Genomic analysis of spermatocytic tumors demonstrates recurrent molecular alterations in cases with malignant clinical behavior.

Spermatocytic tumor (ST) is a rare type of germ cell tumor that occurs exclusively in the postpubertal testis and typically affects elderly men. Most STs are benign, but rare cases exhibit aggressive clinical behavior, often in association with transition to sarcomatoid histology. Limited molecular analyses have been performed on STs; therefore, their genomic and epigenomic features remain incompletely described. Twenty-seven samples from 25 individual patients were analyzed with a combination of DNA sequencing panels, genomic methylation profiling, SNP array, isochromosome (12p) [i(12p)] FISH, and immunohistochemistry. The series included five metastasizing tumors (three with sarcomatoid transformation, one anaplastic, and one conventional) and 20 non-metastasizing tumors (14 anaplastic and six conventional). Anaplastic tumors comprised a monomorphic population of intermediate-sized neoplastic cells, as previously described. Multiomic analyses demonstrated that there were two genomic subgroups of STs: one with diploid genomes and hotspot RAS/RAF variants and the other with global ploidy shift and absence of recurrent mutations. Relative gain of chromosome 9 was a consistent finding in both subgroups. A comparison of metastasizing and non-metastasizing cases demonstrated that aggressive behavior was associated with the acquisition of pathogenic TP53 mutations and/or relative gains of 12p/i(12p). In cases with sarcomatoid transformation, TP53 mutations seem to underlie the transition to sarcomatoid histology. Genomic methylation analysis demonstrated that aggressive cases with gains of 12p cluster closer to pure seminomas than to STs without gains of 12p. In conclusion, STs include two genomic subgroups, characterized by global ploidy shifts without recurrent mutations and diploid genomes with RAS/RAF hotspot mutations, respectively. Biologic progression was associated with relative gains of 12p and TP53 mutations. The findings in STs with relative gains of 12p suggest that they may exhibit biologic characteristics akin to those seen in germ cell neoplasia in situ-related germ cell tumors rather than non-germ cell neoplasia in situ-derived STs. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

IDH2 -Mutated Sinonasal Tumors: A Review.

INTRODUCTION: Genetic profiling has caused an explosion in the subclassification of sinonasal malignancies. Distinguishing several of these tumor types by histomorphology alone has been quite challenging, and although pathologic classification aims to be as specific as possible, it remains to be seen if this recent move toward tumor speciation bears clinical relevance, most particularly focused on subtyping for the sake of prognostication and treatment. One such recently described cohort, predominantly lumped under the moniker of sinonasal undifferentiated carcinoma (SNUC) is IDH2 -mutated sinonasal carcinoma, a high-grade carcinoma associated with mutations in the isocitrate dehydrogenase-2 ( IDH2 ) gene. A hotspot mutation in the R172 codon has been described in 50% to 80% of the tumors classified as SNUC, large cell neuroendocrine carcinomas, and rarely in cases classified as olfactory neuroblastoma. The use of immunohistochemical and molecular approaches is required to correctly identify this subset of sinonasal tumors, with further study necessary to elucidate their unique pathophysiology, ultimately determining whether a revision is required toward the current therapeutic approach. AIMS: Here, we provide an overview of the IDH2- mutated sinonasal tumors, discuss histopathologic and clinical features, and focus on molecular diagnostics and novel immunohistochemical markers. RESULTS: A review of the literature reveals 82 reported cases with IDH2 -mutated sinonasal tumors (IST), confirmed either by molecular studies or diagnostic immunohistochemical markers. The mean patient age is 60 years (female/male: 1/1.4), the median tumor size is 5 cm (range: 2.5 to 7.0 cm), and the most common location is the nasal cavity (81%). IST displays tumor necrosis and increased mitotes. Histopathologically, IST shows SNUC-like, large cell neuroendocrine carcinomas-like, or poorly differentiated carcinoma-like features (77%, 12%, and 9%, respectively). The molecular hotspot alterations in mitochondrial IDH2 are: R172S (61%), R172T (19%), R172G (7%), and R172M (3%). Sixty-five percent of tumors are surgically resectable, and all patients received chemotherapy, radiation therapy, or both. Rates of locoregional recurrence and distant metastasis are 60% and 40%, respectively. One-, 3- and 5-year survival rates are 83%, 50%, and 43%, respectively. In all but 1 study, IST is associated with better outcomes than IDH2 wild-type tumors and SMARCB1 -deficient sinonasal tumors.

