Marina Vivero

Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics

Solitary fibrous tumor (SFT) is composed of spindled to ovoid cells in a patternless architecture with prominent stromal collagen and hemangiopericytoma-like vessels. Some tumors show hypercellularity, nuclear atypia, and significant mitotic activity; the latter feature in particular often portends an aggressive clinical course. SFT can sometimes be difficult to distinguish from other benign mesenchymal tumors and sarcomas. The most characteristic (albeit nonspecific) immunohistochemical finding in SFT is CD34 expression. A NAB2–STAT6 gene fusion, resulting in a chimeric protein in which a repressor domain of NGFI-A binding protein 2 (EGR1 binding protein 2) (NAB2) is replaced with a carboxy-terminal transactivation domain from signal transducer and activator of transcription 6, interleukin-4 induced (STAT6), was recently identified as a consistent finding in SFT. However, as these genes are located in close proximity on 12q13, this fusion can only rarely be detected by conventional chromosomal banding or fluorescence in situ hybridization analysis. Nuclear expression of the carboxy terminal part of STAT6 is a consistent finding in SFT of the meninges (so-called ‘meningeal hemangiopericytoma’). We investigated STAT6 expression by immunohistochemistry in SFTs and other soft tissue tumors arising outside the central nervous system to validate the diagnostic utility of this novel marker. Whole-tissue sections of 231 tumors were evaluated, including 60 cases of SFT as well as other benign and malignant mesenchymal neoplasms and sarcomatoid mesotheliomas. Fifty-nine of 60 SFT cases (98%) showed nuclear expression of STAT6, which was usually diffuse and intense. All other tumor types were negative for STAT6, except for three dedifferentiated liposarcomas and one deep fibrous histiocytoma, which showed weak staining. In conclusion, STAT6 is a highly sensitive and almost perfectly specific immunohistochemical marker for SFT and can be helpful to distinguish this tumor type from histologic mimics.

Risk Stratification of Follicular Variant of Papillary Thyroid Carcinoma

BACKGROUND Recent studies have described an encapsulated and an infiltrative form of follicular variant of papillary thyroid carcinoma (FVPTC). While encapsulated tumors have been reported to have virtually no metastatic potential or recurrence risk if angioinvasion and capsular penetration are absent, infiltrative tumors have been found to have a significant metastatic potential and a risk of recurrence. In our experience, a substantial number of FVPTCs are neither fully encapsulated nor infiltrative, but instead are partially-encapsulated (PE) or well-circumscribed (WC). Thus, the aim of this study was to investigate the metastatic potential and recurrence risk of PE/WC FVPTCs in comparison with that of encapsulated and infiltrative tumors. METHODS We studied 77 FVPTCs resected between 2000 and 2002 and characterized the tumors as encapsulated, PE/WC, or infiltrative. Histologic assessment was then correlated with lymph node status and clinical outcome. RESULTS In our cohort, 27 (35%) tumors were encapsulated, 35 (45%) were PE/WC, and 15 (19%) were infiltrative. Lymph node status was similar between PE/WC and encapsulated tumors, but was significantly different between encapsulated and infiltrative groups (p<0.001), and PE/WC and infiltrative groups (p<0.001). Lymph node metastases were absent in all 15 cases of encapsulated tumors and all 9 cases of PE/WC tumors with sampled lymph nodes, but were present in 7 of 9 (78%) cases of infiltrative tumors with sampled lymph nodes. For patients with available clinical follow-up (66 cases, 86%), the median follow-up time was 111 months. No patients with encapsulated tumors recurred, one (3%) patient with a PE/WC tumor had recurrent/residual disease, and two (15%) patients with infiltrative tumors had recurrent/residual disease. The one patient with a PE/WC tumor who had recurrent/residual disease had a tumor bed recurrence 7 years after initial resection. Significantly, this was the only patient in the PE/WC group that had a positive resection margin. CONCLUSIONS Our results demonstrate that PE/WC FVPTCs have a very low metastatic potential/recurrence risk, indicating that they should be distinguished from more aggressive infiltrative FVPTCs.

Liquid biopsy in lung cancer: A perspective from members of the pulmonary pathology society

Liquid biopsy has received extensive media coverage and has been called the holy grail of cancer detection. Attempts at circulating tumor cell and genetic material capture have been progressing for several years, and recent financially and technically feasible improvements of cell capture devices, plasma isolation techniques, and highly sensitive polymerase chain reaction- and sequencing-based methods have advanced the possibility of liquid biopsy of solid tumors. Although practical use of circulating RNA-based testing has been hindered by the need to fractionate blood to enrich for RNAs, the detection of circulating tumor cells has profited from advances in cell capture technology. In fact, the US Food and Drug Administration has approved one circulating tumor cell selection platform, the CellSearch System. Although the use of liquid biopsy in a patient population with a genomically defined solid tumor may potentially be clinically useful, it currently does not supersede conventional pretreatment tissue diagnosis of lung cancer. Liquid biopsy has not been validated for lung cancer diagnosis, and its lower sensitivity could lead to significant diagnostic delay if liquid biopsy were to be used in lieu of tissue biopsy. Ultimately, notwithstanding the enthusiasm encompassing liquid biopsy, its clinical utility remains unproven.

