Xuemo Fan

Evidence-based evaluation of the risks of malignancy predicted by thyroid fine-needle aspiration biopsies

A National Cancer Institute (NCI) “Thyroid Fine‐Needle Aspiration (FNA) State of the Science Conference” recently proposed standardized nomenclature and “risks of malignancies” associated with various diagnostic categories. We evaluated the evidence levels of the data used by NCI to predict malignancy risks and whether those estimates had clinical validity in our patient population.

A simplified Bethesda system for reporting thyroid cytopathology using only four categories improves intra‐ and inter‐observer diagnostic agreement and provides non‐overlapping estimates of malignancy risks

Our previous study utilizing the 2008 NCI six‐category system (also known as The Bethesda System) for reporting thyroid fine‐needle aspirations (FNA) identified considerable overlap in diagnosis and in assigned malignancy risk estimates for the “follicular lesion of undetermined significance (FLUS)” and “follicular neoplasm (FN)” categories and for the “suspicious for malignancy (Susp)” and “malignant” categories. We proposed a simplified Bethesda System for reporting thyroid FNAs that provided four non‐overlapping, statistically significant, and more clinically relevant diagnostic categories: unsatisfactory, benign, FLUS/FN, and Susp/malignant. In the current study, six cytopathologists participated in a blinded retrospective review of 60 thyroid FNAs and kappa statistics were utilized to compare the intra‐ and inter‐observer diagnostic agreements obtained using the six‐category and the simplified four‐category schemes. Surgical follow‐up was used to determine which scheme provided more discrete malignancy risk estimates. Use of the simplified four‐category scheme significantly improved intra‐ and inter‐observer diagnostic agreement levels, significantly increased the sensitivity of FNA for a diagnosis of carcinoma in the subsequently resected thyroid glands, and provided non‐overlapping malignancy risk estimates for each diagnostic category. Diagn. Cytopathol. 2012;40:E62–E68.

Comparative analysis of size estimation by mapping and counting number of blocks with ductal carcinoma in situ in breast excision specimens.

CONTEXT The size of ductal carcinoma in situ (DCIS) is a significant predictor of local tumor recurrence and is used for selection of patients for conservative versus aggressive therapy. A standardized method for size assessment is lacking. OBJECTIVE To evaluate 2 commonly used methods for measurement of DCIS extent: one based on the distribution of the lesion in sequential series of sections (mapping method) and the other on the number of sections with DCIS (block method). DESIGN Ninety-eight consecutive cases of DCIS, measuring at least 1.0 cm, were retrieved from our files. All specimens were serially sectioned along the long axis. The size of DCIS was calculated for each case by 2 different methods: (1) mapping method (average thickness of each slice x number of consecutive slices with DCIS) and (2) block method (number of blocks with DCIS x 0.3 cm). Additional calculations were performed by using 0.35, 0.4, and 0.5 cm as multiplication factors for the block method in order to improve concordance. RESULTS The block method underestimated the size in 71 cases (72%) by 4.5% to 81.3% (mean, 33%). Using 0.4 cm as the multiplication factor improved concordance, while multiplying by 0.5 cm led to an overestimation of size. CONCLUSIONS Assessment of DCIS size by the block method is inaccurate and underestimates size in most cases (72%), with an average reduction of 33%. Using 0.4 cm as the multiplication factor improves concordance. A standardized method for size estimation is necessary for effective patient management.

Interobserver and intraobserver variability in evaluating vascular invasion in hepatocellular carcinoma.

Background and Aim:  Hepatocellular carcinoma (HCC) is unique in that the presence of vascular invasion significantly changes tumor stage. Even though searching for vascular invasion is a common practice in surgical pathology, there appears to be a great variation among pathologists in its recognition. This study was designed to assess whether HCC could be accurately staged using vascular invasion as a staging parameter.