Cystatin SN is a potent upstream initiator of epithelial-derived type 2 inflammation in chronic rhinosinusitis.

BACKGROUND: Cystatin SN (CST1) and cystatin SA (CST2) are cysteine protease inhibitors that protect against allergen, viral, and bacterial proteases. Cystatins are overexpressed in the setting of allergic rhinitis and chronic rhinosinusitis with nasal polyps (CRSwNP); however, their role in promoting type 2 inflammation remains poorly characterized. OBJECTIVE: The purpose of this study was to use integrated poly-omics and a murine exposure model to explore the link between cystatin overexpression in CRSwNP and type 2 inflammation. METHODS: In this institutional review board- and institutional animal care and use committee-approved study, we compared tissue, exosome, and mucus CST1 and CST2 between CRSwNP and controls (n = 10 per group) by using matched whole exome sequencing, transcriptomic, proteomic, posttranslational modification, histologic, functional, and bioinformatic analyses. C57/BL6 mice were dosed with 3.9 µg/mL of CST1 or PBS intranasally for 5 to 18 days in the presence or absence of epithelial ABCB1a knockdown. Inflammatory cytokines were quantified by using Quansys multiplex assays or ELISAs. RESULTS: Of the 1305 proteins quantified, CST1 and CST2 were among the most overexpressed protease inhibitors in tissue, exosome, and mucus samples; they were localized to the epithelial layer. Multiple posttranslational modifications were identified in the polyp tissue. Exosomal CST1 and CST2 were strongly and significantly correlated with eosinophils and Lund-Mackay scores. Murine type 2 cytokine secretion and TH2 cell infiltration increased in a time-dependent manner following CST1 exposure and was abrogated by epithelial knockdown of ABCB1a, a regulator of epithelial cytokine secretion. CONCLUSION: CST1 is a potent upstream initiator of epithelial-derived type 2 inflammation in CRSwNP. Therapeutic strategies targeting CST activity and its associated posttranslational modifications deserve further interrogation.

Cell-free human papillomavirus DNA kinetics after surgery for human papillomavirus-associated oropharyngeal cancer.

BACKGROUND: New ultrasensitive methods for detecting residual disease after surgery are needed in human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC). METHODS: To determine whether the clearance kinetics of circulating tumor human papillomavirus DNA (ctHPVDNA) is associated with postoperative disease status, a prospective observational study was conducted in 33 patients with HPV+OPSCC undergoing surgery. Blood was collected before surgery, postoperative days 1 (POD 1), 7, and 30 and with follow-up. A subcohort of 12 patients underwent frequent blood collections in the first 24 hours after surgery to define early clearance kinetics. Plasma was run on custom droplet digital polymerase chain reaction (ddPCR) assays for HPV genotypes 16, 18, 33, 35, and 45. RESULTS: In patients without pathologic risk factors for recurrence who were observed after surgery, ctHPVDNA rapidly decreased to <1 copy/mL by POD 1 (n = 8/8). In patients with risk factors for macroscopic residual disease, ctHPVDNA was markedly elevated on POD 1 (>350 copies/mL) and remained elevated until adjuvant treatment (n = 3/3). Patients with intermediate POD 1 ctHPVDNA levels (1.2-58.4 copies/mL) all possessed pathologic risk factors for microscopic residual disease (n = 9/9). POD 1 ctHPVDNA levels were higher in patients with known adverse pathologic risk factors such as extranodal extension >1 mm (P = .0481) and with increasing lymph nodes involved (P = .0453) and were further associated with adjuvant treatment received (P = .0076). One of 33 patients had a recurrence that was detected by ctHPVDNA 2 months earlier than clinical detection. CONCLUSIONS: POD 1 ctHPVDNA levels are associated with the risk of residual disease in patients with HPV+OPSCC undergoing curative intent surgery and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. LAY SUMMARY: Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC) is increasing at epidemic proportions and is commonly treated with surgery. This report describes results from a study examining the clearance kinetics of circulating tumor HPV DNA (circulating tumor human papillomavirus DNA [ctHPVDNA]) following surgical treatment of HPV+OPSCC. We found that ctHPVDNA levels 1 day after surgery are associated with the risk of residual disease in patients with HPV+OPSCC and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. These findings are the first to demonstrate the potential utility of ctHPVDNA in patients with HPV+OPSCC undergoing surgery.

