Molecular pathology of thyroid tumours of follicular cells: a review of genetic alterations and their clinicopathological relevance

Thyroid cancer is the most common endocrine malignancy. Knowledge of the molecular pathology of thyroid tumours originating from follicular cells has greatly advanced in the past several years. Common molecular alterations, such as BRAF p.V600E, RAS point mutations, and fusion oncogenes (RET–PTC being the prototypical example), have been, respectively, associated with conventional papillary carcinoma, follicular‐patterned tumours (follicular adenoma, follicular carcinoma, and the follicular variant of papillary carcinoma/non‐invasive follicular thyroid neoplasm with papillary‐like nuclear features), and with papillary carcinomas from young patients and arising after exposure to ionising radiation, respectively. The remarkable correlation between genotype and phenotype shows how specific, mutually exclusive molecular changes can promote tumour development and initiate a multistep tumorigenic process that is characterised by aberrant activation of mitogen‐activated protein kinase and phosphoinositide 3‐kinase–PTEN–AKT signalling. Molecular alterations are becoming useful biomarkers for diagnosis and risk stratification, and as potential treatment targets for aggressive forms of thyroid carcinoma. What follows is a review of the principal genetic alterations of thyroid tumours originating from follicular cells and of their clinicopathological relevance.     

Poorly differentiated oncocytic thyroid carcinoma--diagnostic implications and outcome

Dettmer M, Schmitt A, Steinert H, Moch H, Komminoth P & Perren A
(2012) Histopathology  60, 1045–1051 Poorly differentiated oncocytic thyroid carcinoma – diagnostic implications and outcome Aims: Poorly differentiated thyroid carcinomas (PDTC) are an ongoing diagnostic challenge. Although the Turin consensus criteria for PDTC excluded consideration of oncocytic tumours, the World Health Organization (WHO) classification does recognise an oncocytic variant of conventional PDTC. The aims of this study were to establish whether the Turin criteria can be applied to oncocytic PDTC, and to determine if there are prognostic differences between conventional and oncocytic PDTC. Methods and results: We applied the Turin criteria to 129 thyroid carcinomas. We identified 18 oncocytic PDTC and 16 conventional PDTC. Kaplan–Meier analysis revealed a significantly worse outcome for oncocytic PDTC with regard to overall and tumour‐specific survival but no difference for relapse‐free survival, all of which were confirmed by multivariate analysis. There was no association of survival with gender, age or tumour stage. Conclusions: The Turin criteria can be applied to oncocytic PDTC and patients with this variant have a decreased survival using conventional radioiodine treatment compared to conventional PDTC and might therefore be candidates for novel treatment modalities.     

Bcl-2 and p53 expression in insular and in well-differentiated thyroid carcinomas with an insular pattern

Expression of p53 and bcl-2 oncogenes was investigated in poorly differentiated, so-called insular carcinomas of the thyroid gland and also in the follicular and papillary carcinomas with an insular component. Hematoxylin-eosin sections of 217 thyroid carcinomas were reevaluated for insular carcinoma and also for thyroid carcinomas with an insular component. Immunohistochemical staining method was used for detecting p53 and bcl-2 expression on paraffin blocks of three pure insular, five follicular or papillary thyroid carcinomas with a major insular component (more than 50%) and six with a minor insular component (20–50%). Flow cytometry was also performed in these cases. None of the cases showed p53 immunoreactivity. Bcl-2 expression was observed in all cases and the most intense staining was seen in insular areas. All the cases were diploid. We suggest that bcl-2 plays a role in loss of differentiation of thyroid carcinomas.     

Treatment outcome of patients with anaplastic thyroid cancer: a single center experience

Purpose

Anaplastic thyroid cancer is known to have a poor prognosis due to its aggressive and rapid metastasis with median survival of less than 6 months. Multimodal treatment involving surgery and chemoradiotherapy has been used to improve the survival of patients. Here, we retrospectively review of treatment outcome of 13 consecutive patients who were treated at a single center.

Materials and Methods

We retrospectively reviewed medical records of 13 anaplastic thyroid cancer patients who received multidisciplinary treatment between 2006 and 2010. Kaplan-Meier survival curve was used to analyze progression-free survival and overall survival of patients.

Results

The median patient age at diagnosis was 69 years, and six patients had stage IVc diseases. Eight patients received primary surgery followed by radiotherapy or concurrent chemoradiotherapy (CCRT). Five patients received weekly doxorubicin-based definitive CCRT, but only one patient''s condition remained stable, while the rest experienced rapid disease progression. The median progression-free survival was 2.8 months (95% CI, 1.2-4.4 months), and the median overall survival was 3.8 months (95% CI, 3.0-4.6 months).

