Alfred King-Yin Lam

Association Between BRAF V600E Mutation and Mortality in Patients With Papillary Thyroid Cancer

IMPORTANCE BRAF V600E is a prominent oncogene in papillary thyroid cancer (PTC), but its role in PTC-related patient mortality has not been established. OBJECTIVE To investigate the relationship between BRAF V600E mutation and PTC-related mortality. DESIGN, SETTING, AND PARTICIPANTS Retrospective study of 1849 patients (1411 women and 438 men) with a median age of 46 years (interquartile range, 34-58 years) and an overall median follow-up time of 33 months (interquartile range, 13-67 months) after initial treatment at 13 centers in 7 countries between 1978 and 2011. MAIN OUTCOMES AND MEASURES Patient deaths specifically caused by PTC. RESULTS Overall, mortality was 5.3% (45/845; 95% CI, 3.9%-7.1%) vs 1.1% (11/1004; 95% CI, 0.5%-2.0%) (P < .001) in BRAF V600E-positive vs mutation-negative patients. Deaths per 1000 person-years in the analysis of all PTC were 12.87 (95% CI, 9.61-17.24) vs 2.52 (95% CI, 1.40-4.55) in BRAF V600E-positive vs mutation-negative patients; the hazard ratio (HR) was 2.66 (95% CI, 1.30-5.43) after adjustment for age at diagnosis, sex, and medical center. Deaths per 1000 person-years in the analysis of the conventional variant of PTC were 11.80 (95% CI, 8.39-16.60) vs 2.25 (95% CI, 1.01-5.00) in BRAF V600E-positive vs mutation-negative patients; the adjusted HR was 3.53 (95% CI, 1.25-9.98). When lymph node metastasis, extrathyroidal invasion, and distant metastasis were also included in the model, the association of BRAF V600E with mortality for all PTC was no longer significant (HR, 1.21; 95% CI, 0.53-2.76). A higher BRAF V600E-associated patient mortality was also observed in several clinicopathological subcategories, but statistical significance was lost with adjustment for patient age, sex, and medical center. For example, in patients with lymph node metastasis, the deaths per 1000 person-years were 26.26 (95% CI, 19.18-35.94) vs 5.93 (95% CI, 2.96-11.86) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 4.43 [95% CI, 2.06-9.51]; adjusted HR, 1.46 [95% CI, 0.62-3.47]). In patients with distant tumor metastasis, deaths per 1000 person-years were 87.72 (95% CI, 62.68-122.77) vs 32.28 (95% CI, 16.14-64.55) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 2.63 [95% CI, 1.21-5.72]; adjusted HR, 0.84 [95% CI, 0.27-2.62]). CONCLUSIONS AND RELEVANCE In this retrospective multicenter study, the presence of the BRAF V600E mutation was significantly associated with increased cancer-related mortality among patients with PTC. Because overall mortality in PTC is low and the association was not independent of tumor features, how to use BRAF V600E to manage mortality risk in patients with PTC is unclear. These findings support further investigation of the prognostic and therapeutic implications of BRAF V600E status in PTC.

Osteoprotegerin and Osteopontin Are Expressed at High Concentrations Within Symptomatic Carotid Atherosclerosis

Background and Purpose— The aim of this study was to compare the concentration of osteoprotegerin (OPG), receptor activator of nuclear factor κB ligand (RANKL), and osteopontin (OPN) in stable (asymptomatic) and unstable (symptomatic) carotid atherosclerosis. In addition, we were interested in the effect of angiotensin II blockade on the secretion of these proteins by unstable atherosclerosis. Methods— Endarterectomy samples removed from patients with recent (within 6 weeks) or no previous focal neurological symptoms were assessed by immunohistochemistry, Western analysis, and explant culture. Concentrations of OPG, RANKL, and OPN were measured by mean optical density (MOD), densitometry of protein bands, and enzyme-linked immunosorbent assay of supernatants from explant culture, and compared between symptomatic and asymptomatic patients. Results— The concentration of OPG and OPN within the proximal internal carotid (PIC) part of the endarterectomy specimen removed from symptomatic patients was elevated 2- and 4-fold, respectively. Although the concentration of RANKL did not differ according to patients’ symptoms, the quantity of OPG secreted by explants of the PIC was greater in explants from symptomatic patients and could be significantly reduced within 48 hours of incubation with the angiotensin II blocker irbesartan. Conclusion— OPG and OPN are upregulated in symptomatic human carotid atherosclerosis with possible implications for plaque stability. Angiotensin II blockade is able to downregulate OPG secretion in vitro.

