Salivary duct carcinoma: Updates in histology, cytology, molecular biology, and treatment.

Salivary duct carcinoma (SDC) is an aggressive subtype of primary salivary gland carcinoma, often with an advanced stage at presentation and high rates of metastasis and recurrence. It most commonly arises in the parotid gland of older men and microscopically resembles high-grade breast ductal carcinoma. While 50 years have lapsed since the first report of this entity, recent intensive studies have shed light on its biologic, genetic, and clinical characteristics. The diagnosis of SDC is aided by the immunohistochemical expression of androgen receptor (AR) coupled with its characteristic histomorphology. Fine-needle aspiration typically reveals cytologic features of high-grade carcinoma, and ancillary studies using cell block material can facilitate the specific diagnosis of SDC. In surgical specimens, certain histologic features are important prognostic factors, including nuclear pleomorphism, mitotic counts, vascular invasion, and the morphology at the invasion front. Several clinical studies have shown promising results using targeted therapy for AR and human epidermal growth factor receptor 2 (HER2), and the latest version of the National Comprehensive Cancer Network guidelines recommends the evaluation of AR and HER2 status before treatment. Recent molecular analyses have revealed multiple heterogeneous alterations in well-known oncogenes and tumor suppressor genes, including TP53, HRAS, PIK3CA, PTEN, and BRAF. Clinical trials of drugs targeting these genes may broaden the treatment options for SDC in the near future.

Pericytes Elicit Resistance to Vemurafenib and Sorafenib Therapy in Thyroid Carcinoma via the TSP-1/TGFß1 Axis.

PURPOSE: The BRAFV600E oncogene modulates the papillary thyroid carcinoma (PTC) microenvironment, in which pericytes are critical regulators of tyrosine-kinase (TK)-dependent signaling pathways. Although BRAFV600E and TK inhibitors are available, their efficacy as bimodal therapeutic agents in BRAFV600E-PTC is still unknown. EXPERIMENTAL DESIGN: We assessed the effects of vemurafenib (BRAFV600E inhibitor) and sorafenib (TKI) as single agents or in combination in BRAFWT/V600E-PTC and BRAFWT/WT cells using cell-autonomous, pericyte coculture, and an orthotopic mouse model. We also used BRAFWT/V600E-PTC and BRAFWT/WT-PTC clinical samples to identify differentially expressed genes fundamental to tumor microenvironment. RESULTS: Combined therapy blocks tumor cell proliferation, increases cell death, and decreases motility via BRAFV600E inhibition in thyroid tumor cells in vitro. Vemurafenib produces cytostatic effects in orthotopic tumors, whereas combined therapy (likely reflecting sorafenib activity) generates biological fluctuations with tumor inhibition alternating with tumor growth. We demonstrate that pericytes secrete TSP-1 and TGFß1, and induce the rebound of pERK1/2, pAKT and pSMAD3 levels to overcome the inhibitory effects of the targeted therapy in PTC cells. This leads to increased BRAFV600E-PTC cell survival and cell death refractoriness. We find that BRAFWT/V600E-PTC clinical samples are enriched in pericytes, and TSP1 and TGFß1 expression evoke gene-regulatory networks and pathways (TGFß signaling, metastasis, tumor growth, tumor microenvironment/ECM remodeling functions, inflammation, VEGF ligand-VEGF receptor interactions, immune modulation, etc.) in the microenvironment essential for BRAFWT/V600E-PTC cell survival. Critically, antagonism of the TSP-1/TGFß1 axis reduces tumor cell growth and overcomes drug resistance. CONCLUSIONS: Pericytes shield BRAFV600E-PTC cells from targeted therapy via TSP-1 and TGFß1, suggesting this axis as a new therapeutic target for overcoming resistance to BRAFV600E and TK inhibitors.

Pediatric thyroidectomy in a high volume thyroid surgery center: Risk factors for postoperative hypocalcemia.

INTRODUCTION: Hypocalcemia is a common complication following thyroid surgery. We seek to report on our experience in pediatric thyroidectomy in a high volume thyroid surgery center and accurately assess the incidence of postoperative hypocalcemia. MATERIALS AND METHODS: A retrospective review of patients aged 18 and younger who underwent thyroid surgery between 1992 and 2013. The primary endpoints were the occurrence of postoperative hypocalcemia as by defined as a nadir calcium <8.0mg/dL and being discharged on oral calcium supplementation, need for intravenous calcium and the occurrence of permanent hypoparathyroidism. RESULTS: 171 patients who underwent 186 thyroid operations were analyzed. The average age was 15.4years with 82.3% female. The most common indications for surgery were nodular disease (74.7%) and hyperthyroidism (12.4%). 24 patients (12.9%) experienced postoperative hypocalcemia with 13 (7.0%) requiring intravenous calcium infusion. One patient (0.9%) experienced permanent hypoparathyroidism. Risk factors for postoperative hypocalcemia included total thyroidectomy (OR 7.39, p<0.01), central and bilateral lateral neck dissection (OR 22.26, p=0.01), Graves' disease (OR 3.99, p=0.02), and malignancy (OR 2.96, p=0.03). CONCLUSIONS: Pediatric patients who undergo total thyroidectomy for underlying malignancy or Graves' disease and those who have more extensive nodal dissections are at increased risk of developing this postoperative hypocalcemia. These patients may benefit from more vigilant preoperative preparation and postoperative calcium and vitamin D supplementation.

Role of BRAFV600E in the first preclinical model of multifocal infiltrating myopericytoma development and microenvironment.

Myopericytoma (MPC) is a rare tumor with perivascular proliferation of pluripotent stem-cell-like pericytes. Although indolent, MPC may be locally aggressive with recurrent disease. The pathogenesis and diagnostic biomarkers of MPC are poorly understood. We discovered that 15% of benign MPCs (thyroid, skin; 3 of 20 samples) harbored BRAF(WT/V600E); 33.3% (1 of 3 samples) of BRAF(WT/V600E)-MPCs were multifocal/infiltrative/recurrent. Patient-MPC and primary MPC cells harbored BRAF(WT/V600E), were clonal and expressed pericytic-differentiation biomarkers crucial for its microenvironment. BRAF(WT/V600E)-positive thyroid MPC primary cells triggered in vitro (8.8-fold increase) and in vivo (3.6-fold increase) angiogenesis. Anti-BRAF(V600E) therapy with vemurafenib disrupted angiogenic and metabolic properties (~3-fold decrease) with down-regulation (~2.2-fold decrease) of some extracellular-matrix (ECM) factors and ECM-associated long non-coding RNA (LincRNA) expression, with no effects in BRAF(WT)-pericytes. Vemurafenib also inhibited (~3-fold decrease) cell viability in vitro and in BRAF(WT/V600E)-positive thyroid MPC patient-derived xenograft (PDX) mice (n = 5 mice per group). We established the first BRAF(WT/V600E)-dependent thyroid MPC cell culture. Our findings identify BRAF(WT/V600E) as a novel genetic aberration in MPC pathogenesis and MPC-associated biomarkers and imply that anti-BRAF(V600E) agents may be useful adjuvant therapy in BRAF(WT/V600E)-MPC patients. Patients with BRAF(WT/V600E)-MPC should be closely followed because of the risk for multifocality/recurrence.