Conclusion

Patients with anaplastic thyroid cancer showed poor prognosis despite multimodality treatment. Therefore, identification of novel therapeutic targets is warranted to take an effective mode of treatment.     

Columnar cell carcinoma of the thyroid

A case of columnar cell carcinoma of the thyroid occurring in a 50-yearoid female is described. Histologically, the 2 cm tumor showed a prominent papillary architecture with thin fibrous cores covered by columnar cells and marked nuclear stratiflcation. It also showed microfollicular, glandular, and solid pattems. The nuclear features were different to those of conventional papillary carcinomas and similar to those of follicular tumors. The tumor was principally encapsulated with vascular and minimal capsular invaslon. The tumor cells were positive for thymglobulin. The tumor was DNA diploid with a low S phase fraction as determined by flow cytometry. The patient had no lymph node or distant metastasis. The patient was well and without disease 9 months after surgery. The possibility that the neoplasm is one of poorly differentiated thyroid carcinomas rises.     

Poorly differentiated clusters in colorectal cancer: a current review and implications for future practice

Poorly differentiated clusters (PDC), defined as small groups of ≥5 tumour cells without glandular differentiation, have gained recent attention as a promising prognostic factor in colorectal cancer (CRC). Numerous studies have shown PDC to be significantly associated with other adverse histopathological features and worse clinical outcomes. PDC may hold particular promise in stage II colon cancer, where risk stratification plays a critical role in patient selection for adjuvant chemotherapy. In addition, emerging evidence suggests that PDC can predict lymph node metastasis in endoscopically resected pT1 CRC, potentially helping the selection of patients for oncological resection. In ‘head-to-head’ comparisons, PDC grade has consistently outperformed conventional histological grading systems both in terms of risk stratification and reproducibility. With a number of large-scale studies now available, this review evaluates the evidence regarding the prognostic significance of PDC, considers its relationship with other emerging invasive front prognostic markers (such as tumour budding and stroma type), assesses its ‘practice readiness’, addressing issues such as interobserver reproducibility, scoring methodologies and special histological subtypes (e.g. micropapillary and mucinous carcinoma), and draws attention to ongoing challenges and areas in need of further study. Finally, emerging data on the role of PDC in non-colorectal cancers are briefly considered.     

Special types of thyroid carcinoma

This article reviews the small percentage of thyroid tumours that are not classified as classic papillary thyroid carcinoma, follicular thyroid carcinoma, and medullary thyroid carcinoma. It includes subtypes of papillary thyroid carcinoma, including, tall‐cell, hobnail/micropapillary, columnar cell, diffuse sclerosing and solid variants. Poorly differentiated carcinoma, high‐grade carcinoma and anaplastic thyroid carcinoma are reviewed. Also discussed are entities that are unusual but need to be recognized as primary thyroid neoplasms, i.e. mucoepidermoid carcinoma, sclerosing mucoepidermoid carcinoma with eosinophilia, and mammary analogue secretory carcinoma/secretory carcinoma. The pathological features and prognostic factors are described; a brief review of molecular correlates of these neoplasms is included.     

Thyroid remnant ablation with radioiodine activity of 30, 60, and 100 mCi in patients with differentiated thyroid cancer – a prospective comparison of long-term outcomes

IntroductionThe aim of this prospective study was to evaluate long-term outcomes in differentiated thyroid cancer (DTC) patients postoperatively treated with distinct RAI activities of 30 mCi, 60 mCi, and 100 mCi.Material and methodsThe analysis involved 277 low-risk and 46 intermediate-risk patients, who underwent radioiodine (RAI) ablation with 30 mCi, 60 mCi or 100 mCi under prospective, randomized clinical trials. Seventy-eight patients from the low-risk group received 30 mCi, whereas 125 and 74 patients received 60 mCi and 100 mCi, respectively. Regarding the intermediate-risk group, 20 patients were given 60 mCi, and 26 subjects were given 100 mCi. The mean time of follow-up was 11 years.ResultsAn excellent treatment response was obtained in 88%, 89% and 90% of low-risk patients treated with 30 mCi, 60 mCi, and 100 mCi, respectively, and in 85% of intermediate-risk patients, who were administered 60 or 100 mCi. An indeterminate response was achieved in 9.4% and 6.5%, whereas an incomplete structural response was obtained in 1.4% and 6.5% of low-risk and intermediate-risk patients, respectively. An incomplete biochemical response was observed only in 2.2% of intermediate-risk patients. The differences in treatment response regarding RAI activity were not significant.ConclusionsRAI activity of 30 mCi demonstrates a comparable efficacy as 60 mCi and 100 mCi in low-risk DTC. RAI activity of 60 mCi seems to be effective in intermediate-risk DTC.     