KRAS and NKX2-1 Mutations in Invasive Mucinous Adenocarcinoma of the Lung

Introduction: Mucinous differentiation is observed in a subset of lung adenocarcinomas with unique clinical and pathological features, but the biology of these neoplasms is poorly understood. Methods: We apply targeted next‐generation sequencing to characterize the mutational profiles of 21 invasive mucinous adenocarcinomas, mixed mucinous/nonmucinous adenocarcinomas, and adenocarcinomas with mucinous features of the lung and validate key findings on 954 additional lung adenocarcinomas from our institution and 514 lung adenocarcinomas from The Cancer Genome Atlas. Results: Sequencing identifies pathogenic mutations in the oncogenes Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA), erb‐b2 receptor tyrosine kinase 2 (ERBB2), and anaplastic lymphoma receptor tyrosine kinase (ALK) and recurrent mutations in tumor protein p53 (TP53), serine/threonine kinase 11 (STK11), NK2 homeobox 1 (NKX2‐1), and SET domain containing 2 (SETD2). In the combined discovery and validation cohorts, we identify nine neoplasms with distinct molecular and pathological features. All are invasive mucinous adenocarcinomas or mixed mucinous/nonmucinous adenocarcinomas with mutations of KRAS and frameshift or nonsense mutations of NKX2‐1. Immunohistochemical analysis shows that these neoplasms are associated with altered differentiation states, including loss of expression of the pulmonary marker thyroid transcription factor 1 (also called Nkx2.1) and expression of gastrointestinal markers. Conclusions: These findings describe recurrent NKX2‐1 mutations in invasive mucinous adenocarcinomas of the lung and support NKX2‐1 as a lineage‐specific tumor suppressor gene in lung carcinogenesis.

GRIA2 is a novel diagnostic marker for solitary fibrous tumour identified through gene expression profiling

The NAB2–STAT6 fusion was recently identified as a consistent finding in solitary fibrous tumour (SFT), resulting in nuclear expression of the C‐terminal part of STAT6. Gene expression studies of SFT revealed high expression of the GRIA2 gene. The aim of this study was to examine GRIA2 expression in SFTs and other soft tissue tumours to evaluate its diagnostic utility.

Immunohistochemistry of Pulmonary Biomarkers: A Perspective From Members of the Pulmonary Pathology Society

The use of immunohistochemistry for the determination of pulmonary carcinoma biomarkers is a well-established and powerful technique. Immunohistochemisty is readily available in pathology laboratories, is relatively easy to perform and assess, can provide clinically meaningful results very quickly, and is relatively inexpensive. Pulmonary predictive biomarkers provide results essential for timely and accurate therapeutic decision making; for patients with metastatic non-small cell lung cancer, predictive immunohistochemistry includes ALK and programmed death ligand-1 (PD-L1) (ROS1, EGFR in Europe) testing. Handling along proper methodologic lines is needed to ensure patients receive the most accurate and representative test outcomes.

Histopathology of Lung Disease in the Connective Tissue Diseases

The pathologic correlates of interstitial lung disease (ILD) secondary to connective tissue disease (CTD) comprise a diverse group of histologic patterns. Lung biopsies in patients with CTD-associated ILD tend to demonstrate simultaneous involvement of multiple anatomic compartments of the lung. Certain histologic patterns tend to predominate in each defined CTD, and it is possible in many cases to confirm connective tissue-associated lung disease and guide patient management using surgical lung biopsy. This article will cover the pulmonary pathologies seen in rheumatoid arthritis, systemic sclerosis, myositis, systemic lupus erythematosus, Sjögren syndrome, and mixed CTD.

Influence of descriptive terminology on management of atypical thyroid fine‐needle aspirates

The Bethesda System category of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) is used to classify a variety of mild abnormalities in thyroid FNAs. Modifying terminology is often added to FNA reports, but it is unknown whether specific phrases affect clinical management. To answer this question, the authors correlated treatment of patients who had initial AUS/FLUS diagnoses from Baptist Hospital (Miami, Fla) (BH) and Brigham and Womens Hospital (Boston, Mass) (BWH) with the language used in pathology reports.

Cytologic-histologic correlation of programmed death-ligand 1 immunohistochemistry in lung carcinomas: PD-L1 Staining in Cytology Specimens

Programmed cell death protein 1 inhibitors increasingly are being used to treat patients with advanced lung carcinomas. Programmed death‐ligand 1 (PD‐L1) immunohistochemistry (IHC) in tumor cells (TCs) and tumor‐infiltrating immune cells (ICs) is used to select patients for programmed cell death protein 1 inhibition, but few studies have evaluated PD‐L1 IHC in cytology specimens. The objective of the current study was to compare PD‐L1 IHC in cytology cell blocks and matched surgical specimens.

Adequacy criteria for thyroid FNA evaluated by ThinPrep slides only

Adequacy criteria for thyroid fine‐needle aspiration (FNA) recommended by The Bethesda System for Reporting Thyroid Cytopathology (TBS) were developed with smears, but they are commonly applied to ThinPreps (TPs). This study evaluated adequacy in TPs at different diagnostic thresholds.