFV600E: follicular structure (p < 0.001), round nuclei (p = 0.015), and clear chromatin (p = 0.049), while the diagnostic factors: "non-follicular" (positive predictive value [PPV] 82.9, sensitivity 79.1, negative predictive value [NPV] 59.1, specificity 65.0), "non-round nuclei" (PPV 76.6, sensitivity 83.7, NPV 56.3, specificity 45.0), and "non-clear chromatin" (PPV 75.6, sensitivity 79.1, NPV 50.0, specificity 45.0) have predictive value for the mutation. There was no individual significance for the remaining cytological features. CONCLUSIONS: Our study found no association between cytomorphological signs of thyroid FNA and BRAFV600E mutation. Considering the Bethesda System, there is an association (p = 0.045) with numerous cases of mutated PTC in categories V and VI. Our results indicate, however, that the presence of signs referred to as "non-follicular," "non-round nuclei," and "non-clear chromatin" in biopsy of papillary thyroid carcinoma is predictive of BRAF type mutation, whereas follicular signs indicate a RAS type PTC, according to published literature. These results need to be confirmed or modified by further research.

SOCS2 protects against chemical-induced hepatocellular carcinoma progression by modulating inflammation and cell proliferation in the liver.

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide, but the precise intracellular mechanisms underlying the progression of this inflammation associated cancer are not well established. SOCS2 protein plays an important role in the carcinogenesis of different tumors by regulating cytokine signalling through the JAK/STAT axis. However, its role in HCC is unclear. Here, we investigate the role of SOCS2 in HCC progression and its potential as HCC biomarker. The effects of SOCS2 in HCC progression were evaluated in an experimental model of diethylnitrosamine (DEN)-induced HCC in C57BL/6 and SOCS2 deficient mice, in cultured hepatic cells, and in liver samples from HCC patients. Mice lacking SOCS2 showed higher liver tumor burden with increased malignancy grade, inflammation, fibrosis, and proliferation than their controls. Protein and gene expression analysis reported higher pSTAT5 and pSTAT3 activation, upregulation of different proteins involved in survival and proliferation, and increased levels of proinflammatory and pro-tumoral mediators in the absence of SOCS2. Clinically relevant, downregulated expression of SOCS2 was found in neoplasia from HCC patients compared to healthy liver tissue, correlating with the malignancy grade. In summary, our data show that lack of SOCS2 increases susceptibility to chemical-induced HCC and suggest the tumor suppressor role of this protein by regulating the oncogenic and inflammatory responses mediated by STAT5 and STAT3 in the liver. Hence, SOCS2 emerges as an attractive target molecule and potential biomarker to deepen in the study of HCC treatment.

Adult-onset Alexander disease with a heterozygous D128N GFAP mutation: a pathological study.

The various forms of Alexander disease (AD) have been linked to heterozygous point mutations in the coding region of the human Glial Fibrillary Acidic Protein (GFAP) gene. The aim of this study was to confirm and characterise an adult variant of AD based on the presence of Rosenthal fibres, which were identified at brain autopsy. We performed histological and immunohistochemical studies and mutation screening by cycle sequencing of exons 1, 4, 6, and 8. A heterozygous D128N GFAP mutation, previously described in three other cases of adult-onset AD (AOAD), was genetically confirmed. The mutation was seemingly sporadic. Symptoms of the female, 65-year-old patient started with occasionally asymmetric motor impairment and concluded, 23 months later, with a lack of spontaneous movement in all four limbs, reduced consciousness, an acute respiratory problem, and eventually lethal exitus. The most striking characteristics were a cerebellar syndrome with subsequent clinical signs due to brainstem and spinal cord involvement. The final diagnosis was based on a complete autopsy, detection of Rosenthal fibres, GFAP, vimentin, alpha B-crystallin, ubiquitin, hsp27, neurofilament, and synaptophysin, and the identification of the corresponding GFAP gene mutation. Blood analyses were positive for ANA and rheumatoid factor. In conclusion, this work describes sporadic, rapidly advancing AOAD in a female patient and links it with other published cases with the same mutation. Reflections are provided on the influence of vasculitis and ANA in AD as well as the presence of Rosenthal fibres in the neurohypophysis.

Distinct Patterns of Hair Graft Survival After Transplantation Into 2 Nonhealing Ulcers: Is Location Everything?

BACKGROUND: Studies highlighting the role of hair follicles (HFs) in wound healing have raised the challenge of bringing this knowledge to clinical applications. A successful translation is the transplantation of scalp HFs into chronic wounds to promote healing. OBJECTIVE: To characterize scar formation and hair growth in nonhealing ulcers after transplantation. PATIENTS AND METHODS: Nonhealing ulcers were treated with hair transplantation to promote wound healing. Hair follicles were harvested from the patient's scalp and inserted into the wound bed. Wound repair and hair growth were assessed clinically. Further analyses were performed in situ, using biopsies from the central and peripheral scar. RESULTS: Rapid wound closure and differences of scar quality and hair growth between the central and peripheral wound areas were observed: the periphery healed with no hair shaft survival and an almost scarless appearance, the center healed with a fibrotic scar, with some hair shaft growth. In situ analyses revealed differences in dermal remodeling and collagen formation between central and peripheral scar areas. CONCLUSION: Besides confirming the effectiveness of this therapy to promote wound healing in human skin, location-dependent disparities in scar quality and hair growth raise the intriguing question whether they are due to clinically important differences in mechanical forces and/or wound microenvironments between ulcer center and periphery.