Definition of poorly differentiated carcinoma of the thyroid: The Japanese experience

The terminology and definitions pertaining to thyroid malignancies of follicular cell origin that are neither well-differentiated papillary or follicular carcinomas nor undifferentiated anaplastic carcinomas remain controversial. Against this background, we previously proposed that “poorly differentiated carcinoma” should be added to the classification of thyroid carcinoma arising from follicular epithelium. The histological criteria and biological characteristics of poorly differentiated carcinoma of the thyroid were described. In this discussion, we make a new proposal concerning the histological classification of thyroid cancers derived from follicular epithelium. According to this proposal, thyroid cancers can be divided into common types and special types. In the common types, the usual histology should be included. The common types are well-differentiated carcinoma, poorly differentiated carcinoma, and undifferentiated carcinoma. The specific types include columnar-cell carcinoma, tall cell carcinoma, cribriform carcinoma, and other rare carcinomas.     

Decreased expression of lncRNA GAS5 predicts a poor prognosis in cervical cancer

Introduction: Cervical cancer is the second leading cause of cancer morbidity and mortality for women around the world. Long non-coding RNAs (lncRNAs) have been investigated as a new class of regulators of cellular processes, such as cell growth, apoptosis, and carcinogenesis. Although downregulation of lncRNA GAS5 in several cancers has been studied, its role in cervical cancer remains unknown. The aim of this study is to investigate the expression, clinical significance and biological role in cervical cancer. Methods: Expression of GAS5 was analyzed in cervical cancer tissues by quantitative Real-time PCR (qRT-PCR). And its association with overall survival of patients was analyzed by statistical analysis. Small interfering RNA (siRNA) was used to suppress GAS5 expression in cervical cancer cells. In vitro assays were performed to further explore the biological functions of GAS5 in cervical cancer. Results: We found that GAS5 expression was markedly downregulated in cervical cancer tissues than in corresponding adjacent normal tissues. Decreased GAS5 expression was significantly correlated with FIGO stage, vascular invasion and lymph node metastasis. Moreover, cervical cancer patients with GAS5 lower expression have shown significantly poorer overall survival than those with higher GAS5 expression. And GAS5 expression was an independent prognostic marker of overall survival in a multivariate analysis. In vitro assays our data indicated that knockdown of GAS5 promoted cell proliferation, migration, and invasion. Conclusions: Our study presents that lncRNA GAS5 is a novel molecule involved in cervical cancer progression, which provide a potential prognostic biomarker and therapeutic target.     

Improved prognosis of solid-type poorly differentiated colorectal adenocarcinoma: a clinicopathological and immunohistochemical study

Aims : We rarely encounter solid-type poorly differentiated colorectal carcinoma, and their histogenesis and biological behaviour are not fully disclosed. Methods and results : A review of 60 poorly differentiated carcinomas of the colorectum was undertaken, 36 (59%) of which were located in the right side of the colorectum. Although, on the basis of the World Health Organization (WHO) classification solid carcinomas are included among undifferentiated carcinomas, the poorly differentiated carcinomas were divided into four types; 27 solid carcinomas (Sol.), 17 poorly differentiated adenocarcinomas (PDA), six signet-ring cell carcinomas (Sig.) and 10 mucinous carcinomas (Muc.). Solid carcinomas revealed a solid alveolar growth of fairly uniformly sized tumour cells with occasional mitotic figures. This type of tumour had a relatively lower percentage of lymphatic permeation and lymph node metastasis compared with the other three types. The 5-year survival rates were 31% for all poorly differentiated carcinomas, 47% for the Sol. type, 32% for the PDA type, and 0% for both the Sig. and the Muc. types, with a rate of 72% for well-differentiated adenocarcinomas selected as controls. Immunohistochemically, bcl-2 protein expression was demonstrated in 38% of the Sol. type, but in only 12 % of the other three non-solid types, this difference being significant ( P  < 0.05). Conclusions : These findings suggest that solid carcinomas of the colorectum should be regarded as a distinct type of poorly differentiated carcinoma, leading to a good prognosis.     