Implementation and Clinical Adoption of Precision Oncology Workflows Across a Healthcare Network.

BACKGROUND: Precision oncology relies on molecular diagnostics, and the value-proposition of modern healthcare networks promises a higher standard of care across partner sites. We present the results of a clinical pilot to standardize precision oncology workflows. METHODS: Workflows are defined as the development, roll-out, and updating of disease-specific molecular order sets. We tracked the timeline, composition, and effort of consensus meetings to define the combination of molecular tests. To assess clinical impact, we examined order set adoption over a two-year period (before and after roll-out) across all gastrointestinal and hepatopancreatobiliary (GI) malignancies, and by provider location within the network. RESULTS: Development of 12 disease center-specific order sets took ~9 months, and the average number of tests per indication changed from 2.9 to 2.8 (P = .74). After roll-out, we identified significant increases in requests for GI patients (17%; P < .001), compliance with testing recommendations (9%; P < .001), and the fraction of "abnormal" results (6%; P < .001). Of 1088 GI patients, only 3 received targeted agents based on findings derived from non-recommended orders (1 before and 2 after roll-out); indicating that our practice did not negatively affect patient treatments. Preliminary analysis showed 99% compliance by providers in network sites, confirming the adoption of the order sets across the network. CONCLUSION: Our study details the effort of establishing precision oncology workflows, the adoption pattern, and the absence of harm from the reduction of non-recommended orders. Establishing a modifiable communication tool for molecular testing is an essential component to optimize patient care via precision oncology.

Diagnostic Value of MAML2 Rearrangements in Mucoepidermoid Carcinoma.

Mucoepidermoid carcinoma (MEC) is often seen in salivary glands and can harbor MAML2 translocations (MAML2+). The translocation status has diagnostic utility as an objective confirmation of the MEC diagnosis, for example, when distinction from the more aggressive adenosquamous carcinoma (ASC) is not straightforward. To assess the diagnostic relevance of MAML2, we examined our 5-year experience in prospective testing of 8106 solid tumors using RNA-seq panel testing in combinations with a two-round Delphi-based scenario survey. The prevalence of MAML2+ across all tumors was 0.28% (n = 23/8106) and the majority of MAML2+ cases were found in head and neck tumors (78.3%), where the overall prevalence was 5.9% (n = 18/307). The sensitivity of MAML2 for MEC was 60% and most cases (80%) were submitted for diagnostic confirmation; in 24% of cases, the MAML2 results changed the working diagnosis. An independent survey of 15 experts showed relative importance indexes of 0.8 and 0.65 for "confirmatory MAML2 testing" in suspected MEC and ASC, respectively. Real-world evidence confirmed that the added value of MAML2 is a composite of an imperfect confirmation test for MEC and a highly specific exclusion tool for the diagnosis of ASC. Real-world evidence can help move a rare molecular-genetic biomarker from an emerging tool to the clinic.

Oncocytic intraductal carcinoma of salivary glands: a distinct variant with TRIM33-RET fusions and BRAF V600E mutations.

