The critical advantage of this approach is that it allows early dissection of the most vulnerable portion of the nerve; the distal segment that passes through the fascial tunnel created by the ...vascular and fibrous leaflets of the ligament of Berry (LB).3 This point of tethering cannot be released during the lateral approach until complete anteromedial mobilisation has occurred. The inferior cornu of the thyroid cartilage can be palpated at this stage to assist with estimation of the position of the RLN entry point to the larynx, which is reliably identifiable and not subject to the anatomical variation that makes the lateral approach challenging. Furthermore, the superior approach negates the risks associated with variations in RLN course, such as passage lateral to the TZ (7% of cases), on the anterior surface of the thyroid gland (6% of cases) or non-recurrence on the right side (0.5% of cases).8 Once retrograde exposure of the RLN has been completed, the plane lateral to the nerve is developed and thyroidectomy using capsular dissection is completed in a standard fashion.Conclusion By identifying the RLN at its insertion to the larynx and performing a retrograde dissection, the multiple points of RLN fixation caused by fascial bands and SILABs can be defused prior to manipulating the thyroid lobe, thereby minimising the forces exerted on the RLN.Declaration of competing InterestCOI There is no conflict of interest to declare.Funding No funding or other support was received to carry out this work.
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression in a sequence-specific manner. Due to its association with an assortment of diseases, miRNAs have been extensively studied in ...the last decade. In this review, the current understanding of the role of miRNAs in the pathophysiology of adrenal tumors is discussed. The recent contributions of high-throughput miRNA profiling studies have identified miRNAs that have functional and molecular roles in adrenal tumorigenesis. With respect to the biological heterogeneity of adrenal tumors and the limitations of the current treatments, an improved understanding of miRNAs may hold potential diagnostic and therapeutic value to facilitate better clinical management.
•Canonical miRNAs promote translational repression by binding on to its target.•Unique miRNA expression patterns were found in benign and malignant adrenal tumors.•Distinct miRNAs identified in adrenal tumors still need further functional analysis.•MicroRNAs are a novel class of therapeutics in adrenal disease.
Summary Up to 30% of pheochromocytomas and paragangliomas are associated with germline RET , Von Hippel–Lindau ( VHL ), neurofibromatosis type I ( NF1 ), and succinate dehydrogenase subunits ( SDHB, ...SDHC , and SDHD ) mutations. Genetic testing allows familial counseling and identifies subjects at high risk of malignancy ( SDHB mutations) or significant multiorgan disease ( RET , VHL , or NF1 ). However, conventional genetic testing for all loci is burdensome and costly. We performed immunohistochemistry for SDHB on 58 tumors with known SDH mutation status. We defined positive as granular cytoplasmic staining (a mitochondrial pattern), weak diffuse as a cytoplasmic blush lacking definite granularity, and negative as completely absent staining in the presence of an internal positive control. All 12 SDH mutated tumors (6 SDHB, 5 SDHD, and 1 SDHC) showed weak diffuse or negative staining. Nine of 10 tumors with known mutations of VHL, RET , or NF1 showed positive staining. One VHL associated tumor showed weak diffuse staining. Of 36 tumors without germline mutations, 34 showed positive staining. One paraganglioma with no known SDH mutation but clinical features suggesting familial disease was negative, and one showed weak diffuse staining. We also performed immunohistochemistry for SDHB on 143 consecutive unselected tumors of which 21 were weak diffuse or negative. As SDH mutations are virtually always germline, we conclude that approximately 15% of all pheochromocytomas or paragangliomas are associated with germline SDH mutation and that immunohistochemistry can be used to triage genetic testing. Completely absent staining is more commonly found with SDHB mutation, whereas weak diffuse staining often occurs with SDHD mutation.
Background
Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumours, often associated with germline mutations that influence the disease biology and clinical course. We aimed to ...describe the genotypic and phenotypic characteristics of a consecutive series of PPGL patients and correlate mutation status with clinical outcomes.
Methods
We performed a retrospective cohort study of all PPGL patients who presented to a tertiary referral centre between March 2005 and February 2022. Genotypic, phenotypic and follow-up data were analysed.