Cyfra 21-1表达与分化型甲状腺癌临床病理特征及其预后的相关性

目的:探讨术前血清Cyfra 21-1水平与分化型甲状腺癌(differentiated thyroid cancer,DTC)临床病理特征的关系及对预后评估的意义.方法:收集2013年1月至2016年6月在第三军医大学附属西南医院治疗的124例DTC患者的临床资料,选取同时期152例甲状腺良性肿瘤及66名健康体检患者作为对照,比较3组患者术前血清Cyfra 21-1水平,并分析其与DTC患者临床病理特征及术后复发的关系.结果:DTC组及良性肿瘤组的血清Cyfra 21-1水平均显著高于正常对照组(均P<0.01),但DTC 组及良性肿瘤组间的血清Cyfra 21-1水平差异无统计学意义(均P＞0.05).术前血清Cyfra21-1水平与DTC病理类型、TNM分期、是否出现淋巴结转移及局部浸润相关(均P＜0.05),与年龄、性别及肿瘤大小无关(均P＞0.05).DTC患者的5年累计无瘤生存率为83.3％.单因素分析显示性别、病理类型、TNM分期、是否有淋巴结转移、局部浸润、术前血清Cyfra21-1水平与DTC术后复发相关(均P＜0.05);多因素分析显示TNM分期较晚及术前高水平的血清Cyfra21-1是DTC患者术后复发的独立危险因素(均P＜0.05).结论:术前血清Cyfra21-1水平对DTC的诊断帮助不大,但是有助于提示部分临床病理特征,而且术前血清Cyfra21-1升高是影响DTC患者术后复发的独立危险因素.     

Improved prognosis of solid-type poorly differentiated colorectal adenocarcinoma: a clinicopathological and immunohistochemical study

Aims: We rarely encounter solid-type poorly differentiated colorectal carcinoma, and their histogenesis and biological behaviour are not fully disclosed. Methods and results: A review of 60 poorly differentiated carcinomas of the colorectum was undertaken, 36 (59%) of which were located in the right side of the colorectum. Although, on the basis of the World Health Organization (WHO) classification solid carcinomas are included among undifferentiated carcinomas, the poorly differentiated carcinomas were divided into four types; 27 solid carcinomas (Sol.), 17 poorly differentiated adenocarcinomas (PDA), six signet-ring cell carcinomas (Sig.) and 10 mucinous carcinomas (Muc.). Solid carcinomas revealed a solid alveolar growth of fairly uniformly sized tumour cells with occasional mitotic figures. This type of tumour had a relatively lower percentage of lymphatic permeation and lymph node metastasis compared with the other three types. The 5-year survival rates were 31% for all poorly differentiated carcinomas, 47% for the Sol. type, 32% for the PDA type, and 0% for both the Sig. and the Muc. types, with a rate of 72% for well-differentiated adenocarcinomas selected as controls. Immunohistochemically, bcl-2 protein expression was demonstrated in 38% of the Sol. type, but in only 12 % of the other three non-solid types, this difference being significant (P < 0.05). Conclusions: These findings suggest that solid carcinomas of the colorectum should be regarded as a distinct type of poorly differentiated carcinoma, leading to a good prognosis.     

Clear-cell carcinomas of thyroid gland: a clinicopathological study of 13 cases

Thirteen primary thyroid clear-cell carcinomas and eight thyroid metastases of renal carcinomas are described. A broad variety of features is shown to be responsible for this follicle cell phenotype, some of which also occur in renal carcinomas. In biopsy specimens these two conditions can only be distinguished by immunohistochemistry. Clinical follow-up disclosed that in the papillary and follicular categories of thyroid cancer the biological behaviour of clear-cell tumours exhibits no significant difference to their non clear-cell counterparts. In the case of eight follicle cell carcinomas, various samples were available for study. These revealed some striking variations in histology at different stages, and even during the same stage, of disease. Both reversal of clear cell change and transitions towards other kinds of metaplasia occurred. Morever, maintenance of follicle cell function was documented in several of these lesions by estimations of serum thyroglobulin levels and radioiodine scans. On the basis of these findings the concept of regarding the clear-cell variant as a distinct subtype of thyroid cancer is refuted. Previous statements on the causal mechanism of clear-cell change are discussed and it is suggested that metaplastic transformation accounts for this phenomenon in at least some instances of this heterogeneous condition.