Occult multifocal papillary thyroid carcinoma presenting as anaplastic carcinoma in the metastatic neck deposit – A rare case report along with review of literature

Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma that carries a favourable prognosis. However, a small subset unfortunately shows transformation to least differentiated anaplastic carcinoma (AC) having a highly aggressive behavior. This process usually occurs within thyroid but is rare in metastatic cervical lymph node or soft tissue neck and exceedingly rare at distant sites. We report a unique case of a 75 years female who presented with anaplastic carcinoma in metastatic neck deposit with occult papillary thyroid carcinoma. To the best of our knowledge, this is the first case in the world literature having anaplastic transformation (AT) in the metastatic neck deposit, right at the presentation with a totally unnoticed PTC clinically. We present this case to emphasize that the transformation process can occur even when the differentiated malignancy in thyroid is small, insignificant or hidden and that metastasis solely can be the presenting feature which can be misleading clinically and even histopathologically. As AC is very aggressive, there is need for early and precise diagnosis & prompt therapeutic intervention.

Anaplastic Thyroid Carcinoma in Metastatic Lateral Cervical Neck Lymph Node. Case Report and Review literatures

Introduction: Papillary thyroid carcinoma is one of the commonest human malignancies. It usually follows an indolent clinical course with localized disease and rare metastasis [1]. Anaplastic transformation of thyroid carcinoma although rare but is well-accepted phenomena. It goes through multiple steps of genetic alterations leading to an ultimate de-differentiation. Most of the anaplastic carcinoma occurs in the thyroid glands with very aggressive behavior and locally advanced disease [2]. Recently some case reports described the anaplastic transformation of thyroid carcinoma in a distant site. It occurred either synchronously or years after diagnosis of thyroid carcinoma.

Progression of Papillary Thyroid Carcinoma to Anaplastic Carcinoma in Metastatic Lymph Nodes: Solid/Insular Growth and Hobnail Cell Change in Lymph Nodes Are Predictors of Subsequent Anaplastic Transformation

Most anaplastic thyroid carcinomas (ATCs) arise from papillary thyroid carcinoma (PTC). This process is also called anaplastic transformation, and the morphological harbingers of this phenomenon in nodal recurrence have not been assessed systematically. For this reason, the current study focused on features of 10 PTCs with regional lymph node recurrence that was accompanied with disease progression due to anaplastic transformation in at least one of the nodal recurrences. The findings of additional 19 PTCs which recurred without anaplastic transformation after ≥ 10 years of follow-up served as the control group. There were no clinicopathological differences between the two groups at initial surgery including age, gender, tumor size, lymph node metastasis, distant metastasis, extrathyroidal extension, histologic subtype, and treatment. The median time from the initial thyroid surgery to anaplastic transformation in the nodal recurrence was 106 months (range 6 to 437 months). Mutational analyses showed recurrent PTCs with anaplastic transformation had a high prevalence of BRAFV600E mutation (8/9) and TERT promoter mutation (9/9), both of which were detected in primary tumors. PIK3CAH1047R mutation was detected in one case. No case had RAS mutation. Nineteen recurrent PTCs without anaplastic transformation harbored BRAFV600E mutation and seventeen of these had TERT promoter mutation. Unlike primary tumors with subsequent nodal anaplastic transformation, TERT promoter mutation was only present in the metastatic nodal recurrence from 4 patients without transformation. No patients had neither high-grade features (necrosis and increased mitotic activity) nor solid/insular growth or hobnail cell features in their primary tumors. In the group of patients with transformation, 3 had solid/insular growth in the lymph node metastasis at the time of primary tumor resection (one displaying nuclear features of PTC and solid growth with increased mitotic activity, one with insular component consistent with poorly differentiated carcinoma component, and one displaying nuclear features of PTC and solid growth), and additional 2 patients had solid/insular growth with no high-grade features or poorly differentiated carcinoma component at the time of subsequent nodal recurrence prior to anaplastic transformation. Hobnail cell features were exclusively seen in subsequent metastatic lymph nodes prior to anaplastic transformation. The control group lacked solid/insular growth and hobnail cell features in the metastatic nodal disease. Aberrant p53 expression and loss of TTF-1 featured tumor components with anaplastic transformation. This series identified a subset of recurrent PTCs with TERT promoter mutation was prone to undergo anaplastic transformation, and that solid/insular growth and hobnail cell features were morphological predictors of anaplastic transformation in the nodal recurrence.