Results
A total of 140 patients were included. Of these, 94 (67%) patients underwent genetic testing and a mutation was detected in 36 (38%) patients. Mutation presence was associated with younger age, smaller tumour size and bilateral adrenal tumours. Disease recurrence occurred at a median time of 5.4 (IQR 2.8–11.0) years after treatment in 21 (15%) patients, of which 14 (67%) had a mutation in a susceptibility gene. Recurrence pattern was influenced by mutation type; higher local recurrence risk for
SDHA
,
SDHB,
and MEN2B disease, and higher metastatic risk for
SDHB
,
VHL
and MEN2A disease. Recurrence occurred in three (3%) patients with mutation absence. Multivariate analysis revealed that age ≤40 years and mutation presence were associated with increased risk of disease recurrence.
Conclusions
Genotypic characteristics strongly influence disease presentation and recurrence risk, which may occur more than 5 years after initial treatment. Routine genetic testing of PPGL patients is warranted given the high prevalence of mutations, allowing for prognostication and tailored follow-up. In the presence of germline mutations, follow-up should be life-long.
Graphical abstract
In this article, we aim to describe our modern‐day approach to total thyroidectomy, detailing the subtle refinements of our technique, as it has evolved over three decades and 21 000 cases. Since ...Delbridge's seminal paper in 2003, the major changes to our approach include a retrograde approach to the recurrent laryngeal nerve that allows dissection of the distal RLN from fascial bands within the ligament of Berry before medialisation of the thyroid lobe. Routine use of intraoperative nerve monitoring systems has increased our awareness of temporary neuropraxia, facilitated a reduction in the risk of bilateral RLN palsy and improved our identification and preservation of the external branch of the superior laryngeal nerve. The increasing use of advanced energy devices has been associated with a reduction in post‐operative haematoma rates. We adopt a low threshold to parathyroid auto‐transplantation, unless all glands are assessed to be clearly not at risk, and routinely supplement patients with Caltrate in the immediate post‐operative period to minimize the risk of symptomatic hypocalcaemia. Ultimately, when we reflect on the subtle refinements that have contributed to improved outcomes, the fundamental principles of exposure and dissection that have evolved over decades remain the basis of our surgical approach and must continue to do so.
In this article, we aim to describe our modern‐day approach to thyroidectomy, detailing the subtle refinements of our technique, as it has evolved over three decades and 21000 cases.
We investigated the prognostic value of a range of histologic parameters in medullary thyroid carcinoma (MTC) to design a grading system to predict overall survival. We assessed 76 patients with MTCs ...undergoing primary tumor resection for age, sex, tumor size, vascular space invasion, lymph node metastasis, multiple endocrine neoplasia type 2 (MEN2) status, mitotic count, Ki-67 proliferative index, spindled morphology, sheet-like growth pattern, coagulative necrosis, incipient necrosis, nuclear grade, multinucleation, prominent nucleoli, fibrosis, and amyloid deposition. In addition to the clinical features of age and the diagnosis of MEN2, the only histologic features that significantly predicted reduced overall survival were Ki-67 proliferative index, mitotic count, and the presence of coagulative necrosis. Using a combination of these 3 variables, we propose a 3-tiered grading system based solely on proliferative activity (Ki-67 proliferative index and mitotic count) and necrosis. There were 62 (82%) low-grade MTCs (low proliferative activity, no necrosis), 9 (12%) intermediate grade (low proliferative activity and necrosis present, or intermediate proliferative activity and no necrosis), and 5 (7%) high grade (intermediate proliferative activity and necrosis present, or high proliferative activity with or without necrosis). The mean overall survival was 193, 146, and 45 months, respectively (P=0.0001) for the 3 grades. The grading system remained prognostic when controlled for other factors associated with survival including age and known MEN2 syndrome. We conclude that this proposed grading system, which uses only a combination of proliferative activity (Ki-67 index, mitotic count) and coagulative necrosis, is a strong predictor of overall survival in MTC.
