Molecular Profile and Clinical-Pathologic Features of the Follicular Variant of Papillary Thyroid Carcinoma: An Unusually High Prevalence of ras Mutations

Departments of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, 231 Albert Sabin Way, PO Box 670529, Cincinnati, OH 45267-0529, USA.
American Journal of Clinical Pathology (Impact Factor: 2.51). 08/2003; 120(1):71-7. DOI: 10.1309/ND8D-9LAJ-TRCT-G6QD
Source: PubMed


The follicular variant (FV) of papillary thyroid carcinoma is characterized by a follicular growth pattern and cytologic features of papillary carcinoma. ret/PTC rearrangements are common in classic papillary thyroid carcinoma (PTC) and PAX8-PPAR gamma and ras mutations in follicular thyroid carcinoma. Their prevalence in FV has not been established. We studied these genetic alterations and clinical-pathologic features in 30 FV cases and compared those with 46 non-FV papillary carcinomas. FV cases revealed 1 ret/PTC rearrangement (3%) and 13 ras mutations (43%). Non-FV cases harbored 13 ret/PTC (28%) (P = .006) and no ras mutations (P = .0002). No PAX8-PPAR gamma was found in either group. FV cases demonstrated a significantly higher prevalence of tumor encapsulation, angiovascular invasion, and poorly differentiated areas and a lower rate of lymph node metastases. These data indicate that the FV of papillary carcinoma has a distinct set of molecular alterations and is characterized by a high frequency of ras point mutations.