Heterogeneity and excitability of BRAFV600E-induced tumors is determined by PI3K/mTOR-signaling state and Trp53-loss

BackgroundDevelopmental brain tumors harboring BRAFV600E somatic mutation are diverse. Here, we describe molecular factors that determine BRAFV600E-induced tumor biology and function.MethodsIntraventricular in utero electroporation in combination with the piggyBac transposon system is employed as a tool to generate developmental brain neoplasms. In vivo tumor growth is monitored by using the infrared fluorescent protein (iRFP). Lineage inference is carried out by using the Brainbow transgene. Neural activity from tumor slices is assessed by multielectrode array. RNA sequencing is exploited to analyze the induced neoplasms at the transcriptomic level.ResultsBRAFV600E in murine neural progenitors only in concert with active PI3K/mTOR-signaling through constitutively phosphorylated Akt-kinase (pAkt) elicits benign neoplasms composed of enlarged dysmorphic neurons and neoplastic astroglia recapitulating ganglioglioma (GG). Purely glial tumors partially resembling polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) emerge from BRAFV600E alone. Additional somatic Trp53-loss is sufficient to induce anaplastic GGs (aGGs) with glioneuronal clonality. Functionally, only BRAFV600E/pAkt tumors intrinsically generate substantial neuronal activity and show enhanced relay to adjacent tissue conferring high epilepsy propensity. In contrast, PLNTY- and aGG-models lack significant spike activity, which appears in line with the glial differentiation of the former and a dysfunctional tissue structure combined with reduced neuronal transcript signatures in the latter.ConclusionmTOR-signaling and Trp53-loss critically determine the biological diversity and electrical activity of BRAFV600E-induced tumors.Key pointsIUE of BRAFV600E and activation of mTOR leads to ganglioglioma (GG)-like tumors, while BRAFV600E alone give rise to PLNTY-like neoplasms.Anaplastic GGs depend on the Trp53 deletion in combination to BRAFV600E and PI3K-mTOR signaling cascade.Importance of the StudyGlioneuronal tumors are challenging with respect to biological behavior and seizure emergence. While BRAFV600E in murine neural precursors induces oligoid tumors, it requires an overactivation of PI3K/mTOR-signaling for the development of hyperexcitable gangliogliomas and additional Trp53-loss for anaplastic transformation.

The miRNA Content of Exosomes Released from the Glioma Microenvironment Can Affect Malignant Progression

Low-grade gliomas (LGG) are infiltrative primary brain tumors that in 70% of the cases undergo anaplastic transformation, deeply affecting prognosis. However, the timing of progression is heterogeneous. Recently, the tumor microenvironment (TME) has gained much attention either as prognostic factor or therapeutic target. Through the release of extracellular vesicles, the TME contributes to tumor progression by transferring bioactive molecules such as microRNA. The aim of the study was to take advantage of glioma-associated stem cells (GASC), an in vitro model of the glioma microenvironment endowed with a prognostic significance, and their released exosomes, to investigate the possible role of exosome miRNAs in favoring the anaplastic transformation of LGG. Therefore, by deep sequencing, we analyzed and compared the miRNA profile of GASC and exosomes obtained from LGG patients characterized by different prognosis. Results showed that exosomes presented a different signature, when compared to their cellular counterpart and that, although sharing several miRNAs, exosomes of patients with a bad prognosis, selectively expressed some miRNAs possibly responsible for the more aggressive phenotype. These findings get insights into the value of TME and exosomes as potential biomarkers for precision medicine approaches aimed at improving LGG prognostic stratification and therapeutic strategies.

CS-01 Rapid Recurrence and Anaplastic Transformation of a Pilocytic Astrocytoma in an Elderly Patient

BACKGROUND: Rapid recurrence of a pilocytic astrocytoma with anaplastic transformation is extremely rare. The case of an elderly patient with a cerebellar pilocytic astrocytoma with anaplastic transformation during short-term follow-up is reported. CASE DESCRIPTION: An 83-year-old woman presented initially with dizziness and a gait deviation to the right. Magnetic resonance imaging (MRI) demonstrated a homogeneously enhanced mass in the right cerebellar hemisphere, and the tumor was subtotally removed by right suboccipital craniotomy. Histological examination showed that the tumor cells contained eosinophilic cytoplasm and spindle-shaped processes with Rosenthal fibers and eosinophilic granular bodies, diagnosed as a typical pilocytic astrocytoma (PA). The MIB-1 index was less than 1%. The patient did not receive postoperative adjuvant radiation and chemotherapy. Two months after surgery, MRI showed growth of the residual tumor adjacent to the fourth ventricle, causing obstructive hydrocephalus. She underwent surgery again, and the tumor was totally removed. Histological findings showed mitotic cells and increased cellularity compared with the primary tumor, which was compatible with anaplastic transformation of PA with a MIB-1 index of 50%. Postoperatively, she was observed with best supportive care without postoperative adjuvant therapy. Nine months after the second operation, she died due to tonsillar herniation and obstructive hydrocephalus caused by a recurrent tumor. An autopsy was performed. CONCLUSION: It is extremely rare, as in the present case, that a cerebellar PA in an elderly patient recurs rapidly with anaplastic transformation, despite deferred postoperative adjuvant therapy including radiation and chemotherapy A novel molecular-targeted therapy is needed for anaplastic PA showing aggressive biological behavior.