Differential regulation of Effector and Regulatory T cell function by Blimp1

The transcriptional regulator Blimp1 plays crucial roles in controlling terminal differentiation in several lineages. In T cells, Blimp1 is expressed in both effector (Teff) and regulatory (Treg) cells, and mice with T cell-specific deletion of Blimp1 (Blimp1CKO mice) spontaneously develop severe intestinal inflammation, indicating a crucial role for Blimp1 in T cell homeostasis regulation. Blimp1 has been shown to function as a direct activator of the Il10 gene and although its requirement for IL10 expression has been demonstrated in both Treg and Teff cells under inflammatory conditions, the intrinsic requirement of Blimp1 for homeostatic maintenance of these T cell subsets had not been investigated. Using mice with Foxp3+ Treg-cell specific deletion of Blimp1 and other approaches, here we show that Foxp3+ Treg cell-intrinsic expression of Blimp1 is required to control Treg and Teff cells homeostasis but, unexpectedly, it is dispensable to prevent development of severe spontaneous intestinal inflammation. In addition, we show that Blimp1 controls common and unique aspects of Treg and Teff cell function by differentially regulating gene expression in these T cell subsets. These findings document previously unappreciated aspects of Blimp1’s role in T cell biology and shed light on the intricate mechanisms regulating Treg and Teff cell function.

A Clinicopathological Study of Malignant Insulinoma in a Contemporary Series.

Objective The aim of the study was to address the origin and natural history of malignant insulinoma. Methods Retrospective review of medical records of patients diagnosed with insulinoma at Cedars-Sinai Medical Center between 2000 and 2015 was conducted. Hormonal expression in tumor specimens was examined by immunostaining. Results All the 9 patients with malignant insulinoma (35% of 26 patients with insulinoma) already had liver metastasis at hypoglycemia presentation with bulky cumulative tumor burden. Six patients had de novo diagnosis, 2 had known metastatic nonfunctioning pancreatic neuroendocrine tumor, and 1 had a known pancreatic mass. Tumor grade at presentation was G1 in 4 patients, G2 in 4, and unknown in 1. Four patients died 2 to 32 months after presentation, all with extensive liver tumor involvement. Tumor expression of proinsulin and insulin was heterogeneous and overall infrequent. The proinsulin levels and proinsulin/insulin molar ratio in patients with malignant versus benign insulinoma were 334 versus 44 pmol/L and 2.1 versus 0.9, respectively. Conclusions Malignant insulinoma seems to arise from and behave like nonfunctioning pancreatic neuroendocrine tumor oncologically but with metachronous hyperinsulinemic hypoglycemia. High proinsulin levels and proinsulin/insulin molar ratio may suggest malignant insulinoma.

Blimp-1 Functions as a Molecular Switch to Prevent Inflammatory Activity in Foxp3+RORγt+ Regulatory T Cells

SUMMARY Foxp3+ regulatory T cells (Treg) are essential modulators of immune responses, but the molecular mechanisms underlying their function are not fully understood. Here we show that the transcription factor Blimp-1 is a crucial regulator of the Foxp3+RORγt+ Treg subset. The intrinsic expression of Blimp-1 in these cells is required to prevent production of Th17-associated cytokines. Direct binding of Blimp-1 to the Il17 locus in Treg is associated with inhibitory histone modifications but unaltered binding of RORgt. In the absence of Blimp-1, the Il17 locus is activated, with increased occupancy of the co-activator p300 and abundant binding of the transcriptional regulator IRF4, which is required, along with RORγt, for IL-17 expression in the absence of Blimp-1. We also show that despite their sustained expression of Foxp3, Blimp-1−/− RORγt+IL-17-producing Treg lose suppressor function and can promote intestinal inflammation, indicating that repression of Th17-associated cytokines by Blimp-1 is a crucial requirement for RORγt+ Treg function.

