Salivary gland fine-needle aspiration biopsy: quality assurance results from a tertiary cancer center.

INTRODUCTION: Fine-needle aspiration biopsy (FNAB) plays a critical role in the management of patients with salivary gland lesions. A specific diagnosis can be difficult due to the wide range of lesions with overlapping morphologic features, potentially leading to interpretation errors. We analyzed the cytologic-histologic discrepancies identified in the quality assurance program of a major cancer center in cases of salivary gland FNAB and performed a root cause analysis. MATERIALS AND METHODS: Salivary gland FNAB specimens performed during a 12-year period at a major tertiary cancer center were reviewed. The inclusion criteria for this study included FNAB cases of salivary glands with subsequent histologic or flow cytometry follow up. The cytologic diagnoses for these cases were recategorized according to the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) based on the original reports. The risk of neoplasm and malignancy based on the cases with subsequent resection or flow cytometry and the most common causes of discrepancy were analyzed. RESULTS: The risk of neoplasm ranged from 41% to 99% and the risk of malignancy ranged from 22% to 99% among the different MSRSGC categories. Lymphoid and myoepithelial rich lesions were the most common miscategorized lesions using the MSRSGC. Reactive changes due to inflammation were associated with overcalls. The most common malignancy in the atypical category was mucoepidermoid carcinomas. CONCLUSIONS: Myoepithelial and lymphoid rich lesions arising in the salivary gland are associated with a higher risk of misclassification. The use of category IVB in the MSRSGC is appropriate for lesions with abundant myoepithelial cells. Reactive atypia seen in sialadenitis was the most common feature associated with overcall.

A Phase I Study of Alpelisib in Combination with Trastuzumab and LJM716 in Patients with PIK3CA-Mutated HER2-Positive Metastatic Breast Cancer.

PURPOSE: Activating mutations in PIK3CA promote resistance to HER2-targeted therapy in breast cancer; however, inhibition of PI3K alone leads to escape via feedback upregulation of HER3. Combined inhibition of HER2, HER3, and PI3K overcomes this mechanism preclinically. PATIENTS AND METHODS: This phase I study investigated the MTD of alpelisib given in combination with trastuzumab and LJM716 (a HER3-targeted antibody) in patients with PIK3CA-mutant HER2-positive (HER2+) metastatic breast cancer (MBC) using the continual reassessment method. Secondary analyses included efficacy and exploratory correlative studies. RESULTS: Ten patients were treated initially with daily alpelisib (arm A). Grade ≥3 adverse events seen in ≥2 patients included diarrhea (n = 6), hypokalemia (n = 3), abnormal liver enzymes (n = 3), hyperglycemia (n = 2), mucositis (n = 2), and elevated lipase (n = 2). The MTD of alpelisib in arm A was 250 mg daily. This prompted the opening of arm B in which 11 patients received intermittently dosed alpelisib. Grade ≥3 adverse events seen in ≥2 patients included diarrhea (n = 5), hypokalemia (n = 3), and hypomagnesemia (n = 2). The MTD of alpelisib in arm B was 350 mg given 4 days on, 3 days off. Among 17 patients assessed, 1 had a partial response, 14 had stable disease, and 2 had disease progression at best response. Five patients had stable disease for >30 weeks. mRNA profiling of pre- and on-treatment tissue demonstrated PIK3CA target engagement by alpelisib via induction of downstream signaling and feedback pathways. CONCLUSIONS: Combination treatment with alpelisib, trastuzumab, and LJM716 was limited by gastrointestinal toxicity. Further efforts are warranted to target the PI3K pathway in HER2+ MBC.

Vascularized Temporoparietal Fascial Flap: A Novel Surgical Technique to Bypass the Blood-Brain Barrier in Glioblastoma.

BACKGROUND: The major difficulty in treating glioblastoma stems from the intrinsic privileged nature of the brain. This complicates therapy, as many traditionally potent chemotherapeutics cannot access their target sites in the brain. Several techniques have been investigated to overcome this barrier and facilitate drug delivery. However, these techniques have inherent shortcomings related to the delivery system, the drug itself, or its bioactivity. Periosteal flaps and temporoparietal fascial flaps (TPFFs) are widely used options because they have predictable vasculature and a wide rotational arc. These flaps are not restricted by the blood-brain barrier, as they derive their vascular supply from branches of the external carotid artery, which can be readily identified with Doppler ultrasound. We hypothesized that transposition of a vascularized TPFF to the walls of a resected tumor surgical cavity may bring autologous tissue not restricted by the blood-brain barrier in close vicinity of the resected tumor bed microenvironment. This offers a nonselective, long-lasting gateway to target the residual tumor cells nesting in the brain adjacent to the tumor. CASE DESCRIPTION: A 47-year-old, right-handed woman with newly diagnosed multifocal glioblastoma underwent excision of the tumor and TPFF placement. This illustrative case report represents the first case of the use of this novel surgical technique with radiologic follow-up. CONCLUSIONS: The blood-brain barrier is identified as a major barrier for effective drug delivery in glioblastoma. This study demonstrates the feasibility of the TPFF technique to bypass this barrier and help facilitate the goal of improving drug delivery.

