Tall Cell Papillary Carcinoma Research Articles

Tall cell carcinoma with reversed polarity – a case report

Tall cell carcinoma with reversed polarity is a rare subtype of invasive breast carcinoma. Immunohistochemical and molecular research show that it is a distinct entity. It is negative for thyroid specific markers.1 It also has its own unique molecular mutations (IDH2 hotspot mutations and PI3K pathway mutations).2 We present a case of tall cell carcinoma with reversed polarity in the breast of an 81-year-old woman. The lesion showed papillary morphology and columnar cells exhibiting reversed nuclear polarity. Immunohistochemistry showed the tumour cells were positive for CK5/6. They showed weak positivity for GATA3 and GCDFP and were negative for TTF-1. Stains for p63 and p40 showed an absence of myoepithelial cells around tumour nests. The core biopsy showed triple negative hormone receptor status. Further molecular testing was performed which showed a mutation in the PIK3CA gene. An activating mutation in the IDH2 gene was also detected. The combination of morphologic, immunohistochemical and molecular findings are diagnostic of tall cell carcinoma with reverse polarity. It can present a diagnostic challenge when encountered. IDH2 and PI3K mutation testing may provide more confidence with diagnosing these lesions and to help distinguish it from other breast neoplasms. 1.WHO Classification of Tumours Editorial Board. WHO Classification of Tumours: Breast Tumours. 5th ed. Lyon: IARC, 2019.2.Zhong E, Scognamiglio T, D'Alfonso T, et al. Breast tumour resembling the tall cell variant of papillary thyroid carcinoma: molecular characterization by next-generation sequencing and histopathological comparison with tall cell papillary carcinoma of thyroid. Int J Surg Pathol 2019; 27: 134–41.

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.

New molecular biomarkers in differentiated thyroid carcinoma: Impact of miR-146, miR-221 and miR-222 levels in the evolution of the disease.

MircroRNAs (miR) are small, noncoding RNA molecules of 18-25 nucleotides. Their dysregulation has been widely studied in many human tumours including differentiated thyroid cancer (DTC). miRs more frequently associated with these kinds of tumours are miR-146, miR-221 and miR-222. Our objective was to assess the relationship among circulating miR levels and the evolution and outcomes of disease. We analysed a sample of 60 patients with DTC assigning them to one of three groups according to the dynamic scale of risk (excellent response, incomplete biochemical response and incomplete structural response). At study inclusion, we determined thyroid-stimulating hormone, thyroxine, thyroglobulin, antithyroglobulin antibodies and plasma levels of miR-146, miR-221 and miR-222. Male sex and advanced age at diagnosis were associated with the worst disease progression. miR-222 was twofold to threefold higher in tall cell papillary carcinomas (P=0.038). miR-146 (P=0.016) and miR-221 (P=0.050) had a positive correlation with thyroglobulin at the time of sampling. In regression analysis, miR-146 (P=0.006), miR-221 (P=0.004) and miR-222 (P=0.007) predicted more than 70% of the variation in thyroglobulin levels at the time of sampling. Elevated miR-222 and miR-146 levels are associated with poorer outcomes of the disease and may have a prognostic value in the management and follow-up of DTC.

Breast Tumor Resembling the Tall Cell Variant of Papillary Thyroid Carcinoma: Molecular Characterization by Next-Generation Sequencing and Histopathological Comparison With Tall Cell Papillary Carcinoma of Thyroid

Recent publications have brought attention to the histopathological, immunohistochemical, and molecular aspects of the rare breast tumor resembling the tall cell variant of papillary thyroid carcinoma (BrTC). Nine archived cases of this entity were retrieved, reviewed, and compared with randomly selected tall cell variants of papillary thyroid carcinoma (ThTC). Seven of the BrTC cases as well as 5 cases of solid papillary carcinoma of breast were analyzed by Oncomine next-generation sequencing. BrTC and ThTC were histologically distinguishable by the presence of solid architecture, luminal histiocytes, and reverse polarity in the former, and psammoma bodies, giant cells, and optically clear nuclei in the latter. Sequencing revealed IDH2 R172 single-nucleotide variants in all 7 BrTCs, 6 of which had concurrent PIK3CA mutations. None of the conventional solid papillary carcinomas demonstrated IDH2 mutation. BrTC bears superficial resemblance to other papillary tumors but is unique in terms of histology and molecular profile.

