Hyperplastic Nodules Research Articles

Sonic hedgehog signaling pathway mediates development of hepatocellular carcinoma.

Although abnormal activation of the sonic hedgehog (Shh) signaling pathway has been demonstrated in human hepatocellular carcinoma (HCC) patients and in most HCC cell lines, the mechanism by which the Shh pathway promotes the development of HCC remains uncertain. Using a liver cancer model induced by diethylnitrosamine (DEN) which mimics the process from liver injury, abnormal hepatocyte proliferation, and hepatocirrhosis to hepatocyte canceration, we investigated the abnormal activation of the Shh pathway by examining the expression of Shh, patched-1 (Ptch), smoothened (SMO), and glioma-associated oncogene-1 (Gli1) genes. During this process, the expression of CDK1 and cyclin B1 protein, which are two components of the M-phase promoting factor (MPF) controlling G2/M transition, was also examined to explore the potential relationship between Shh activation and cell cycle progression. We observed that the cells with Shh, Ptch, and Gli1 protein expression were mainly distributed in hyperplastic nodule, cancerous node, the epithelia of interlobular bile duct, and precancerous tissues. A gradually increasing tendency of the positive expression rate of Shh, Ptch, and Gli1 proteins in the process from the beginning normal tissue to the final cancer formation was revealed. The cyclin B1 and CDK1 expression level was higher in the DEN-induced rats as compared with normal rats, and their expression was mainly distributed in the portal area of the liver, hyperplastic nodule, cancerous node, and precancerous tissues. Our results suggested that the Shh signaling pathway is activated during liver carcinogenesis, and activated Shh signaling promotes the cell proliferation by facilitating the G2/M transition through increasing the expression of cyclin B1 and CDK1 protein, which eventually results in the development of liver cancer. Better understanding of the Shh signaling pathway in HCC may contribute to the development of novel therapeutic strategies in inhibiting cell proliferation and promoting cell cycle arrest.

Nodular Regenerative Hyperplasia Associated with Celiac Disease and Limited Sclerosis without Pulmonary Hypertension

Nodular Regenerative Hyperplasia (NRH) is a rare liver disease characterized by a diffuse transformation of the hepatic parenchyma into small regenerative hyperplastic and atrophic nodules, in the absence of fibrosis (1, 2). Due to the lack of major epidemiologic studies, most of the knowledge about NRH has been defined by case series (4). Reports have suggested the immune misbalance in Limited Sclerosis, Celiac Disease, and administration of immunosuppressants as possible causes of Obliterative Portal Venopathy (OPV) and NRH (4, 5). We present the first case to our knowledge, of a patient with OPV/NRH exacerbated by use of Azathioprine in the setting of simultaneous Celiac disease and Limited Sclerosis. Case Report: A 63 year old female presented with progressive increase in abdominal girth, shortness of breath and melena. She denied history of alcohol abuse or toxic exposure. Review of systems was significant for Raynaud's phenomenon, dysphagia and esophageal reflux. CBC showed anemia with normal platelet count. Liver panel showed mild elevation of alkaline phosphatase and normal levels of AST, ALT and bilirubin. Coagulation tests were normal. Viral hepatitis markers were negative. Serology was positive for antinuclear antibody, as well as transglutaminase and gliadin antibodies. At this point, antismooth muscle antibodies (ASMA) titers were 1:20, anti-mitochondrial, and anti-endomysial antibodies were negative. Echocardiogram showed normal ejection fraction with normal pulmonary pressures. CT scan of the abdomen revealed nodular contour of the liver with hypertrophic opacification of the Inferior Vena Cava and evidence of portal hypertension. The patient was clinically diagnosed with cryptogenic cirrhosis, and liver biopsy was arranged. While awaiting the result, she was encouraged to continue medical follow up. During outpatient rheumatologic consult, anti-centromere antibody was positive at high titers, as well as weak ASMA antibody titers. At this point, the patient was started on azathioprine. Two weeks later, she presented again with worsening abdominal distention, shortness of breath and multiple episodes of melena causing fatigue and dizziness. Pathological report of liver biopsy showed portal tracts with lymphoplasmacytic infiltrate, fibrosis, ductular reaction and centrilobular congestion, alternating with regenerative areas without signs of cirrhosis. She was treated with paracentesis, gentle diuresis, variceal banding, gluten restriction and discontinuation of azathioprine. Overall, her condition improved with these measures. Multiple conditions associated with NRH overlap in this case. Liver injury is a rare complication of Limited Sclerosis, Primary Biliary Cholangitis (PBC) being the most commonly reported disease (4). An overlapping syndrome including Limited Sclerosis, PBC and NRH has been established as well (6, 7). This patient had negative anti-mitochondrial antibodies. The liver biopsy findings were consistent with Obliterative Portal Venopathy and Nodular Regenerative Hyperplasia with secondary effect on the biliary tree, likely causing Secondary Sclerosing Cholangitis instead. Interestingly, there were no signs of pulmonary hypertension or extensive vascular damage to justify the development of Portal Venopathy. The clinical presentation, in addition to the weakly positive titers of anti-smooth muscle antibodies, erroneously led to the diagnosis of Autoimmune Hepatitis (AIH). Azathioprine, a mainstay of treatment for AIH, is an immunosuppressant that has been allegedly linked to the progression of NRH, consequently exacerbating this patient's symptoms (8, 9). Additionally, the patient was diagnosed with celiac disease, another disorder that can result in an increased immune reaction in the splenoportal axis of susceptible affected individuals (10, 11, 12). This reinforces that patients with Idiopathic Portal Hypertension should be evaluated for Celiac disease. Nodular Regenerative Hyperplasia appears to be an adaptive response to the vasculopathy that results in injury of the hepatocytes (1, 2), with the potential complications of portal hypertension, liver damage and death. This case highlights the difficulties that may be encountered in determining the etiology and proper treatment for this disease. It is of relevance to obtain a prompt liver biopsy, and an interdisciplinary approach with close communication between specialists. The coexistence of Obliterative Portal Venopathy, Celiac Disease, Limited Sclerosis and exposure to Azathioprine, supports the hypothesis of autoimmune mediation in the development of NRH and Portal Hypertension. With so many variables at play, further research in the field of liver immunology will be necessary to achieve a timely diagnosis and treatment of Nodular Regenerative Hyperplasia.Figure 1Figure 2Figure 3

