Targeted Therapy of Papillary Thyroid Cancer: A Comprehensive Genomic Analysis

BackgroundA limited number of targeted therapy options exist for papillary thyroid cancer (PTC) to date. Based on genetic alterations reported by the “The Cancer Genome Atlas (TCGA)”, we explored whether PTC shows alterations that may be targetable by drugs approved by the FDA for other solid cancers.MethodsDatabases of the National Cancer Institute and MyCancerGenome were screened to identify FDA-approved drugs for targeted therapy. Target genes were identified using Drugbank. Genetic alterations were classified into conferring drug sensitivity or resistance using MyCancerGenome, CiViC, TARGET, and OncoKB. Genomic data for PTC were extracted from TCGA and mined for alterations predicting drug response.ResultsA total of 129 FDA-approved drugs with 128 targetable genes were identified. One hundred ninety-six (70%) of 282 classic, 21 (25%) of 84 follicular, and all 30 tall-cell variant PTCs harbored druggable alterations: 259 occurred in 29, 39 in 19, and 31 in 2 targetable genes, respectively. The BRAF V600 mutation was seen in 68% of classic, 16% of follicular variant, and 93% of tall-cell variant PTCs. The RET gene fusion was seen in 8% of classic PTCs, NTRK1 and 3 gene fusions in 3%, and other alterations in <2% of classic variant PTCs. Ninety-nine of 128 (77%) FDA-approved targetable genes did not show any genetic alteration in PTC. Beside selective and non-selective BRAF-inhibitors, no other FDA-approved drug showed any frequent predicted drug sensitivity (<10%).ConclusionTreatment strategies need to focus on resistance mechanisms to BRAF inhibition and on genetic alteration–independent alternatives rather than on current targeted drugs.

Triple-negative breast carcinomas of low malignant potential: review on diagnostic criteria and differential diagnoses

Triple-negative breast carcinomas constitute a wide spectrum of lesions, mostly being highly aggressive. Nevertheless, some special histologic subtypes can have low malignant potential. The purpose of the present paper is to review diagnostic criteria and prognostic parameters of breast neoplasms of special histotypes. Specifically, adenoid cystic carcinoma, adenomyoepithelioma, acinic cell carcinoma, mucoepidermoid carcinoma, tall cell carcinoma with reverse polarity, and secretory carcinoma will be discussed. For each tumour, definition and morphological and molecular features, together with prognostic parameters, will be presented. Paradigmatic cases will be illustrated.

Tall cell percentage alone in PTC without aggressive features should not guide patients' clinical management

Purpose Recent diagnostic criteria updates of the tall cell variant of papillary thyroid carcinoma (TCPTC) by the World Health Organization (WHO) have determined the inclusion of tumours with 30-49% of tall cells. However, the impact of tall cell percentage on papillary thyroid carcinoma (PTC) patients’ prognosis is still debated. We aimed to evaluate whether tall cell percentage affects patients’ outcome in the absence of aggressive features. Methods Rates of aggressive features, recurrence-free survival (RFS) and distant RFS (DRFS) (5-year median follow-up) were compared among tumours with less than 30%, 30-49% and at least 50% of tall cells. We also evaluated the impact of the new tall cell cut-off on patient management. Results Overall, 3092 tumours (15.7% of all PTC) were collected: 792 PTC had less than 30%, 503 had 30-49%, and 1797 had 50% or more tall cell areas. With the new definition of WHO, the number of TCPTC increased by 28%. There were no differences in recurrence rates according to tall cell percentage. The coexistence of BRAF and TERT promoter mutations predicted a worse RFS. Considering the new definition of TCPTC, the level of risk according to the American Thyroid Association increased from low to intermediate in 4.2% of cases. However, the recurrence rate within this subgroup was comparable to low-risk. Conclusions TCPTC and PTC with tall cell areas can be considered as a unique group with similar recurrence risk. However, whenever aggressive features are absent, tumors have a low risk of recurrence independently of tall cell percentage.