Thyroid neoplasia is common and requires appropriate clinical workup with imaging and fine-needle aspiration (FNA) biopsy to evaluate for cancer. Yet, up to 20% of thyroid nodule FNA biopsies will be ...indeterminate in diagnosis based on cytological evaluation. Genomic approaches to characterize the malignant potential of nodules showed initial promise but have provided only modest improvement in diagnosis. Here, we describe a method using metabolic analysis by desorption electrospray ionization mass spectrometry (DESI-MS) imaging for direct analysis and diagnosis of follicular cell-derived neoplasia tissues and FNA biopsies. DESI-MS was used to analyze 178 tissue samples to determine the molecular signatures of normal, benign follicular adenoma (FTA), and malignant follicular carcinoma (FTC) and papillary carcinoma (PTC) thyroid tissues. Statistical classifiers, including benign thyroid versus PTC and benign thyroid versus FTC, were built and validated with 114,125 mass spectra, with accuracy assessed in correlation with clinical pathology. Clinical FNA smears were prospectively collected and analyzed using DESI-MS imaging, and the performance of the statistical classifiers was tested with 69 prospectively collected clinical FNA smears. High performance was achieved for both models when predicting on the FNA test set, which included 24 nodules with indeterminate preoperative cytology, with accuracies of 93% and 89%. Our results strongly suggest that DESI-MS imaging is a valuable technology for identification of malignant potential of thyroid nodules.
Purpose: Adrenocortical adenomas are common, whereas adrenocortical carcinomas are rare. Discriminating between benign and malignant
adrenocortical tumors using conventional histology can be ...difficult. In addition, adrenocortical carcinomas generally have
poor prognosis and limited treatment options. MicroRNAs are short noncoding RNAs that are involved in regulation of gene transcription.
Experimental Design: To identify microRNAs involved in the pathogenesis of adrenocortical tumors, expression profiling of microRNAs was done on
a cohort of 22 adrenocortical carcinomas, 27 adrenocortical adenomas, and 6 normal adrenal cortices.
Results: Twenty-three microRNAs were found to be significantly differentially expressed between adrenocortical carcinomas and adrenocortical
adenomas. miR-335 and miR-195 were significantly downregulated in adrenocortical carcinomas compared with adrenocortical adenomas.
This result was further validated in an external cohort of six adrenocortical carcinomas and four adrenocortical adenomas.
Using Kaplan-Meier analysis, downregulation of miR-195 and upregulation of miR-483-5p in adrenocortical carcinomas were significantly
associated with poorer disease-specific survival.
Conclusions: These findings indicate that deregulation of microRNAs is a recurring event in human adrenocortical carcinomas and that aberrant
expression of miR-195 and miR-483-5p identifies a subset of poorer prognosis adrenocortical carcinomas. (Clin Cancer Res 2009;15(24):7684–92)
Previous studies have profiled breast cancer compared to normal breast tissue and identified differentially expressed microRNAs (miRNAs). These miRNAs are then assessed in serum of breast cancer ...patients compared to healthy volunteers. MiRNAs in serum however do not always reflect what is in tissue and important serum miRNAs may be missed. PCR arrays were therefore performed on serum samples from breast cancer patients compared to healthy volunteers with the aim of identifying circulating miRNAs that are more highly expressed in serum from early breast cancer patients compared to controls.
Taqman low density array (TLDA) cards were used to profile serum miRNAs in a discovery cohort of serum from 39 early breast cancer patients compared to 10 healthy volunteers. The results were confirmed in a validation cohort of serum from 98 early breast cancer patients compared to 25 healthy volunteers using customized qPCR plates.
Seventeen miRNAs were found to have significantly higher levels in breast cancer serum compared to serum of healthy volunteers in the discovery cohort. Fourteen of these miRNAs were studied in the validation cohort and serum miR-484 was found to be at a significantly higher level in breast cancer serum compared to healthy volunteers.
In this study, we found that miR-484 is significantly differentially expressed in serum of early breast cancer patients compared to healthy volunteers. We did not however find any correlation between miR-484 levels with histopathological parameters of the breast cancers. With further studies, miR-484 may prove useful as an adjunct to mammography for detection of early breast cancer.
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