Immunohistochemical detection of human intestinal spirochetosis

Human intestinal spirochetosis (HIS) is a colorectal infection by Brachyspira species of spiral bacteria. Immunohistochemical cross-reaction to an antibody for Treponema pallidum aids its histologic diagnosis. This study's aim was to analyze the immunohistochemical characteristics of HIS. In this analysis, on 223 specimens from 83 HIS cases, we focused on so-called fringe formation (a histologic hallmark of HIS), spiral organisms within mucus or within crypts, and strong immunopositive materials in the mucosa, together with their location and the types of lesions. Fringe formation was found in 81.6% of all specimens and spiral organisms within mucus or within crypts in 97.3% and 57.0%, respectively. Strong immunopositive materials were observed in the surface epithelial layer in 87.9%, in the subepithelial layer in 94.6%, and in deeper mucosa in 2.2% of all specimens. The positive rates in conventional adenomas (24.0%, n = 146) and hyperplastic nodules (100%, n = 17) were each different from that found in inflammation (70.8%, n = 24), and spiral organisms were seen more frequently in the right-side large intestine than in the left (within mucus, 100%, n = 104 versus 95.0%, n = 119; within crypts, 65.4%, n = 104 versus 49.6%, n = 119). Thus, immunohistochemistry was effective not only in supporting the diagnosis of HIS but also in highlighting spiral organisms within mucus or crypts that were invisible in routine histology. Possibly, these spiral organisms may spread throughout the entire large intestine, although there is a potential problem with antibody specificity.

Pseudohyperplastic Adenocarcinoma With Foamy Changes in Needle Prostate Biopsy and Prostatectomy.

Pseudohyperplastic adenocarcinoma (PHA) with foamy changes is composed of neoplastic glands that show a cytoarchitectural combination of both neoplasms. However, none of the previously reported cases have shown typical areas of foamy or PHA. We report on the clinicopathological characteristics of 5 cases consisting predominantly of pseudohyperplastic and foamy adenocarcinomas. In several histological fields, this neoplasm mimicked hyperplastic nodules or prostatic adenosis because they showed the nodular pattern of the PHA and the inconspicuous cytological atypia of foamy gland carcinoma. Four cases had a Gleason score of 6. In the prostatectomies, the neoplasm was limited to the prostatic gland. The evolution has been favorable in all patients after 3 years of follow-up, on average. The cases reported herein demonstrate that PHA and foamy adenocarcinoma may be associated and occasionally show overlapping histological criteria. The PHA with foamy changes must be distinguished from conventional foamy adenocarcinoma and PHA because it can closely resemble hyperplastic glands mainly in needle prostatic biopsy.

Value of distinguishing differentiated thyroid carcinoma by miRNA.