Association Between BRAF V600E Mutation and Recurrence of Papillary Thyroid Cancer

PURPOSE To investigate the prognostic value of BRAF V600E mutation for the recurrence of papillary thyroid cancer (PTC). PATIENTS AND METHODS This was a retrospective multicenter study of the relationship between BRAF V600E mutation and recurrence of PTC in 2,099 patients (1,615 women and 484 men), with a median age of 45 years (interquartile range [IQR], 34 to 58 years) and a median follow-up time of 36 months (IQR, 14 to 75 months). RESULTS The overall BRAF V600E mutation prevalence was 48.5% (1,017 of 2,099). PTC recurrence occurred in 20.9% (213 of 1,017) of BRAF V600E mutation-positive and 11.6% (125 of 1,082) of BRAF V600E mutation-negative patients. Recurrence rates were 47.71 (95% CI, 41.72 to 54.57) versus 26.03 (95% CI, 21.85 to 31.02) per 1,000 person-years in BRAF mutation-positive versus -negative patients (P < .001), with a hazard ratio (HR) of 1.82 (95% CI, 1.46 to 2.28), which remained significant in a multivariable model adjusting for patient sex and age at diagnosis, medical center, and various conventional pathologic factors. Significant association between BRAF mutation and PTC recurrence was also found in patients with conventionally low-risk disease stage I or II and micro-PTC and within various subtypes of PTC. For example, in BRAF mutation-positive versus -negative follicular-variant PTC, recurrence occurred in 21.3% (19 of 89) and 7.0% (24 of 342) of patients, respectively, with recurrence rates of 53.84 (95% CI, 34.34 to 84.40) versus 19.47 (95% CI, 13.05 to 29.04) per 1,000 person-years (P < .001) and an HR of 3.20 (95% CI, 1.46 to 7.02) after adjustment for clinicopathologic factors. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analyses in various clinicopathologic categories. CONCLUSION This large multicenter study demonstrates an independent prognostic value of BRAF V600E mutation for PTC recurrence in various clinicopathologic categories.

Prospective randomized study of selective neck dissection versus observation for N0 neck of early tongue carcinoma

There are controversies on the benefits of elective neck dissection (END) for oral tongue carcinoma.

Classical and follicular variant of papillary thyroid carcinoma: a comparative study on clinicopathologic features and long-term outcome.

IntroductionThe follicular variant of papillary thyroid carcinoma (FVPTC) is the most common histologic subtype of papillary thyroid carcinoma (PTC). However, it is still controversial whether FVPTC should behave differently from classical PTC (CPTC). The present study aimed at evaluating any potential difference in clinicopathologic features and long-term outcome of FVPTC as compared with CPTC.Patients and MethodsOf 568 patients with PTC managed from 1973 to 2004, 308 were shown to have CPTC (54.2%) and 67 (11.8%) FVPTC after histologic review. The mean (± SD) follow-up period was 11.3 (± 8.9) years. The two groups were compared in terms of clinicopathological features, treatment received, and outcome regarding recurrence and disease-specific survival.ResultsThere was no difference in age and gender ratio between the CPTC and FVPTC patients. Both groups had similar tumor characteristics in terms of tumor size, presence of multifocality, capsular invasion, lymphovascular permeation, and perineural infiltration. However, FVPTC patients had significantly fewer histologically confirmed cervical lymph node metastases (P = 0.027) and extrathyroidal involvement (P = 0.005). The proportion of bilateral resection, adjuvant radioactive iodine, and lymph node dissection did not differ significantly between the two groups. The FVPTC patients had a more favorable tumor risk by DeGroot classification (P = 0.003) and MACIS (Metastasis, Age, Completeness of excision, Invasiveness, and Size) score (P = 0.026). The 10- and 15-year actuarial disease-specific survivals did not differ significantly between FVPTC and CPTC patients (96.2% versus 90.7% and 96.2% versus 89.1%, respectively).ConclusionsAlthough patients with FVPTC had more favorable clinicopathologic features and a better tumor risk group profile, their long-term outcome was similar to that of CPTC patients.