AIMS: Salivary gland intraductal carcinoma (IDC) is a complex ductal neoplasm surrounded by a layer of myoepithelial cells. Recent insights have shown that there are three different types: intercalated duct-like, with frequent NCOA4-RET fusions; apocrine, with salivary duct carcinoma-like mutations; and mixed intercalated duct-like/apocrine, with RET fusions, including TRIM27-RET. In addition, an oncocytic IDC has been described, but it remains unclear whether it represents a fourth variant or simply oncocytic metaplasia of another IDC type. Our aim was to more completely characterize oncocytic IDC. METHODS AND RESULTS: Six IDCs with oncocytic changes were retrieved from the authors' archives, from three men and three women ranging in age from 45 to 75 years (mean, 63 years). Five arose in the parotid gland, with one in an accessory parotid gland. Four patients with follow-up were free of disease after 1-23 months. Several immunostains (S100, mammaglobin, androgen receptor, and p63/p40) and molecular tools (RNA sequencing, RET fluorescence in-situ hybridisation, BRAF V600E VE1 immunohistochemistry, and Sanger sequencing) were applied. Histologically, the tumours were variably cystic with solid intracystic nodules often difficult to recognise as intraductal. In all, tumour ducts were positive for S100 and mammaglobin, negative for androgen receptor, and completely surrounded by myoepithelial cells positive for p63/p40. Molecular analysis revealed TRIM33-RET in two of six cases, NCOA4-RET in one of six cases, and BRAF V600E in two of six cases. One case had no identifiable alterations. CONCLUSIONS: Oncocytic IDC shares similarities with intercalated duct-like IDC. Although additional verification is needed, the oncocytic variant appears to be sufficiently unique to be now regarded as the fourth distinct subtype of IDC. Because of its indolent nature, oncocytic IDC should be distinguished from histological mimics.

To stage or not to stage: determining the true clinical significance of the biopsy tract through perinephric fat in assessing renal cell carcinoma.

AIMS: Perinephric fat invasion (PFI) is a key component of renal cell carcinoma (RCC) staging, but there are limited data pertaining to biopsy tract seeding (BTS) resulting in perirenal tissue involvement [BTS with perinephric fat invasion (BTS-P)].The aim is to correlate clinical outcomes with pathologic stage to determine whether the presence of BTS-P should be considered a criterion to stage RCC as part of the pT3a category in the absence of any other upstaging variables. MATERIALS AND RESULTS: We identified 304 renal biopsies from patients with subsequent nephrectomies for RCC; 33 of the tumours contained PFI. Each case was reviewed to determine the presence of BTS-P and other forms of invasion [e.g. non-BTS-P PFI, sinus fat invasion (SFI), and/or renal vein invasion (RVI)], and these findings were compared with survival outcomes. Ten (30%) of 33 tumours with PFI showed BTS-P as the only finding, and were otherwise pT1 tumours; six (60%) patients were alive without disease (AWOD) (mean, 77.5 months), three were lost to follow-up (LTF), and one died of other disease (DOOD). Two patients showed true PFI plus BTS-P; one was LTF and one is AWOD at 107 months. Ten (43%) of 23 patients with tumours with true invasion (PFI ± SFI and/or RVI) are AWOD (mean, 97.7 months), eight (35%) died of disease (DOD), four were LTF, and one DOOD. Kaplan-Meier survival curves showed that the cancer-specific survival was significantly worse in patients with true invasion (P = 0.044) than in those with BTS-P as the sole finding. CONCLUSION: Patients with tumours showing BTS-P only appear to have better outcomes than those with other non-PFI invasion, suggesting that this finding should not be upstaged to pT3a. Additional studies are needed to corroborate the significance of our observations.

Comparison between computed tomography and ultrasound for presurgical evaluation of oral tongue squamous cell carcinoma tumor thickness.

PURPOSE: To compare the accuracy of oral tongue squamous cell carcinoma (OTSCC) tumor thickness (TT) measured on CT to intraoperative ultrasound (US) and histopathology. METHODS AND MATERIALS: Twenty-six patients with OTSCC who underwent tumor resection by a single surgeon with simultaneous intraoperative US between 3/2016 and 4/2019 were prospectively identified, and their data reviewed. TT was independently measured in 19 patients who underwent preoperative CT (cTT) by two neuroradiologists blinded to US and histological results. The confidence level of interpretation of cTT was recorded by each reader using a 5-point Likert scale. The degree of dental artifact on CT was also scored. cTT was compared to TT measured on intraoperative US (uTT) and histopathologic assessment of TT (hTT). RESULTS: OTSCC was visualized on CT in 52% (10/19) and 63% (12/19) of cases for readers 1 and 2, respectively. Mean Likert score was 0.42 for reader 1 and 0.73 for reader 2. Mean cTT of OTSCCs was 5.8 mm +/- 1.7 mm (n = 11). In comparison, mean uTT and hTT were 7.6 mm±3.5 mm and 7.1 +/- 4.2 mm, respectively. The Pearson coefficient (95% confidence interval) was 0.10 (-0.53-0.66) between cTT and hTT (n = 11) and 0.93 (0.74-0.98) between uTT and hTT. CONCLUSIONS: Preoperative CT is not reliable for assessment of TT in OTSCC compared to US and histopathology, particularly for OTSCC under 10 mm. US offers a practical complementary imaging tool with a unique role for primary tumor assessment that can aid in pre-operative planning, especially for small tumors.