Current methods for diagnosing thyroid carcinoma are time consuming or expensive. Thus, alternative approaches are required. In the present study, microRNAs (miRNAs) with higher sensitivity and specificity were screened while distinguishing between differentiated thyroid carcinoma (DTC) and subtype papillary thyroid carcinoma (PTC). A total of 120 cases suspected of having thyroid carcinoma were selected and examined using clinical color Doppler ultrasound, and computed tomography scan at the same time. The tissue specimens were obtained with fine needle aspiration, multiphase biopsy and surgical resection. The expression of miR146b, miR221 and miR222 was detected uisng the RT-quantitative polymerase chain reaction method. The receiver operating characteristic curve was used to obtain the cut-off value. Pathological examination identified 8 cases of normal thyroid tissue; 9 cases of hyperplastic nodules; 12 cases of thyroid adenoma; and 91 cases of thyroid carcinoma, of which 59 cases were DTC, 15 cases were follicular carcinoma and 17 cases were undifferentiated carcinoma. In the thyroid carcinoma, the expression levels of miR146b, miR221 and miR222 were significantly higher than those of other tissues (P<0.05). The expression levels of these miRNAs in the differentiated type were also significantly higher than those in the undifferentiated type (P<0.05). A comparison of the differentiated subunit identified no statistically significant difference (P>0.05). Following diagnosis of DTC, the area under curve (AUC) of miR146b, miR221 and miR222 was 0.832, 0.806 and 0.745, respectively; the cut-off values were 1.346, 1.213 and 1.425, respectively; susceptibility was 72.8, 71.5 and 68.7%, respectively; and specificity was 62.3, 60.9 and 59.3%, respectively. The AUC of the combined miR-146b and −221 following diagnosis of PTC was 0.695; the cut-off values were 1.506 and 1.462, respectively; susceptibility was 78.9%; and specificity was 68.5%. The AUC of the combined miR-146b and −222 was 0.677; the cut-off values were 1.523 and 1.443, respectively; susceptibility was 76.3%; and specificity was 66.4%. The AUC of the combined miR-221 and −222 was 0.662; the cut-off values were 1.564 and 1.437, respectively; susceptibility was 74.9%; and specificity was 68.2%. In conclusion, miR146b, miR221 and miR222 may be used as susceptibility and specificity indices of DTC, although they cannot be used as susceptibility or specificity indices for distinguishing PTC. Combining the two indices together can improve diagnostic accuracy to a certain extent.

Feasibility Study of Texture Analysis Using Ultrasound Shear Wave Elastography to Predict Malignancy in Thyroid Nodules

Textural analysis of ultrasound shear wave elastography (SWE) was evaluated to discriminate benign and malignant thyroid nodules. Sixteen papillary thyroid cancers and 89 benign hyperplastic nodules in 105 patients underwent SWE using four static pre-compression levels. Fifteen gray level co-occurrence matrix textural features and six absolute SWE indices were computed from SWE images. Diagnostic performances of each SWE index for malignancy were calculated and compared using the area under the receiver operating characteristic curve (AUC), and optimal models were generated at each pre-compression level. The optimal model comprised two SWE textural features at the highest pre-compression level, which attained AUC, sensitivity and specificity of 0.973, 97.5% and 90.0%, respectively. By comparison, absolute SWE indices attained AUC of 0.709 as well as 18.8% sensitivity and 95.8% specificity. These preliminary results suggest SWE textural analysis can distinguish benign and malignant thyroid nodules and SWE spatial heterogeneity is greater in malignant nodules.

Morphological evaluation of non neoplastic lesions of the thyroid gland

Objective: This study was conducted to see the frequency of non neoplastic lesions of thyroid glands in patients who underwent thyroid surgery at Mayo hospital, Lahore. Study design: It was a descriptive cross sectional study. Place and Duration of study: It was a retrospective and prospective study commencing from Ist July 1999 to 30th June 2002 and was conducted at Pathology Department King Edward Medical University, Lahore. Materials and methods: All thyroid samples submitted and reported at the Department of Pathology, King Edward Medical University, Lahore during a three year period commencing from Ist July 1999 to 30th June 2002 were included in this study. Results: Out of the total number of 1136 thyroid surgical specimens, 855 specimens (75.26%) were shown to comprise of non-neoplastic lesions and were more common in females (77.2%) as compared to males (22.8%) giving a male to female ratio of 1:3.4. Regarding non neoplastic lesions maximum comprised of diffuse(74%) and multi nodular goiters (16% ). Others consisted of inflammatory conditions (5%), hyperplastic nodules(4%) and simple colloid filled cysts 1%. Inflammatory conditions included Hashimotos` thyroiditis (67.3%) deQuervain`s thyroiditis (granulomatous thyroiditis) (16.3 %), Lymphocytic thyroiditis (11.7%), and Riedel`s thyroiditis(4.7%). Conclusions: Non neoplastic thyroid lesions are more common than neoplastic lesions, especially in females. The frequency of diffuse colloid goiter was very high, while among inflammatory lesions Hashimotos` thyroiditis was the commonest lesion. Most of the cases of hypothyroidism were associated with iodine deficiency.