BRAF Mutated Tall Cell Papillary Carcinoma Lung Metastasis Following Thyroidectomy

SESSION TITLE: Metastatic and Other Primary Lung Tumors SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: BRAF Mutated Tall Cell Papillary Carcinoma is a rare tumor infrequently presented as lung metastasis. Although Papillary Carcinoma is one of the most frequent Thyroid Cancers, BRAF-Tall Cell Variant carries the worst prognosis. CASE PRESENTATION: A 65-year-old male former 12-pack year smoking history and total thyroidectomy as a child presents for evaluation of hematochezia. He has no prior history of radiation exposure or familial history of thyroid cancer. Supplemental thyroid replacement therapy was started at age 21 due to clinical hypothyroidism. Residual thyroid glandular tissue was not visible on CT scan or ultrasound studies. Abdominal and pelvic computed tomography (CT) scan demonstrated the incidental finding of a 1.2 cm non-calcified lobulated and speculated pulmonary nodule. Positron Emission Test (PET) Scan demonstrated maximum SUV uptake of 11.0 in mediastinal and pretracheal structures. Mediastinoscopy aborted after experiencing intraoperative bleeding complications. Endobronchial Ultrasound Trans-bronchial fine needle aspiration (EBUS-TB FNA) was was non-diagnostic. Exploratory thoracotomy with right middle lobe wedge resection and mediastinal lymph node dissection was performed. Surgical biopsy diagnosed a poorly differentiated tall cell papillary carcinoma, BRAF positive mutation. DISCUSSION: BRAF is a important oncoprotein responsibile for the MAPK-pathway output. Its role suppresses the expression of genes required for iodide incorporation. Due to poor iodide uptake, radioactive iodine is not useful diagnostically or therapeutically in tall cell variant disease. CONCLUSIONS: BRAF-mutated classical or tall-cell-variant papillary thyroid carcinomas have a high frequency of lymph-node metastases and recurrence after thyroidectomy. These associated carcinomas have a poor response to radioiodine therapy due to the high MAPK-pathway output, which is driven by the BRAF V600E oncoprotein. This case demonstrates the difficulty with diagnosis of mediastinal lymphadenopathy and rare presentation of tall cell variant papillary cell carcinoma as lung metastasis. Reference #1: American Cancer Society: Cancer Facts and Figures 2016. Atlanta, Ga: American Cancer Society, 2016. Reference #2: Gimm, O., Rath, F. W. and Dralle, H. (1998), Pattern of lymph node metastases in papillary thyroid carcinoma. Br J Surg, 85: 252-254. doi:10.1046/j.1365-2168.1998.00510.x Reference #3: Xing M, Westra WH, Tufano RP, et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 2005;90:6373-9. DISCLOSURE: The following authors have nothing to disclose: Brandon Hooks No Product/Research Disclosure Information

Surgical Treatment of Large Neglected Tall-Cell Thyroid Papillary Cancer with Neck Skin Infiltration and Exulceration: A Case Report and Literature