Papillary carcinoma of thyroid: a 30-yr clinicopathological review of the histological variants

Many histological variants of PTC have been described and some are known to have prognostic significance. However, their relative frequencies and associated clinicopathological features in a large cohort of patients with PTC treated at a single institution have seldom been documented. We reclassified 1035 malignant thyroid tumors treated in a 30-yr study period, into variants of PTC according to current histological criteria and analyzed their features. Six hundred and fifty two patients (153 men; 499 women) with PTC were identified. PTC accounted for 72.8% of primary thyroid cancers. Conventional papillary carcinoma (n=300) accounted for 46% of PTC and papillary microcarcinoma 27.8% (n=181). The frequencies of the common histological variants were follicular (17.6%, n=115), tall cell (4%, n=26), and diffuse sclerosing (1.8%, n=12). Uncommon histological variants including solid (n=5), diffuse follicular (n=5), papillary carcinoma with focal insular component (n=3), columnar cell (n=2), papillary carcinoma with fasciitis-like stroma (n=2), and oncocytic (n=1) were also noted. Histological variants of PTC had different age presentation, tumor size, frequencies of lymph node metastases, calcification, metaplastic bone, and psammoma bodies, when compared with conventional PTC. We conclude that a high prevalence of different variants of PTC with distinct clinico-pathological features can be documented. Recognition of these histological variants may be important for better management of patients with PTC.

Diffuse Sclerosing Variant of Papillary Carcinoma of the Thyroid: A 35-Year Comparative Study at a Single Institution

BackgroundDiffuse sclerosing variant (DSV) is a rare variant of papillary thyroid carcinoma (PTC), and the features of this carcinoma have not been fully characterized. The aim of this study was to analyze the clinicopathologic features of a large cohort of patients with this disease.MethodsWe reclassified primary thyroid carcinomas treated in a 35-year study period and studied the clinicopathologic features and outcomes of DSV of PTC in comparison with classic PTC.ResultsFifteen patients (2 men and 13 women) with DSV of PTC were identified who had surgical resection of the thyroid. Fine-needle aspiration biopsy diagnosed 83% (10 of 12) of the tumors. Compared with classic PTC, patients with DSV presented at a younger age (mean age, 29 vs. 46 years; P = .0001), had larger tumors (mean diameter, 3.6 vs. 2.2 cm; P = .002), and had a higher incidence of cervical nodal metastases (80% vs. 43%; P = .006). Ten patients had received postoperative iodine 131 ablation, and four had also received external-beam irradiation. Distant metastases were detected in two patients (one in lung and one in brain). One third (5 of 15) of the patients developed disease recurrence. Lymph node recurrence was detected in one patient 12 years after the initial operation. Over a median follow-up period of 10.7 years, one patient with an initial incomplete excision died of the carcinoma. The overall disease-specific survival rate was 93%.ConclusionsDSV of PTC had distinctive clinicopathologic features and a high incidence of recurrence after operation but had a prognosis similar to that of classic PTC.Diffuse sclerosing variant (DSV) is a rare variant of papillary thyroid carcinoma (PTC), and the features of this carcinoma have not been fully characterized. The aim of this study was to analyze the clinicopathologic features of a large cohort of patients with this disease. We reclassified primary thyroid carcinomas treated in a 35-year study period and studied the clinicopathologic features and outcomes of DSV of PTC in comparison with classic PTC. Fifteen patients (2 men and 13 women) with DSV of PTC were identified who had surgical resection of the thyroid. Fine-needle aspiration biopsy diagnosed 83% (10 of 12) of the tumors. Compared with classic PTC, patients with DSV presented at a younger age (mean age, 29 vs. 46 years; P = .0001), had larger tumors (mean diameter, 3.6 vs. 2.2 cm; P = .002), and had a higher incidence of cervical nodal metastases (80% vs. 43%; P = .006). Ten patients had received postoperative iodine 131 ablation, and four had also received external-beam irradiation. Distant metastases were detected in two patients (one in lung and one in brain). One third (5 of 15) of the patients developed disease recurrence. Lymph node recurrence was detected in one patient 12 years after the initial operation. Over a median follow-up period of 10.7 years, one patient with an initial incomplete excision died of the carcinoma. The overall disease-specific survival rate was 93%. DSV of PTC had distinctive clinicopathologic features and a high incidence of recurrence after operation but had a prognosis similar to that of classic PTC.