Targeted Foxe1 Overexpression in Mouse Thyroid Causes the Development of Multinodular Goiter But Does Not Promote Carcinogenesis.

Recent genome-wide association studies have identified several single nucleotide polymorphisms in the forkhead box E1 gene (FOXE1) locus, which are strongly associated with the risk for thyroid cancer. In addition, our recent work has demonstrated FOXE1 overexpression in papillary thyroid carcinomas. To assess possible contribution of Foxe1 to thyroid carcinogenesis, transgenic mice overexpressing Foxe1 in their thyroids under thyroglobulin promoter (Tg-Foxe1) were generated. Additionally, Tg-Foxe1 mice were exposed to x-rays at the age of 5 weeks or crossed with Pten(+/-) mice to examine the combined effect of Foxe1 overexpression with radiation or activated phosphatidylinositol-3-kinase/Akt pathway, respectively. In 5- to 8-week-old Tg-Foxe1 mice, severe hypothyroidism was observed, and mouse thyroids exhibited hypoplasia of the parenchyma. Adult 48-week-old mice were almost recovered from hypothyroidism, their thyroids were enlarged, and featured colloid microcysts and multiple benign nodules of macrofollicular-papilloid growth pattern, but no malignancy was found. Exposure of transgenic mice to 1 or 8 Gy of x-rays and Pten haploinsufficiency promoted hyperplastic nodule formation also without carcinogenic effect. These results indicate that Foxe1 overexpression is not directly involved in the development of thyroid cancer and that proper Foxe1 dosage is essential for achieving normal structure and function of the thyroid.

Tumoral angiogenesis in both adrenal adenomas and nonadenomas: a promising computed tomography biomarker for diagnosis.

To explore the correlation between the typical findings of dynamic contrast-enhanced computed tomography (DCE-CT) and tumoral angiogenesis (microvessel density [MVD] and vascular endothelial growth factor [VEGF]) in adenomas and nonadenomas such that the enhancement mechanism of DCE-CT in adrenal masses can be explained more precisely. Forty-two patients with 46 adrenal masses confirmed by surgery and pathology were included in the study; these masses included 23 adenomas, 18 nonadenomas, and 5 hyperplastic nodules. The findings of DCE-CT and angiogenesis in adrenal masses were studied. The features of DCE-CT in adenomas and nonadenomas were evaluated to determine whether the characteristics of DCE-CT in adrenal masses were closely correlated with tumoral angiogenesis. Adrenal adenomas were significantly different from nonadenomas in the time density curve and the mean percentage of enhancement washout at the 7-minute delay time in DCE-CT. The mean MVD and VEGF expression exhibited significant differences between the rapid washout group (types A and C) and the slow washout group (types B, D, and E) and between the relative washout (Washr) ≥34% and the absolute washout (Washa) ≥43% on the 7-minute enhanced CT scans (P=0.000). Adenomas were suggested when adrenal masses presented as types A and C, and/or the Washr ≥34%, and/or the Washa ≥43%, and the opposite was suggested for nonadenomas. These results showed a close correlation between the characteristics of DCE-CT and both MVD and VEGF expression in adrenal masses. There was also a significant difference in MVD and VEGF expression between adenomas and nonadenomas. In conclusion, MVD and VEGF expression are two important pathological factors that play important roles in the characterization of DCE-CT in adrenal masses because they cause different time density curve types, the Washr and the Washa for adrenal adenomas and nonadenomas.

Prevalence and phenotypic correlations of EIF1AX mutations in thyroid nodules

The EIF1AX gene mutations have been recently found in papillary thyroid carcinoma (PTC) and anaplastic thyroid carcinoma (ATC). The prevalence of these mutations in other types of thyroid cancers and benign nodules is unknown. In this study, we analyzed the occurrence of EIF1AX mutations in exons 2, 5, and 6 of the gene in a series of 266 thyroid tumors and hyperplastic nodules by either Sanger or next-generation sequencing (ThyroSeq v.2). In addition, 647 thyroid fine-needle aspiration (FNA) samples with indeterminate cytology were analyzed. Using surgically removed samples, EIF1AX mutations were detected in 3/86 (2.3%) PTC, 1/4 (25%) ATC, 0/53 follicular carcinomas, 0/12 medullary carcinomas, 2/27 (7.4%) follicular adenomas, and 1/80 (1.3%) hyperplastic nodules. Among five mutation-positive FNA samples with surgical follow-up, one nodule was PTC and others were benign follicular adenomas or hyperplastic nodules. Overall, among 33 mutations identified, A113_splice mutation at the intron 5/exon 6 splice site of EIF1AX was the most common. All four carcinomas harbored A113_splice mutation and three of them had one or more coexisting mutations, typically RAS All PTC carrying EIF1AX mutations were encapsulated follicular variants. In summary, this study shows that EIF1AX mutations occur not only in thyroid carcinomas, but also in benign nodules. The most common mutation hotspot is the A113_splice, followed by a cluster of mutations in exon 2. When found in thyroid FNA samples, EIF1AX mutations confer ~20% risk of cancer; the risk is likely to be higher in nodules carrying a A113_splice mutation and when EIF1AX coexists with RAS mutations.