Clinicopathologic features of kinase fusion-related thyroid carcinomas: an integrative analysis with molecular characterization.

The discovery of actionable kinase gene rearrangements has revolutionized the therapeutic landscape of thyroid carcinomas. Unsolved challenges include histopathologic recognition of targetable cases, correlation between genotypes and tumor behavior, and evolving resistance mechanisms against kinase inhibitors (KI). We present 62 kinase fusion-positive thyroid carcinomas (KFTC), including 57 papillary thyroid carcinomas (PTC), two poorly differentiated thyroid carcinomas (PDTC), two undifferentiated thyroid carcinomas (ATC), and one primary secretory carcinoma (SC), in 57 adults and 5 adolescents. Clinical records, post-operative histology, and molecular profiles were reviewed. Histologically, all KFTC showed multinodular growth with prominent intratumoral fibrosis. Lymphovascular invasion (95%), extrathyroidal extension, gross and microscopic (63%), and cervical lymph node metastasis (79%) were common. Several kinase fusions were identified: STRN-ALK, EML4-ALK, AGK-BRAF, CUL1-BRAF, MKRN1-BRAF, SND1-BRAF, TTYH3-BRAF, EML4-MET, TFG-MET, IRF2BP2-NTRK1, PPL-NTRK1, SQSTM1-NTRK1, TPR-NTRK1, TPM3-NTRK1, EML4-NTRK3, ETV6-NTRK3, RBPMS-NTRK3, SQSTM1-NTRK3, CCDC6-RET, ERC1-RET, NCOA4-RET, RASAL2-RET, TRIM24-RET, TRIM27-RET, and CCDC30-ROS1. Individual cases also showed copy number variants of EGFR and nucleotide variants and indels in pTERT, TP53, PIK3R1, AKT2, TSC2, FBXW7, JAK2, MEN1, VHL, IDH1, PTCH1, GNA11, GNAQ, SMARCA4, and CDH1. In addition to thyroidectomy and radioactive iodine, ten patients received multi-kinase and/or selective kinase inhibitor therapy, with 6 durable, objective responses and four with progressive disease. Among 47 cases with >6 months of follow-up (median [range]: 41 [6-480] months), persistent/recurrent disease, distant metastasis and thyroid cancer-related death occurred in 57%, 38% and 6%, respectively. In summary, KFTC encompass a spectrum of molecularly diverse tumors with overlapping clinicopathologic features and a tendency for clinical aggressiveness. Characteristic histology with multinodular growth and prominent fibrosis, particularly when there is extensive lymphovascular spread, should trigger molecular testing for gene rearrangements, either in a step-wise manner by prevalence or using a combined panel. Further, our findings provide information on molecular therapy in radioiodine-refractory thyroid carcinomas.

Clinicopathologic and molecular characterization of NTRK-rearranged thyroid carcinoma (NRTC).