Background: To present for the first time a clinical case of a patient with giant neglected and exulcerated tall-cell papillary thyroid cancer, who was surgically treated. Methods: We report a case of a 73-year-old woman with large firm infiltrated and exulcerated anterior neck tumefaction (12 cm in diameter) clinically suspected as anaplastic thyroid cancer. Patient had a goiter for more than 20 years with rapid growth in last months, after that presented with infiltration and exulceration of the skin. Results: Fine needle aspiration biopsy (FNAB) revealed papillary thyroid cancer (PTC). Total thyroidectomy with en-block dissection of the infrahyoid muscles and skin was performed. Lymph node metastasis were not present. Pathologically, goiter and tall-cell papillary carcinoma were present without anaplastic dedifferentiation. Postoperative radioiodine therapy was done, than L-thyroxin suppressive therapy, patient refused transcutaneous radiotherapy. Serum thyroglobulin was 0.15 ng/ml. Vocal cord paralysis and hypocalcaemia were not present. In following 3 years patient did not come to postoperative control, then she came with local recurrence of disease and tracheostomy. Tumor reduction was a second operation which was performed. Pathologically, it was tall-cell papillary carcinoma with regional lymph node metastases. The skin defect was reconstructed with a local transpositional flap. Patient refused radioiodine and transcutaneous radiotherapy and died 4 years after first operation, she was 77-years old. Conclusions: Skin infiltration and exulceration are rare in papillary thyroid cancer but they can be found in patients with neglected and poorly differentiated papillary carcinomas. Exulcerated tall cell papillary carcinoma can be unpredictable even in radically performed operation.

Postoperative fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography: an important imaging modality in patients with aggressive histology of differentiated thyroid cancer.

Aggressive histopathologic subtypes of differentiated thyroid cancer (DTC) are fluorodeoxyglucose (FDG)-avid tumors and are at high risk for persistent/recurrent disease. In these patients, fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is performed in cases of suspicion of recurrence based on thyroglobulin (Tg) levels or thyroglobulin antibodies (TgAb). The goals of this study were to evaluate the sensitivity of systematic postoperative FDG-PET/CT and to identify risk factors for abnormal FDG-PET/CT. Single-center retrospective study of 38 consecutive patients (16 males, 22 females; mean age, 57 years) with aggressive histology DTC, without known persistent disease at the time of postoperative radioactive iodine (RAI) ablation. The most frequent aggressive histologic subtypes were tall cell papillary carcinoma (45%) and poorly differentiated carcinoma (42%). A total of 86 lesions were found in 20 (53%) patients, distributed in 33 organs. FDG-PET/CT and the postablation whole-body scan (RAI WBS) showed persistent disease in 15 and 12 patients, respectively. FDG-PET/CT was more sensitive than WBS for the detection of individual lesions (69% vs. 59%). Both imaging techniques were complementary with 41% of the lesions detected only by FDG-PET/CT and 31% only by RAI WBS. The only risk factor of abnormal FDG-PET/CT was a stimulated Tg level (Tg/TSH) measured at ablation >10 ng/mL with persistent disease showing FDG uptake in 72% of the patients with a Tg/TSH >10 ng/mL and in 10% of the patients with Tg/TSH ≤10 ng/mL. Postoperative FDG-PET/CT should be performed routinely in patients with aggressive histology DTC.

Expression of the cAMP binding protein EPAC1 in thyroid tumors and growth regulation of thyroid cells and thyroid carcinoma cells by EPAC proteins.

The thyrotropin receptor-cAMP pathway is central in growth regulation of thyroid cells and thyroid tumorigenesis, and it regulates expression of thyroid specific genes. Recently, 2 new protein kinase A-independent cAMP effectors named EPAC1 and 2 were described that activate additional intracellular pathways. The aim of our study was to investigate the role of EPAC proteins in growth regulation of thyroid cells and thyroid carcinomas. EPAC1 expression was investigated immunohistochemically in tissues of various thyroid tumors. Utilizing MTT assay, the effect of EPAC stimulation on proliferation in thyroid carcinoma cells and in non-transformed rat FRTL5 cells was investigated. The activation of intracellular signaling pathways was examined by RAP pull-down assay and Western blots. EPAC1 expression was strong in non-oxyphilic follicular thyroid adenomas and carcinomas and in follicular papillary thyroid carcinomas. It was moderate in oxyphilic follicular tumors and classical and tall cell papillary carcinomas. In contrast, EPAC1 expression was low in poorly differentiated carcinomas and very low in anaplastic carcinomas. Thyroid carcinoma cell lines showed no or very weak EPAC1 expression and exhibited no growth-promoting effect after EPAC stimulation. Non-transformed rat FRTL5 cells were growth-stimulated by an EPAC-specific cAMP-analogue and showed EPAC-dependent activation of RAP, ERK, and p70S6 kinase. EPAC1 expression and cellular response to EPAC activation in rat FRTL5 cells reflect cellular responses to cAMP and TSH stimulation in non-transformed thyroid cells. In undifferentiated thyroid carcinomas, loss of EPAC1 expression may be in accordance with the loss of thyroid-specific functions and the loss of responsiveness of the TSHR-cAMP pathway.