Suspicious for follicular neoplasm or follicular neoplasm? The dilemma of a pathologist and a surgeon.

Cytological material obtained from Fine Needle Aspiration Biopsy (FNAB) does not permit us to distinguish between follicular carcinomas, adenomas, and hyperplastic nodules. The limitations of the method are: lack of possibility to assess the presence of tumour capsule, eventual capsular invasion, and angioinvasion. An unequivocal conclusion of whether what we have to deal with is a neoplastic or benign lesion is possible only after histopathological examination. The aim of the study was to confirm justification for using the term "Suspicious for Follicular Neoplasm" (SFN) in cytological diagnostics of thyroid carcinoma. Three hundred and fifty-two primary SFN FNAB diagnoses (diagnostic category IV [DC IV] - according to Bethesda System) obtained from 2010 to 2015 in the Institute of Oncology in Gliwice were analysed, and their correlation with histopathological diagnoses was verified. In the Institute of Oncology in Gliwice, 352 primary SFN diagnoses (diagnostic category IV [DC IV] - according to Bethesda System) were established. Surgical treatment was undertaken after first FNAB in six cases, giving confirmation of a neoplasm in five cases, one of which was a follicular carcinoma. Second FNAB performed in 90 patients confirmed DC IV diagnosis in 53 cases. Third FNAB concerned 26 patients, providing another 14 diagnoses of DC IV. 26 out of 352 patients were subjected to surgery, and then histopathological examination confirmed a neoplasm in 19 cases (which comprises 73%), five of which were carcinomas. High positive predictive value PPV = 73% of SFN diagnosis justifies undertaking surgical treatment in any case of this diagnosis.

Utility of fine-needle aspiration cytology in the identification of parathyroid lesions.

Objectives:Fine-needle aspiration cytology (FNAC) is a first-line investigation in the evaluation of neck nodules. In an attempt to search for reliable cytomorphological criteria for parathyroid lesions, we systematically evaluated cytomorphology of FNAC of parathyroid lesions.Study Design:FNAC of 15 parathyroid and 15 hyperplastic thyroid nodules with histological confirmation were reviewed for following features: Cellularity, follicles, bare nuclei, cohesiveness, vascular profiles, cytoplasmic granularity, intracytoplasmic vacuolation, mitosis, macrophages, and colloid.Results:Vascular proliferation, bare nuclei, intracytoplasmic fat vacuolation, absence of colloid, and high cellularity showed significant association with parathyroid lesions (P ≤ 0.05). Intracytoplasmic fat vacuolation was 53.3% sensitive and 100% specific for parathyroid. Follicular pattern and papillaroid clusters were also important; however, they achieved nearly significant statistical difference (P = 0.05 and P = 0.06, respectively). The combination of vascular proliferation and intracytoplasmic fat vacuolation were significantly associated with parathyroid (P = 0.006) whereas the absence of bare nuclei and the presence of background colloid were associated with thyroid cytomorphology (P = 0.03).Conclusion:No single cytological feature is helpful in differentiating parathyroid from thyroid lesion. Vascular proliferation, bare nuclei, intracytoplasmic fat vacuolation, high cellularity, and the absence of colloid were significantly associated with the parathyroid origin. The combination of at least two features — vascular proliferation and intracytoplasmic fat vacuoles — were highly suggestive of parathyroid origin.

A Review and Report of Peripheral Giant Cell Granuloma in a 4-Year-Old Child.

Peripheral giant cell granuloma is a common benign and reactive gingival epulis in oral cavity. It is often difficult to make a clinical diagnosis; thereby definitive diagnosis depends on histopathologic features. We report a case of a 4-year-old Caucasian boy presenting with a five-month history a 20 × 15 × 12 mm pedunculated, lobular soft tissue mass of the left anterior maxilla gingiva which was misdiagnosed and maltreated before his referral. An excisional biopsy of the lesion followed by histopathologic examination of the biopsy specimen revealed distinctive features of peripheral giant cell granuloma. Early detection and excision of this hyperplastic nodule especially in children are important to minimize potential dentoalveolar complications.