Primary thyroid neoplasms with actionable NTRK rearrangements are rare, and their clinical behavior, histologic characteristics, and molecular landscape are not well understood. We report an institutional series of eleven NTRK-rearranged thyroid carcinomas (NRTC) by performing clinicopathologic review and next-generation sequencing for targeted mutations and gene rearrangements. The NRTC encompass a histomorphologic spectrum of ten papillary thyroid carcinomas (PTC), including one with high-grade features, and one secretory carcinoma (SC), in ten adults and one adolescent. All NRTC were characterized by an unusual multinodular growth pattern, extensive lymphovascular invasion, and cervical lymph node metastases at initial presentation. Immunophenotypically, while most cases were positive for TTF1 and PAX8, the SC case was negative/weak for these markers and instead diffusely expressed GATA3, mammaglobin and S100. Observed gene rearrangements included ETV6-NTRK3 (n = 4, including the SC), TPR-NTRK1 (n = 2), RBPMS-NTRK3 (n = 2), SQSTM1-NTRK1 (n = 1), SQSTM1-NTRK3 (n = 1), and EML4-NTRK3 (n = 1). Mutation profiling revealed a concurrent TERT promotor mutation C228T in two (22%) patients and a novel frameshift MEN1 deletion in one. All patients received total thyroidectomy and radioactive iodine. Despite frequent development of persistent/recurrent disease (9 cases, 82%) and distant metastases (6 cases; 55%), no tumor-related death occurred over a median (range) follow-up of 44 (11 to 471) months. Three patients received NTRK inhibitor therapy, with the SC case showing complete resolution and two other patients experiencing 33% and 69.7% decrease of disease burden. Although the range of features is variable, NRTC appear to be clinically aggressive tumors with high metastatic rate but relatively low mortality with NTRK inhibitor therapy. The histologic findings of multinodular growth and extensive lymphovascular spread, seen in all NRTC, including PTC and SC, may serve as useful histomorphologic clues to prompt NTRK status testing. We also present the first report of concurrent TERT promotor activating mutation which did not appear to confer entrectinib resistance to NRTC.

BRAFV600E Mutation is Associated with an Increased Risk of Papillary Thyroid Cancer Recurrence.

BACKGROUND: Papillary thyroid carcinoma is the most common endocrine malignancy and one of the most common cancers worldwide. However, the optimal timing and frequency of surveillance to assess for recurrence remain undetermined. As the incidence of thyroid cancer continues to rise worldwide, identifying risk factors for recurrence and investigating intervals and durations of surveillance are paramount to adapt treatment and follow-up plans to high-risk individuals and to reduce interventions for low-risk patients. METHODS: Our dataset included an unselected cohort of papillary thyroid carcinoma (PTC) patients who underwent a total thyroidectomy (or unilateral then completion thyroidectomy) at a single institution from 2000 to 2007. BRAF genotyping was performed on available specimens by a validated PCR-based assay. Pathologic structural recurrence was the primary outcome. We performed univariate and multivariable analyses to identify predictors of cancer recurrence. RESULTS: In total, 599 patients underwent complete resection of the thyroid gland for PTC. The cohort was young (mean age 45.0 years), predominately female (n = 462, 76.9%), and median follow-up was 10.3 years (IQR 5.4-12.2). Recurrence occurred more commonly in the BRAFV600E group (18.6 vs. 9.9%, p = 0.02). BRAF independently predicted PTC recurrence (HR 2.81, p = 0.006). CONCLUSIONS: BRAF mutation is an independent predictor of papillary thyroid carcinoma long-term recurrence. Understanding molecular characteristics of individual thyroid cancers may help risk-stratify patients and direct them toward more appropriate initial care and long-term surveillance strategies.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): Diagnostic updates and molecular advances.

The noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a strictly defined thyroid lesion, reclassified in 2016, in order to more accurately reflect the biological behavior of the tumor and thus, modify the way the lesion is clinically approached and perceived both by practitioners and patients. Additionally, this newly specified designation also allows for more uniformity in reporting for general pathologists less comfortable to exclude overt malignancy with certain nuclear features. In recent years, increasing molecular analyses correlated with longitudinal clinical outcomes have fostered improved diagnostic and treatment paradigms. Important revisions made to the definition of NIFTP in 2018 include the prohibition of any true papillae formation and the exclusion of lesions harboring the BRAF V600E mutation and other high-risk genetic abnormalities. These changes reflect the imperfection of the current criteria in outcome prediction and the global efforts for improvement. NIFTP are lesions with a wide range of size and cytomorphology. Although not addressed in the original series, large (≥4 cm) and oncocytic NIFTP have recently been shown to incur no recurrence or metastatic risk. Molecularly, NIFTP have a similar mutational profile as other follicular thyroid neoplasms, with frequent RAS family mutations and PAX8-PPARɤ fusions. However, the transcriptomic landscape is highly heterogenous, adding difficulty to gene expression-based cytopathologic classification. This review summarizes the evolution of the NIFTP concept and important advances in recent literature.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features: a review for pathologists.