Comparison of endoscopic ultrasound guided fine needle aspiration and PET/CT in preoperative diagnosis of pancreatic adenocarcinoma

BACKGROUND Endoscopic ultrasound guided fine needle aspiration (EUS-FNA) is the procedure of choice to investigate and sample pancreatic masses for the preoperative diagnosis of pancreatic ductal adenocarcinoma (PDAC). The role of 18fluoro-deoxyglucose positron emission tomography/computed tomography (PET/CT) in PDAC is debated. This study evaluates the role of EUS-FNA as compared to PET/CT in the preoperative evaluation of PDAC. METHODS Preoperative evaluation by PET/CT and EUS-FNA was performed on 25 patients with pancreatic solid lesions, who underwent a subsequent Whipple procedure or partial pancreatic resection. RESULTS This series included 19 PDACs and 6 non-PDACs including 1 metastatic breast ductal adenocarcinoma, 2 low grade neuroendocrine tumors, 2 chronic pancreatitis and 1 gastrointestinal tumor abutting the pancreas. EUS-FNA correctly diagnosed 18 of 19 PDACs, 1 metastatic breast ductal adenocarcinoma and all 5 of the other non-PDAC cases. One case of well differentiated PDAC was negative on EUS-FNA. PET/CT provided excellent size and was positive in 14 of 19 PDACs and the metastatic breast ductal adenocarcinoma. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy for EUS-FNA in diagnosis of selected pancreatic tumors were 91%, 100%, 100%, 50% and 92%, respectively, while they were 65%, 100%, 100%, 20% and 68% for PET/CT, respectively. CONCLUSIONS Compared to PET/CT, EUS-FNA has a higher sensitivity and accuracy for preoperative diagnosis of PDAC. However, PET/CT provides excellent size, volume and stage information. A combination of both PET/CT and EUS will better help guide diagnosis and treatment of pancreatic adenocarcinoma.

Reduced or absent NA+/I- symporter expression in papillary thyroid microcarcinomas

Background: Radioactive iodine (RAI) is a treatment for patients with thyroid carcinoma after thyroidectomy. The Na+/I− symporter (NIS) plays a role in this ability to concentrate iodide within tumor cells. Recent studies have shown a correlation between immunohistochemical staining of NIS and the ability to concentrate iodide mainly in tumors >1.0 cm. Here only papillary thyroid microcarcinomas (PTMC) with or without LN metastasis (LNM) are evaluated to observe NIS expression. Design: A retrospective study involved 47 cases of PTMC (24 with and 23 without LNM). Immunostains were performed using two different monoclonal anti-NIS antibodies: clone SPM186 from Abcam and clone FP5A from Millipore. Results: The findings were very similar using two different monoclonal antibodies. One out of 24 cases with LNM displayed focal expression of NIS while two cases showed several NIS-positive cells. None of 23 cases without LNM and none of metastatic tumors showed NIS expression. Ten benign nodules with Hürthle cell features exhibited moderate membranous stain. Conclusion: PTMC with or without LNM show minimal to no expression of NIS. NIS expression and function may not be the same in PTMC vs a non-PTMC and RAI therapy may not be effective in treating PTMC due to lack of NIS.

Novel syndrome of four-limb proximal fragility fractures associated with HIV infection, cholestatic liver failure, and histiocytic infiltration of bone marrow.

We report a syndrome of four-limb proximal fragility fractures associated with HIV infection, cholestatic liver failure, and histiocytic infiltration of bone marrow in a 40-year-old African American man. The patient presented with multiple fractures in the proximal humeri and femurs without osteopenia in the vertebrae. His right humerus appeared normal on chest X-ray film 3 years before presentation when he was first diagnosed with HIV infection and abnormal liver functions. At presentation, the patient had vitamin D deficiency, hypogonadism, and low IGF-1 levels, but did not have hyperparathyroidism. Bone biopsy showed diffuse foamy histiocytic infiltration of bone marrow at all fracture sites without evidence of infectious or neoplastic processes. Exhaustive search did not identify any similar cases in the English literature. Our case likely represents a novel syndrome, the etiology of which is probably multifactorial and includes HIV infection, cholestatic liver failure, immobility, and endocrine abnormalities. The case further calls for the need for monitoring of bone health in patients with HIV infection or liver disease.