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    • "The activation of oncogenic RAS causes point mutations that affect the GTP-binding domain (codon 12 or 13) in exon 1 or the GTPase domain (codon 61) in exon 2. These mutations fix the RAS proteins in an activated state, thereby causing chronic stimulation, genomic instability, additional mutations and malignant transformation of these genes. RAS mutations were detected in follicular adenomas and in the follicular variant of papillary thyroid carcinoma (PTC) [12, 13]. In TC, the prevalence of RAS mutations is approximately 20–40%. "
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    ABSTRACT: Aim of the study Important signalling pathways play fundamental roles in the pathogenesis of thyroid carcinoma (TC). PTEN, mTOR, PI3K-p85 and K-Ras are the principal factors involved in these signalling pathways. To immunohistochemically examine the expressions of PI3K, mTOR and PTEN in patients suffering from follicular TC, papillary TC or variants thereof, as well as to investigate KRAS mutations via PCR to determine their clinical and prognostic relevance to differentiated thyroid cancer. Material and methods The expression of PTEN, PI3K-p85 and mTOR was immunohistochemically examined, and the mutation of K-Ras was examined via PCR. The results obtained were compared to the clinico-pathologic characteristics of the patients. Results A significant correlation was found between p85 expression and lymphovascular invasions and between PTEN expression and multifocality (p = 0.048 and p = 0.04, respectively), and a correlation between p85 and capsular invasion was found, with a borderline statistical significance (p = 0.056). No expression of PTEN, p85 or Mtor was detected in normal tissue. K-Ras mutation was examined in 66 of the 101 patients (57.4%), and the percentage of patients exhibiting a K-Ras mutation was 17.4%. All of the patients exhibiting a K-Ras mutation were women (p = 0.047). The disease-free survival was 44.6 months (95% CI: 37.9–51.3) and was statistically significantly higher in the group that displayed level 1 or lower expression of p85 (p = 0.043). Conclusions The expression levels of the aforementioned markers were significantly higher in TC cells than in normal tissue. A significant correlation was detected between K-Ras mutation and gender. This study demonstrates that p85 and PTEN are markers that should be evaluated in further studies of TC.
    Full-text · Article · Jul 2014 · Contemporary Oncology / Wspólczesna Onkologia
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    • "Diagnostic difficulties with follicular variant of papillary cancer result from the absence of papillary proliferation and limited nuclear features typical for papillary cancer. To differentiate between adenoma and follicular cancer, the assessment of vascular invasion and capsule infiltration is necessary, which cannot be based on cytology material obtained from fine-needle aspiration biopsy [39,56]. Most RAS-positive thyroid nodules with indeterminate cytology and without suspicious ultrasonography features turn out to be a follicular form of papillary cancer with low level of malignancy in post-operative histopathology examination [12]. "
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    ABSTRACT: Preoperative diagnostic investigations of nodular goiter are based on two main examinations: ultrasonography of the thyroid gland and ultrasound-guided fine-needle aspiration biopsy. So far, FNAB has been the best method for the differentiation of nodules, but in some cases it fails to produce a conclusive diagnosis. Some of the biopsies do not provide enough material to establish the diagnosis, in some other biopsies cytological picture is inconclusive. Determining the eligibility of thyroid focal lesions for surgery has been more and more often done with molecular methods. The most common genetic changes leading to the development of thyroid cancer include mutations, translocations and amplifications of genes, disturbances in gene methylation and dysregulation of microRNA. The mutations of Ras proto-oncogenes and BRAF gene as well as disturbances of DNA methylation in promoter regions of genes regulating cell cycle (e.g. hypermethylation of RASSF1A gene and TIMP-3 gene) play an important role in the process of neoplastic transformation of thyreocyte. The advances in molecular biology made it possible to investigate these genetic disturbances in DNA and/or RNA from peripheral blood, postoperative thyroid tissue material and cytology specimens obtained through fine-needle aspiration biopsy of focal lesions in the thyroid gland. As it became possible to analyze the mutations and methylation of genes from cell material obtained through fine-needle aspiration biopsy, it would be beneficial to introduce the techniques of molecular biology in the pre-operative diagnosis of nodular goiter as a valuable method, complementary to ultrasonography and FNAB. The knowledge obtained from molecular studies might help to determine the frequency of follow-up investigations in patients with nodular goiter and to select patients potentially at risk of developing thyroid cancer, which would facilitate their qualification for earlier strumectomy.
    Full-text · Article · Jun 2014 · Thyroid Research
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    • "Author Age From time of initial treatment Variant Treatment Survival after diagnosis of pancreatic metastasis Zhu et al. [4] NA NA Tall cell Surgical resection NA Sugimura et al. [5] 53 years 7 years after TT + RAI Classical Surgical resection NA Jobran et al. [6] 53 years male NA Tall cell Surgical resection NA Angeles-Angeles et al. [7] 72 years male NA Classical Surgical resection NA Borschitz et al. [8] 34 years female 9 years after TT + RAI Classical Surgical resection 42 months 46 years male 2 years after TT + RAI Follicular Chen and Brainard [9] 82 years male 5 years after TT + RAI Classical Surgical resection NA Alzahrani et al. [10] 56 years male 6 years after TT + RAI Classical Sorafenib 20 months Present case 67 years 7 years after TT + RAI Tall cell Surgical resection and RAI Alive at 32 months TT: total thyroidectomy, RAI: radioactive iodine therapy, NA: not mentioned. pancreatic metastases are usually sign of extensive disease seen in our patient. "
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    ABSTRACT: Introduction. Follicular variant (FV) papillary thyroid carcinoma (PTC) has aggressive biologic behavior as compared to classic variant (CV) of PTC and frequently metastasizes to the lungs and bones. However, metastasis to the pancreas is extremely rare manifestation of FV-PTC. To date, only 9 cases of PTC have been reported in the literature. Pancreatic metastases from PTC usually remain asymptomatic or manifest as repeated abdominal aches. Associated obstructive jaundice is rare. Prognosis is variable with reported median survival from 16 to 46 months. Case Presentation. Herein we present a 67-year-old Saudi woman, who developed pancreatic metastases seven years after total thyroidectomy and neck dissection followed by radioactive iodine ablation (RAI) for FV-PTC. Metastasectomy was performed by pancreaticoduodenectomy followed by sorafenib as genetic testing revealed a BRAF V600E mutation. She survived 32 months after the pancreatic metastasis diagnosis. Conclusion. Pancreatic metastases are rare manifestation of FV-PTC and are usually sign of extensive disease and conventional diagnostic tools may remain to reach the diagnosis.
    Full-text · Article · Mar 2013
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