The rising incidence of papillary thyroid carcinoma is linked in part to inclusion of noninvasive follicular variant of papillary thyroid carcinoma. Despite its designation as carcinoma, noninvasive follicular variant of papillary thyroid carcinoma appears to be exceptionally indolent, often over treated by current treatment practices. Additionally, criteria for diagnosis have historically been subjective and challenging. Recently, an international multidisciplinary collaborative group performed a clinicopathologic survey of such cases with extended follow-up and concluded based on the outcome data that a revision in nomenclature was warranted, proposing 'Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP).' This monograph is a synopsis and guide for pathologists on NIFTP and focuses on histologic features, including inclusion and exclusion criteria used to define NIFTP, as well as grossing guidelines, reporting practices, and potential diagnostic limitations.

Imaging and Management of Intrathoracic Renal Cell Carcinoma Metastases.

OBJECTIVE: Renal cell carcinoma (RCC) has a propensity to metastasize to the chest, with the lungs being the most common distant metastatic site. The histologic subtype of RCC has implications for prognosis. CONCLUSION: Significant advances have been made in the management of metastatic RCC, both in systemic and locoregional therapies. The aim of this article is to review appearances of intrathoracic metastases from RCC and to discuss treatment considerations.

The follicular variant of papillary thyroid cancer and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).

PURPOSE OF REVIEW: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a new terminology proposed for encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). Recently, thyroid cancer incidence has increased dramatically, without affecting related mortality rate. This increase is widely attributed to the intensified surveillance leading to a substantial increase in the diagnosis of small classic papillary thyroid cancers and EFVPTCs. Recent studies emphasize the indolent behavior of the EFVPTC. Recently, there has been a reclassification of EFVPTC as NIFTP, a benign entity. The financial and emotional burden of 'cancer' diagnosis and treatment can be significant. RECENT FINDINGS: This review recapitulates the literature supporting the reclassification of EFVPTC as NIFTP, a benign entity, and reviews standardized diagnostic criteria for EFVPTC. SUMMARY: The information highlighted in this review will affect surgical decision making and may promote the offering of hemithyroidectomy over a total thyroidectomy to some patients with 'indeterminate' cytopathological category; postoperative radioiodine ablation will not be required for NIFTP patients.

p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer.

Anaplastic thyroid carcinoma (ATC) has among the worst prognoses of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. v-raf murine sarcoma viral oncogene homolog B (BRAF) and tumor protein p53 (TP53) mutations cooccur in a high proportion of ATCs, particularly those associated with a precursor papillary thyroid carcinoma (PTC). To develop an adult-onset model of BRAF-mutant ATC, we generated a thyroid-specific CreER transgenic mouse. We used a Cre-regulated Braf(V600E) mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from PTC to ATC. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis, and rapid lethality. We used small-animal ultrasound imaging to monitor autochthonous tumors and showed that treatment with the selective BRAF inhibitor PLX4720 improved survival but did not lead to tumor regression or suppress signaling through the MAPK pathway. The combination of PLX4720 and the mapk/Erk kinase (MEK) inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small-molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma.

Failure to detect human papillomavirus in focal cortical dysplasia type IIb.

OBJECTIVE: Recent studies have reported evidence of human papillomavirus 16 (HPV-16) in a very high proportion of pathological specimens of focal cortical dysplasia type IIb, but not in control specimens, motivating the proposal that viral infection during fetal development may play a causal role in the pathogenesis of focal cortical dysplasias. However, the significance of the association between HPV infection and focal cortical dysplasia type IIb, and its reproducibility across surgical centers, remain unclear. Here we sought evidence for HPV-16 in an independent cohort of surgical specimens. METHODS: We identified 14 specimens of focal cortical dysplasia type IIb from a single surgical center between 1995 and 2013. Multiple methods were used to establish presence or absence of HPV, including DNA polymerase chain reaction, conventional in situ hybridization, chromogenic in situ hybridization, and immunohistochemistry for p16. RESULTS: We found no conclusive evidence of HPV in any of the specimens. All but 1 of the cases were negative by >1 method. INTERPRETATION: These results raise questions about the prevalence of HPV infection in focal cortical dysplasias and about its potential importance as a causative agent.