Clinicopathological relevance of BRAF mutations in human cancer

Summary BRAF represents one of the most frequently mutated protein kinase genes in human tumours. The mutation is commonly tested in pathology practice. BRAF mutation is seen in melanoma, papillary thyroid carcinoma (including papillary thyroid carcinoma arising from ovarian teratoma), ovarian serous tumours, colorectal carcinoma, gliomas, hepatobiliary carcinomas and hairy cell leukaemia. In these cancers, various genetic aberrations of the BRAF proto-oncogene, such as different point mutations and chromosomal rearrangements, have been reported. The most common mutation, BRAF V600E, can be detected by DNA sequencing and immunohistochemistry on formalin fixed, paraffin embedded tumour tissue. Detection of BRAF V600E mutation has the potential for clinical use as a diagnostic and prognostic marker. In addition, a great deal of research effort has been spent in strategies inhibiting its activity. Indeed, recent clinical trials involving BRAF selective inhibitors exhibited promising response rates in metastatic melanoma patients. Clinical trials are underway for other cancers. However, cutaneous side effects of treatment have been reported and therapeutic response to cancer is short-lived due to the emergence of several resistance mechanisms. In this review, we give an update on the clinical pathological relevance of BRAF mutation in cancer. It is hoped that the review will enhance the direction of future research and assist in more effective use of the knowledge of BRAF mutation in clinical practice.

miR-126 in human cancers: clinical roles and current perspectives.

miR-126 has been implicated in the processes of inflammation and angiogenesis. Through these processes, miR-126 is implicated in cancer biology, but its role there has not been well reviewed. The aim of this review is to examine the molecular mechanisms and clinicopathological significance of miR-126 in human cancers. miR-126 was shown to have roles in cancers of the gastrointestinal tract, genital tracts, breast, thyroid, lung and some other cancers. Its expression was suppressed in most of the cancers studied. The molecular mechanisms that are known to cause aberrant expression of miR-126 include alterations in gene sequence, epigenetic modification and alteration of dicer abundance. miR-126 can inhibit progression of some cancers via negative control of proliferation, migration, invasion, and cell survival. In some instances, however, miR-126 supports cancer progression via promotion of blood vessel formation. Downregulation of miR-126 induces cancer cell proliferation, migration, and invasion via targeting specific oncogenes. Also, reduced levels of miR-126 are a significant predictor of poor survival of patients in many cancers. In addition, miR-126 can alter a multitude of cellular mechanisms in cancer pathogenesis via suppressing gene translation of numerous validated targets such as PI3K, KRAS, EGFL7, CRK, ADAM9, HOXA9, IRS-1, SOX-2, SLC7A5 and VEGF. To conclude, miR-126 is commonly down-regulated in cancer, most likely due to its ability to inhibit cancer cell growth, adhesion, migration, and invasion through suppressing a range of important gene targets. Understanding these mechanisms by which miR-126 is involved with cancer pathogenesis will be useful in the development of therapeutic targets for the management of patients with cancer.

Carcinoma ex Pleomorphic Adenoma: A Comprehensive Review of Clinical, Pathological and Molecular Data

Carcinoma ex pleomorphic adenoma (Ca ex PA) is a carcinoma arising from a primary or recurrent benign pleomorphic adenoma. It often poses a diagnostic challenge to clinicians and pathologists. This study intends to review the literature and highlight the current clinical and molecular perspectives about this entity. The most common clinical presentation of CA ex PA is of a firm mass in the parotid gland. The proportion of adenoma and carcinoma components determines the macroscopic features of this neoplasm. The entity is difficult to diagnose pre-operatively. Pathologic assessment is the gold standard for making the diagnosis. Treatment for Ca ex PA often involves an ablative surgical procedure which may be followed by radiotherapy. Overall, patients with Ca ex PA have a poor prognosis. Accurate diagnosis and aggressive surgical management of patients presenting with Ca ex PA can increase their survival rates. Molecular studies have revealed that the development of Ca ex PA follows a multi-step model of carcinogenesis, with the progressive loss of heterozygosity at chromosomal arms 8q, then 12q and finally 17p. There are specific candidate genes in these regions that are associated with particular stages in the progression of Ca ex PA. In addition, many genes which regulate tumour suppression, cell cycle control, growth factors and cell–cell adhesion play a role in the development and progression of Ca ex PA. It is hopeful that these molecular data can give clues for the diagnosis and management of the disease.