Differentiation of Adrenal Hyperplasia From Adenoma by Use of CT Densitometry and Percentage Washout.

The purpose of this study was to quantitatively differentiate adrenal hyperplasia from adenoma with the use of adrenal CT protocols. Between January 2004 and November 2012, a total of 156 patients (69 men and 87 women; mean age, 48.9 years) underwent unenhanced CT, early contrast-enhanced CT, and delayed contrast-enhanced CT before undergoing adrenalectomy. Of these patients, 142 had 144 adenomas and 14 had nodular (n = 12) or diffuse (n = 2) hyperplasia. An ROI was placed on 144 adenomas and 27 hyperplastic nodules that were 1 cm or larger or on the four thickest areas of both adrenal glands. The number of each type of lesion and the attenuation value, absolute percentage washout (APW), and relative percentage washout (RPW) associated with hyperplasia and adenoma were compared. The reference standard was pathologic examination. A mixed model and the Fisher exact test were used for statistical analysis. On unenhanced CT, the mean (± SD) attenuation value for hyperplasia and adenoma was 18.8 ± 10.8 HU and 13.7 ± 15.6 HU, respectively (p = 0.375). When a threshold of 10 HU or lower was used, 22.6% of hyperplastic lesions (7/31) were misdiagnosed as adenomas. The mean APW associated with hyperplasia and adenoma was 73.7% ± 9.3% and 67.3% ± 26.2%, respectively (p = 0.449), whereas the mean RPW for hyperplasia and adenoma was 61.2% ± 9.2% and 59.9% ± 23.0%, respectively (p = 0.625). When an APW threshold of 60% or higher or an RPW threshold of 40% or higher was used, 100% of hyperplastic lesions (31/31) were misdiagnosed as adenoma. Three or more nodules were detected in 33.3% of patients with nodular hyperplasia (4/12) but in none of the patients with adenoma (p < 0.001). Adrenal hyperplasia cannot be quantitatively differentiated from adenoma because there is significant overlap in findings from CT densitometry and assessment of percentage washout. However, the presence of three or more nodules increases the likelihood of nodular hyperplasia.

Hepatic preneoplasia induction in male Wistar rats: histological studies up to five months post treatment.

Liver preneoplasia development in rats can be mimicked by an initiation-promotion model that induces the appearance of altered hepatocyte foc (FAH). We compare two initiation-promotion models to evaluate the presence of FAH or additional hepatic pathologies in which other organs were affected up to five month post treatment. FAH were induced in male adult Wistar rats with two doses of dietylnitrosamine (DEN, 150 mg/kg bw) followed by 4 doses per week (3 weeks) of 2-acetylaminofluorene (2-AAF, 20 mg/kg bw) or with one dose of DEN (200 mg/kg bw) followed by 2 doses per week (3 weeks) of 2-AAF. DEN 150, DEN 200 and control mice (received the vehicle of the drugs) groups were compared. Rats were euthanized immediately after the last dose of 2-AAF, at 3, 4 and 5 months (n = 3 euthanasia times per group). Samples of livers, lungs, kidneys, pancreatic tissue and small bowel were processed for histological and immunohistochemical analysis. FAH persisted for 5 months in all livers of the DEN groups. Three months after withdrawal of 2-AAF, one rat from the DEN 150 group developed fibrosis and 5 months after 2-AAF removal another rat from the same group presented a microscopic hyperplastic nodule. Only the lungs had damage compatible with lesions induced by gavage-related reflux in DEN groups. We concluded that up to five month post treatments, FAH persisted in all the livers from the DEN groups; livers from the DEN 200 group showed no other hepatic lesions besides FAH, and only the lungs suffered pathological alterations in both treated groups.

The Clinical and Pathological Presentation of Thyroid Nodules in Children and the Comparison with Adult Population: Experience of a Single Institution.

The clinical and pathological presentation of thyroid nodules among younger and adult patients was compared in an iodine-deficient (ID) region. Data of 3,010 consecutive patients younger than 20 years and 3,010 patients older than 20 years were compared. The proportion of nodular goiters (22.8% versus 39.3%), the ratio of surgically treated nodules (33.2% versus 15.2%), and the proportion of malignant nodules (4.3% versus 2.1%) among diseased patients differed significantly between the two groups (younger versus adult). Nine papillary and 1 medullary carcinoma were found among children, while 15 papillary, 2 follicular, 1 insular, 1 anaplastic, and 1 medullary carcinomas occurred among adults. The ratio of follicular adenoma to hyperplastic nodules (3 : 1 to 1 : 1.67), the proportion of follicular variant (77.8% versus 26.7%), T4 tumors (77.8% versus 33.3%), and tumors with lymph node metastasis (88.9% versus 66.7%) were significantly higher among younger papillary carcinoma patients. No malignancies occurred among spongiform and central type cysts. Similarly to iodine-sufficient regions, more nodules are malignant and carcinomas have a clinically more aggressive presentation in children in comparison with adult patients in ID. Taking the significantly greater proportion of adenomas and the lack of follicular carcinoma into account, a conservative approach has to be considered in follicular tumors among children.

