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.

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].

BRAF V600E Immunoexpression in Papillary Thyroid Carcinoma and Its Association with Prognostic Factors and Histopathologic Variant

<p><strong>Aim: </strong>to provide additional information regarding the clinicopathological characteristics of Papillary Thyroid Carcinoma (PTC). Methods: Fifty patient with PTC were reviewed to determine prognostic factors such as age, gender, size of tumor and histologic variant. BRAF V600E mutation was detected by immunohistochemical staining and assessed with H score. Result: BRAF V600E mutations were detected in 17 (34%) cases. There were seven cases with extrathyroidal extension (ETE) p 0,04, 11 cases with lymph node metastasis (LNM) p &lt; 0,001, and 8 cases with tall cell variant p 0,047.The cases with positive BRAF V600E mutation had mean age of 44.71 years, and the size of the tumor between 0.1-4cm. Six cases of them are male and 11 female.</p><p><strong>Conclusion:</strong> There were significant relationships between BRAF V600E mutation with ETE, LNM, and tall cell variant. There was no significant relationship between BRAF V600E mutation, either with age, gender, or size of the tumor. BRAF V600E immunohistochemical examination can be performed as additional investigation for PTC patients.</p>

Tall Cell Variant versus Conventional Papillary Thyroid Carcinoma: A Retrospective Analysis in 351 Consecutive Patients

Background: The aim of this retrospective study was to investigate clinical and pathological characteristics of the tall cell variant of papillary thyroid carcinoma compared to conventional variants. Methods: The clinical records of patients who underwent surgical treatment between 2009 and 2015 were analyzed. The patients were divided into two groups: those with a histopathological diagnosis of tall cell papillary carcinoma were included in Group A, and those with a diagnosis of conventional variants in Group B. Results: A total of 35 patients were included in Group A and 316 in Group B. All patients underwent total thyroidectomy. Central compartment and lateral cervical lymph node dissection were performed more frequently in Group A (42.8% vs. 18%, p = 0.001, and 17.1% vs. 6.9%, p = 0.04). Angiolymphatic invasion, parenchymal invasion, extrathyroidal extension, and lymph node metastases were more frequent in Group A, and the data reached statistical significance. Local recurrence was more frequent in Group A (17.1% vs. 6.3%, p = 0.02), with two patients (5.7%) in Group A showing visceral metastases, whereas no patient in Group B developed metastatic cancer (p = 0.009). Conclusions: Tall cell papillary carcinoma is the most frequent aggressive variant of papillary thyroid cancer. Tall cell histology represents an independent poor prognostic factor compared to conventional variants.