[Hepatocholangiocarcinoma in young patient with a giant liver tumour]. / Hepatocolangiocarcinoma en paciente joven con tumoración hepática gigante.

BACKGROUND: Combined hepatocellular-cholangiocarcinoma is a rare primary hepatic tumour, showing both hepatocellular as well as biliary epithelium differentiation. Its diagnosis is often delayed, as it occurs in young patients without comorbidities and with non-specific symptoms. Most cases are confused with other types of cancer, especially fibrolamellar liver cancer, which is more frequent and has similar clinical and radiological features. CLINICAL CASE: The case is presented of a 26 year old woman with a giant combined hepatocellular-cholangiocarcinoma with difficulties in its diagnosis and a complicated surgical approach. DISCUSSION: The definitive diagnosis of this disease is defined by the histological demonstration of cholangiolar and hepatocellular differentiation, with surgical treatment always being the best choice, but with lower survival than classic hepatocellular carcinoma and cholangiocarcinoma. In some patients with unfavourable prognostic factors, adjuvant chemotherapy mainly directed cholangiolar component can be given. CONCLUSION: The current incidence of combined hepatocellular-cholangiocarcinoma varies from 2 to 5% of cases, and is one of the rarest histological types in the world. The large size and hypervascularisation of the tumour makes a surgical approach difficult in these patients, while the rare histological features require a more detailed study of the piece and the application of immunohistochemical techniques to confirm the diagnosis.

Acute myocardial infarction secondary to catecholamine release owing to cocaine abuse and pheochromocytoma crisis.

Most pheochromocytomas are not suspected clinically while a high percentage of them are curable with surgery. We present the case of an adult cocaine-addicted male patient with an underlying pheochromocytoma and repeated myocardial infarctions. Computed tomography showed a left round adrenal mass, also high 24-hour urine levels of catecholamines and metanephrines were detected from urinalysis. The patient was given alpha and beta blockers, moreover a laparoscopic left adrenalectomy was performed. Cocaine can block the reuptake of noradrenaline, leading to increasing its concentration and consequently its effects as well, and induce local or diffuse coronary vasoconstriction in normal coronary artery segments per se, cocaine can also trigger pheochromocytoma crisis, and therefore, cardiac complications such as myocardial infarction due to these additive effects are intended to occur. For this reason, in the presence of typical clinical manifestations of pheochromocytoma, such as sustained or paroxysmal hypertension, headache, sweating, tachycardia and abdominal pain, probable association of this tumor in patients with cocaine abuse and associated cardiac complications must be ruled out.

Tetralogy of fallot associated with invasive adrenocortical tumor in an adult woman.

Migration of cardiac neural crest cells into the pharyngeal arches and the pharyngeal and splanchnic mesoderm contributes to the development of the cardiac outflow tract. The adrenal cortex is derived from the splanchnic mesoderm. Neuroblastoma is more prevalent in patients with congenital heart disease than in the general population, because both originate from embryonal neural crest-derived cells. Similarly, and in light of recent embryological findings, abnormal development or migration of splanchnic mesoderm, possibly due to an underlying genetic defect, could contribute to the association of adrenocortical carcinoma and tetralogy of Fallot. We present the case of a cardiologically asymptomatic 49-year-old woman with total correction of tetralogy of Fallot in the first year of life.

Ascites in adult patients with cyanotic congenital heart disease.

Hematologic, neurologic, renal, and rheumatic complications in patients with cyanotic congenital heart disease are well known. However, the effects of this condition on the liver are poorly described. Between April 2005 and April 2010, 25 adults with cyanotic congenital heart disease were studied to determine clinical history, liver ultrasonographic data, and liver histological presentation. Twenty-five patients, with a median age of 28.7 ± 8.3 years and a basal tissue hemoglobin oxygen saturation of 83.3% ± 6.8%, were studied. Liver ultrasonographic examination showed abnormalities in 10 of 20 patients (50%): 6 patients (30%) had hepatomegaly, 2 patients (10%) heterogeneous parenchyma echo pattern, and 2 patients (10%) increased portal echogenicity. Ascites was found in 7 patients (28%): 4 patients had refractory ascites and 3 patients anasarca. Patients with anasarca responded well to oral and intravenous furosemide, but those with isolated ascites did not. No data to indicate severe ventricular dysfunction or severe valve regurgitation were seen. In patients with refractory ascites who had therapeutic paracentesis, serum-ascites albumin gradient in ascites was greater than 1.1 g/dL. No significant association was found between patients with or without ascites when laboratory data and New York Heart Association functional class were compared. Liver biopsy was performed in 6 patients (24%). The most remarkable liver histological finding, in those with refractory ascites, was the existence of periportal fibrosis associated with sinusoidal dilatation. Periportal liver fibrosis associated with congestive heart failure, sepsis, or a long-term Fontan procedure can trigger refractory ascites formation.