A Case of Bilateral Testicular Tumors Subsequently Diagnosed as Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency.

21-hydroxylase deficiency (21-OHD) caused congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic disorders resulting from mutations in genes involved with cortisol (CO) synthesis in the adrenal glands. Testicular adrenal rest tumors (TARTs) are rarely the presenting symptoms of CAH. Here, we describe a case of simple virilizing CAH with TARTs, in a 15-year-old boy. The patient showed physical signs of precocious puberty. The levels of blood adrenocorticotropic hormone (ACTH), urinary 17-ketone steroids (17-KS), dehydroepiandrosterone sulfate (DHEA-S), and serum progesterone (PRGE) were elevated, whereas those of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and CO were reduced. Computed tomography (CT) of the adrenal glands and magnetic resonance imaging (MRI) of the testes showed a soft tissue density (more pronounced on the right side) and an irregularly swollen mass (more pronounced on the left side), respectively. Pathological examination of a specimen of the mass indicated polygonal/circular eosinophilic cytoplasm, cord-like arrangement of interstitial cells, and lipid pigment in the cytoplasm. Immunohistochemistry results precluded a diagnosis of Leydig cell tumors. DNA sequencing revealed a hackneyed homozygous mutation, I2g, on intron 2 of the CYP21A2 gene. The patient's symptoms improved after a three-month of dexamethasone therapy. Recent radiographic data showed reduced hyperplastic adrenal nodules and testicular tumors. A diagnosis of TART should be considered and prioritized in CAH patients with testicular tumors. Replacement therapy using a sufficient amount of dexamethasone in this case helps combat TART.

The influence of precompression on elasticity of thyroid nodules estimated by ultrasound shear wave elastography.

To investigate the influence of variations in resting pressure (precompression) on thyroid ultrasound supersonic shear wave elastography (SWE). Thirty-five normal thyroid glands (Norm), 55 benign hyperplastic nodules (BHN), and 17 papillary thyroid cancers (PTC) in 96 subjects underwent thyroid SWE. Four precompression levels were applied manually by the operator, ranging from A (baseline, 0% strain) to D (high, 22-30% strain). SWE results at each precompression level were compared using ANOVA tests with P < 0.05 indicating significance. SWE indices were highest in PTC, followed by BHN and Norm at each precompression level (P < 0.05). All tissue types showed successive increases in SWE results as precompression increased, although the rate was higher for PTC than BHN and Norm (Ps < 0.05). SWE values (kPa) of Norm, BHN, and PTC at baseline precompression (A) were 10.3 ± 3.3, 17.7 ± 7.6, and 22.2 ± 11.9 compared with 21.1 ± 4.2, 42.3 ± 16.0, and 97.6 ± 46.8 at high precompression (D). SWE index differences between precompression levels A and D were 10.8 kPa for Norm, 24.6 kPa for BHN, and 75.4 kPa for PTC. PTCs show greater SWE stiffening than BHN as precompression rises. Precompression effects on thyroid nodules are not negligible and may account for wide discrepancies in published SWE discriminatory performance results for thyroid malignancy. • Increases in resting pressure (precompression) applied by the operator increases thyroid stiffness. • Papillary cancers show greater increases in stiffness (strain hardening) than benign nodules. • Precompression may affect the diagnostic performance of shearwave elastography for thyroid malignancy.

DICER1Mutations and Differentiated Thyroid Carcinoma: Evidence of a Direct Association