Intratubular Teratoma: A Rare Form of Testicular Germ Cell Neoplasia.

Germ cell neoplasia in situ is the initial manifestation for invasive germ cell tumor. Further progression will result in intratubular germ cell tumor with the majority being intratubular seminoma or intratubular embryonal carcinoma. Intratubular teratoma in the testis is exceptionally rare with no well-documented cases to our knowledge. In this article, we report a case of an intratubular teratoma adjacent to mixed germ cell tumor in the testis. The patient is a 34-year-old male who presented with a palpable right testicular mass and underwent right radical orchiectomy. Gross examination of the testis revealed 2.0-cm tan, well-circumscribed, firm, and nodular mass at the inferior pole. Microscopic examination revealed a mixed germ cell tumor, predominantly seminoma (95%) with embryonal carcinoma (4%) and teratoma (1%). There is also germ cell neoplasia in situ, intratubular seminoma, and intratubular teratoma at the periphery of the tumor. Tubules with intratubular teratoma were filled by neoplastic squamous cells with a single layer of germ cell neoplasia in situ at the periphery. Adjacent to the intratubular teratoma was seminoma, embryonal carcinoma, and invasive teratoma. Immunohistochemical stains showed the neoplastic squamous cells in the tubule to be positive for p40 and negative for OCT34 and D2-40. The single layer of germ cell neoplasia in situ at the periphery of the intratubular teratoma was negative for p40 and positive for OCT34 and D2-40. Although teratoma is a common component in an adult germ cell tumor, an intratubular manifestation is exceptional. The present case illustrates this rare finding.

Atypical Vascularity Within a Schwannoma.

We report on the unusual presentation of a schwannoma. Aside from the aberrant dorsolateral anatomical presentation, ultrasonography revealed not only peripheral vascularity but also internal vascularity. Internal vascularity often suggests a malignant process as opposed to a benign one; however, in the presented case, the diagnosis of a benign lesion was confirmed with S100 immunohistochemical staining. In this study, we review the literature on this pathology and present an uncommon presentation of a benign nerve tumor.

Suprasellar and third ventricular cavernous malformation: Lessons learned in differential diagnosis and surgical planning.

BACKGROUND: While craniopharyngiomas (CPs) are the most common cystic suprasellar lesions in adults, cavernous malformations (CMs) only exceptionally occur in this location and are seldom considered in the differential diagnosis of such lesions. However, unlike CPs, suprasellar CMs are not typically approached via an endoscopic endonasal approach. CASE DESCRIPTION: We present a unique clinical case of suprasellar and third ventricular CM mimicking a CP, posing a major decision-making dilemma at the levels of both preoperative diagnosis and surgical planning. CONCLUSION: This case highlights the importance of carefully considering all the differential diagnoses of sellar pathology to select the most appropriate management strategy and surgical approach.

Annotating pathogenic non-coding variants in genic regions.

Identifying the underlying causes of disease requires accurate interpretation of genetic variants. Current methods ineffectively capture pathogenic non-coding variants in genic regions, resulting in overlooking synonymous and intronic variants when searching for disease risk. Here we present the Transcript-inferred Pathogenicity (TraP) score, which uses sequence context alterations to reliably identify non-coding variation that causes disease. High TraP scores single out extremely rare variants with lower minor allele frequencies than missense variants. TraP accurately distinguishes known pathogenic and benign variants in synonymous (AUC = 0.88) and intronic (AUC = 0.83) public datasets, dismissing benign variants with exceptionally high specificity. TraP analysis of 843 exomes from epilepsy family trios identifies synonymous variants in known epilepsy genes, thus pinpointing risk factors of disease from non-coding sequence data. TraP outperforms leading methods in identifying non-coding variants that are pathogenic and is therefore a valuable tool for use in gene discovery and the interpretation of personal genomes.While non-coding synonymous and intronic variants are often not under strong selective constraint, they can be pathogenic through affecting splicing or transcription. Here, the authors develop a score that uses sequence context alterations to predict pathogenicity of synonymous and non-coding genetic variants, and provide a web server of pre-computed scores.