Papillary Thyroid Carcinoma With Axillary Lymph Node Metastasis

Papillary thyroid carcinoma (PTC) is typically known to be a non-aggressive form of thyroid follicular epithelial-derived cancer. It is characterized histologically by classic and variant forms. Metastases are uncommon and spread mainly via lymphatic channels to cervical lymph nodes and less commonly via hematogenous spread to lungs and bone. Axillary lymph node (ALN) metastasis is a rare sequela of disease presentation. A 59-year-old female presented for evaluation of shortness of breath and chest pain for one week. She had a longstanding history of hypothyroidism due to chronic lymphocytic thyroiditis which was stable on levothyroxine. Her physical exam revealed a firm mass on the inferior aspect of the left neck. Computed tomography (CT) angiogram ruled out pulmonary embolism but noted a superior mediastinal mass and significant left axillary and subpectoral adenopathy. Mammogram was negative for breast malignancy. Left axillary ultrasound showed a 1.1 x 1.8 x 1.9 cm enlarged lymph node. Thyroid ultrasound showed a 3 mm nodule on the left lower pole and a 3.7 x 2.9 x 2.1 cm heterogeneous and irregular mass in the left neck. Positron emission tomography/CT showed increased uptake in left lower paratracheal, left supraclavicular and axillary lymph nodes. Fine needle aspiration of the left neck mass and left ALN confirmed metastatic papillary carcinoma. She underwent total thyroidectomy, left modified neck, central neck, and left ALN dissection along with partial esophageal wall excision. Intraoperatively, she was found to have a multifocal tumor in the left thyroid lobe with the largest dimension of 1 cm. Surgical pathology noted that the primary tumor in the left thyroid was classic type of papillary carcinoma, and the metastatic tumor in the lymph nodes was of tall cell variant. I-123 thyroid uptake and scan after surgery showed low residual thyroid uptake of 0.6%. She underwent adjuvant ablation with 155 millicuries (mCi) of radioiodine (RAI or I-131) following levothyroxine withdrawal protocol. Post ablation therapy thyroid uptake and scan showed no radiotracer uptake within the thyroidectomy bed. According to the American thyroid association (ATA) risk stratification system, she was categorized as high risk. This case illustrates that PTC may exceptionally spread to axillary lymph nodes. Physiologic flow is centripetal to the jugulosubclavian junction and there is no communication between cervical and axillary lymphatics. However malignant tumors can alter and partially block lymphatic pathways, resulting in ALN metastasis in a retrograde direction. This case also demonstrates that PTC can be transformed into aggressive forms associated with worse prognosis such as tall cell variant. Further comprehensive monitoring and management approaches are needed to plan treatment and gauge prognosis of patients with PTC who present with ALN metastasis.

Mutation profile of the tall cell variant of papillary thyroid carcinoma: analysis of 5 cases using wide-panel next-generation sequencing

The study objective is to analyze the mutation profile of the tall cell variant (TCV) of papillary thyroid carcinoma (PTC).Materials and methods. The main inclusion criteria according to the WHO classification (2017) was PTC composed of at least 30 % of tall cells. Genetic examination was conducted using the FoundationOne CDx assay (USA) with median depth of coverage of >500x. This study included 5 patients (1 man and 4 women) with a mean age of 52.6 years (range: 48-56 years). The tumor size varied between 0.4 x 0.5 cm and 11.0 x 9.0 cm. All patients have undergone surgical treatment: hemithyroidectomy for patient No. 1 with a small tumor (pT1b); thyroidectomy for patient No. 2 (pT3b); extensive thyroidectomy with the removal of paratracheal tissue for patients No. 3, 4, and 5 (No. 3 - pT3bN0; No. 4 - pT3bN1b; No. 5 - pT3bN1b). Three out of the five patients also had adenomatous goiter. The mean follow-up time was 3.4 to 5.2 years.Results. Tumors in all patients were characterized by low mutational load (0 to 4 mutations per 1 million nucleotides (megabase)) and no microsatellite instability. All study participants were found to have p.V600E mutation in the BRAF gene; two patients had c.-124C>T mutation in the promoter region of the TERT gene. All patients carried mutations with unknown clinical significance: p.V562I in the EPHB1 gene (in 2 patients); mutations in the genes AR, CREBBP, EP300, ERCC4, FLT1, IKBKE, JAK2, MAF, MLL2, MST1R, MYC, MYCL1, NTRK2, TSC2 (each mutation registered in one patient). One individual with the largest tumor and the most aggressive disease was found to have amplifications of the BTG2, MAP3K1, SMAD2, and TBX3 genes.Conclusion. In 5 patients analyzed in this study, the mutation profile of TCV PTC was characterized by low mutational load, no microsatellite instability, and presence of p.V600E mutation in the BRAF gene in all cases. Some patients also had c.-124C>T mutation in the TERT gene and p.V562I mutation in the EPHB1 gene.

Tall Cell Variant of Papillary Thyroid Carcinoma: Recognizing a Rare Aggressive Variant

Papillary Thyroid Cancer (PTC) accounts for 80–90% of all thyroid malignancies [1]. The most common morphology is the classical papillary which has an indolent course. Aggressive variants exist, of which Tall Cell Variant (TCV) is the most common. TCV is defined as a PTC in which 30% or more of tumor cells are 2-3 times as long as they are wide [1,2]. The histology image (Figure 1A, magnification 4x) shows tumor cells arranged back to back with abundant eosinophilic cytoplasm, and typical nuclear features of PTC; namely overlapping enlarged nuclei, intranuclear grooves, and occasional pseudoinclusions. Figure 1B (magnification: 20x) shows a high power view of the same case where the tall cell features of individual tumor cells can be better appreciated (arrows). This important feature should be recognized and reported in pathology reports as TCVs exhibit worse clinical course with extensive lymph node metastasis, extra thyroidal extension and high rate of recurrence [1,2].