Anaplastic spindle-cell squamous carcinoma arising in association with tall-cell papillary cancer of the thyroid: A potential pitfall.

Transformation of a differentiated thyroid carcinoma is an infrequent occurrence and is usually associated with a dismal prognosis. Following a long-standing history of papillary carcinoma of the thyroid, the patient in the present report developed anaplastic thyroid carcinoma. The anaplastic component initially arose in the setting of papillary carcinoma with tall-cell features, represented a very small proportion of the tumor, and was overlooked at the time of the original diagnosis. Several years later, the patient developed a recurrent neck mass. Fine-needle aspiration (FNA) of this mass revealed a population of atypical spindle cells arranged singly and in papillary clusters which lacked the classical cytologic features of papillary carcinoma of the thyroid. Histology of the resected mass revealed an unusual and recently described subtype of thyroid carcinoma, termed "anaplastic spindle-cell squamous carcinoma," which has been reported as occurring in association with tall-cell papillary carcinoma. The FNA findings of this unusual subtype of anaplastic thyroid carcinoma are presented. Diagn. Cytopathol. 1999;21:413-418.

Immunohistochemical Localization of p53 in Human Thyroid Neoplasms: Correlation with Biological Behavior.

Molecular analyses of thyroid tumors have documented mutations in the tumor suppressor p53 gene almost exclusively in anaplastic carcinomas. In contrast, immunohistochemistry has localized p53 in differentiated papillary and follicular thyroid cancers. To establish the significance of p53 immunolocalization in these lesions, 78 thyroid tumors of follicular derivation were examined. All tumors were classified by strict criteria and the extent of tumor was determined morphologically. Immunohistochemical staining for p53 was performed on paraffin sections of formalin-fixed tumor tissue. The results of staining were correlated with diagnosis, tumor extent and clinical outcome. Immunopositivity for p53 was diffuse and strong in all five anaplastic carcinomas examined. There was no staining in five of six follicular adenomas. Four of nine follicular carcinomas had some degree of nuclear staining, but this was focal; all nine tumors were confined to the thyroid at the time of examination. Of 49 papillary carcinomas, 26 were intrathyroidal, and 7 of these were occult; there was no p53 positivity in any occult lesion and only S of the 19 palpable lesions stained. In contrast, among 23 papillary carcinomas with extra thyroidal extension or metastases, only 9 were negative for p53 immunoreactivity. Five of seven tall cell papillary carcinomas and one of two insular carcinomas had p53 immunopositivity and this correlated with aggressive behavior. These results support the tumorigenic role of p53 mutations postulated for anaplastic thyroid carcinomas and indicate that localization of p53 by immunohistochemistry is a useful prognostic index of clinical behavior in differentiated thyroid carcinomas of follicular cell derivation.

Prognostic features in tall cell papillary carcinoma and insular thyroid carcinoma.