DICER1 germline mutation carriers have an increased predisposition to cancer, such as pleuropulmonary blastoma (PPB) and Sertoli-Leydig cell tumor (SLCT), and a high prevalence of multinodular goiter (MNG). Although differentiated thyroid carcinoma (DTC) has been reported in some DICER1 mutation carriers with PPB treated with chemotherapy, the association of DTC with DICER1 mutations is not well established. We report a family with DICER1 mutation and familial DTC without a history of chemotherapy. A 12-year-old female (patient A) and her 14-year-old sister (patient B) presented with MNG. Family history was notable for a maternal history of DTC and bilateral ovarian SLCT. Both sisters underwent total thyroidectomy. Pathological examination showed nodular hyperplasia and focal papillary thyroid carcinoma within hyperplastic nodules. Subsequently, patient A developed virilization secondary to a unilateral ovarian SLCT. During her evaluation, an incidental cystic nephroma was also found. Three other siblings had MNG on surveillance ultrasound examination; two had thyroidectomies, and one had two microscopic foci of papillary carcinoma. Patient A, her mother, and four affected siblings had a germline heterozygous pathogenic DICER1 mutation c.5441C>T in exon 25, resulting in an amino acid change from p.Ser1814Leu of DICER1. Somatic DICER1 RNase IIIb missense mutations were identified in thyroid nodules from three of the four siblings. This family provides novel insight into an emerging phenotype for DICER1 syndrome, with evidence that germline DICER1 mutations are associated with an increased risk of developing familial DTC, even in the absence of prior treatment with chemotherapy.

MRI features of cerebral parenchymal tuberculosis and the dynamic evolution during antituberculous treatment

To investigate the MRI features, classification and the evolution of cerebral parenchymal tuberculosis (TB) during anti-tuberculosis treatment. A total of 134 patients with cerebral parenchymal TB registered in our hospital from Sep. 2010 to Aug. 2010 were studied retrospectively. There were 68 males and 66 females, aged 14 to 77 years. The MRI characteristics of these patients were analyzed after T1WI, T2WI, DWI and enhanced scan.The millet, small and large nodules were named by the lesion diameter of less than 0.3 cm, 0.3 to 1.0 cm and lager than 1.0 cm in brain parenchymal TB, respectively, and accordingly the cerebral parenchymal TB cases were divided into millet nodule type, small nodule type, large nodule type and mixed nodule type with at least 2 of 3 nodule sizes. According to the enhanced scanning patterns and signal characteristics, the cases were divided into hyperplastic nodule, tuberculoma type, abscess type and mixed type. Serial follow-up MRI scans were performed in 76 patients during their anti-tuberculosis treatment.Data on lesions of different size were analyzed by Chi-square test and the follow-up results were analyzed by single-factor logistic regression. Of all the 134 patients, the lesions were commonly found in the cerebral hemisphere and cerebellar hemisphere, often multiple in different locations. Three patterns of homogeneous enhancement, ring enhancement, and variegated enhancement were found in the 134 patients after the enhanced scan, of which 2 or more patterns co-existed in 72 cases. There were 124 cases with millet nodules, of which 116 were homogeneous enhancement and 32 were heterogeneous enhancement (including ring enhancement and variegated enhancement). Ninety cases were found to have small nodules, of which 34 were homogeneous enhancement and 69 were heterogeneous enhancement. Sixty cases were found to have large nodules, of which 1 was of homogeneous enhancement and 16 were of heterogeneous enhancement. The case number of the homogeneous enhancement and heterogeneous enhancement was significantly different for the 3 different sized nodules, respectively (P<0.05). Homogeneous enhancement was seen commonly in millet nodules, while heterogeneous enhancement in small nodules especially large nodules. In contrast to small nodule type (8 cases) and large nodule type (1 case), millet nodule type (68 cases) and mixed nodule type (57 cases) were predominant. The hyperplastic nodule type (64 cases) and mixed cerebral tuberculosis (60 cases) were predominant in contrast to tuberculoma type (9 cases) and abscess type (1 case) in the 134 patients. The cases with lesion diameter more than 0.5 cm mostly showed tuberculoma. The disappearance rates were 23 (30.3%) among 76 patients with serial MRI follow-up scans. The disappearance rate of hyperplastic nodule type (17/37) was significantly higher than that of the non-hyperplastic nodule type (including tuberculoma and mixed type) (6/39) (P=0.004). The disappearance rate of millet nodule type (15/38) was significantly higher than that of the non-millet nodule type (8/38) (P=0.02). Single-factor logistic regression analysis showed that, the results of the follow-up only related to 2 classifications (P<0.05). Fourteen patients were found to have enlarged lesions or newly appeared lesion during anti-tuberculosis treatment, of which 3 were refractory. Cerebral parenchymal TB showed certain MRI characteristics. Homogeneous enhancement, ring enhancement, and variegated enhancement. About half of the patients had more than 2 enhancement patterns. Homogeneous enhancement and heterogeneous enhancement were commonly seen in millet nodules and small nodules especially large nodules, respectively. According to the classification of lesion size, millet nodule type and mixed nodule type were predominant. According to the characteristics of the lesion enhancement pattern and signal characteristics, hyperplastic nodule type and mixed type were predominant. This classification would help to guide the treatment of cerebral parenchymal TB. The treatment effect of hyperplastic nodule type was better than non-hyperplastic nodule type, and millet nodule type was better than non-millet nodule types.