Tall cell papillary carcinoma (TCPC) and insular carcinoma (IC) are variants of thyroid carcinoma that are considered to be more aggressive than well differentiated papillary or follicular carcinoma. To determine the clinical significance of these diagnoses, we evaluated 65 patients with these tumors. There were 30 TCPCs, 27 ICs, and 8 ICs or TCPCs with focal anaplastic carcinoma (FAC). Forty-two patients (27 TCPCs, 14 ICs, and 1 FAC) are alive and free of disease. Nine patients with IC are alive with distant metastases. Ten patients (2 TCPCs, 2 ICs, and 7 FACs) died of disease. Univariate analysis of disease-free interval determined that, as for all thyroid carcinomas, patient age, tumor size, extrathyroidal extension, and lymph node metastases were significant for prognosis. ICs did significantly worse than TCPCs. Focal anaplastic dedifferentiation predicted a worse prognosis. Multivariate analysis for disease-free interval showed age, number of lymph node metastases, and tumor type to be significant. Analysis of the same factors for prediction of mortality showed that TCPC and IC were not significantly different. These data suggest that TCPC is less aggressive than IC, which often results in disseminated disease. Focal AC predicts poor survival.

Bcl-2 and Bax expression in thyroid tumours. An immunohistochemical and western blot analysis.

Bcl-2 and Bax proteins, which are involved in repressing and promoting programmed cell death, respectively, have been investigated immunohistochemically and by Western blot analysis in a series of thyroid tumours. Three immunostaining patterns were identified. Benign lesions and well-differentiated thyroid carcinomas displayed a profile similar to that of normal follicular epithelium, in which Bcl-2 immunostaining was predominant. Thyroid carcinomas associated with an aggressive behaviour, such as the tall-cell variant of papillary carcinoma and the poorly differentiated carcinomas, co-expressed both proteins. Finally, anaplastic carcinomas expressed only the Bax protein. Western blot analyses revealed that the anti-Bcl-2 antibody recognized two bands, of molecular weights 21 kDa and 25 kDa. This was only seen in the tall-cell papillary carcinomas and in the anaplastic carcinomas.

Ret/PTC-1, -2, and -3 oncogene rearrangements in human thyroid carcinomas: implications for metastatic potential?

The ret/PTC oncogene is unique to papillary thyroid cancer. Three forms of this oncogene, formed by translocation of three different genes to the tyrosine kinase domain of the ret protooncogene, result in constitutive kinase activation. Correlation with clinical outcome is controversial; ret/PTC-1 has been suggested to predict aggressive behavior. There is no morphological description of ret/PTC-positive tumors. We analyzed 60 thyroid carcinomas for ret/PTC expression to determine correlation with clinical history, disease stage, or tumor morphology. Ribonucleic acid extracted from frozen tissue was reverse transcribed; PCR was performed to amplify ret/PTC-1, 2, and -3. The TPC-1 cell line was the positive control for ret/PTC-1. All tumors were characterized morphologically. Clinical data were collected. The 57 papillary and 3 follicular carcinomas were resected from 44 female patients and 15 males. The average age at diagnosis was 46.2 yr (range. 24-83 yr). Three patients had a history of neck irradiation. At diagnosis, 11 patients had extrathyroidal tumor extension, 20 had lymph node metastases, and 1 had lung metastasis. Thirteen patients had tall cell papillary carcinomas; 3 tumors had focal insular or anaplastic dedifferentiation. The average follow-up was 13.4 months, during which 4 patients had recurrent disease. No deaths occurred. One papillary carcinoma (1.7%) was positive for ret/PTC-1, none was positive for ret/PTC-2, and 2(3.4%) were positive for ret/PTC-3. Although all 3 patients who had tumors containing ret/PTC rearrangements were under the age of 45 yr (range, 26-44 yr) and had small tumors (< 1.2 cm), 2 of these 3 patients presented with lymph node metastases, and the third had lymphatic invasion. ret/PTC oncogene expression did not correlate with radiation history. In summary, ret/PTC oncogene rearrangements were found in 3 of 60 (5%) thyroid carcinomas and were not present in tumors with aggressive morphological features. However, we found ret/PTC rearrangements in young patients (< 45 yr of age) with small thyroid carcinomas showing a predisposition for lymphatic involvement, suggesting a possible role in the development of this subgroup of tumors.