Comprehensive evaluation of cytomorphologic, histologic, and molecular features of DICER1-altered thyroid lesions on FNA: A multipractice experience.

BACKGROUND: DICER1 mutations, though infrequent, are encountered on preoperative molecular testing of indeterminate adult and pediatric thyroid fine-needle aspiration (FNA) specimens. Yet, published cytomorphologic features of DICER1-altered thyroid lesions are limited. Cytomorphological features of DICER1-altered thyroid lesions were examined in a multipractice FNA cohort with clinical, radiological, and histologic data. METHODS: The cohort comprised 18 DICER1-altered thyroid FNAs, with 14 having slides available and eight having corresponding surgical resections. Smears, ThinPrep, and formalin-fixed cell block slides were reviewed and correlated with histology, when available. Clinical and radiologic data were obtained from the medical record. RESULTS: Most DICER1-altered FNAs were classified as atypia of undetermined significance (94.4%). DICER1 mutations occurred in codons 1709 (50%), 1810 (27.8%), and 1813 (22.2%). One patient had an additional DICER1 p.D1822N variant in both of their FNAs. Lesions were often hypoechoic (35.3%) and solid (47.1%) on ultrasound. Notable cytomorphologic features include mixed but prominent microfollicular or crowded component, variable colloid, and insignificant nuclear atypia. On resection (n = 10), histologic diagnoses ranged from benign follicular adenoma and low-risk follicular thyroid carcinoma to high-grade follicular-derived nonanaplastic thyroid carcinoma. Subcapsular infarct-type change was the most common histologic change. There was no evidence of recurrence or metastasis in eight patients on limited follow-up. CONCLUSION: DICER1-altered thyroid lesions occurred frequently in young females and FNAs show RAS-like cytomorphology including crowded, mixed macro-/microfollicular pattern, and bland nuclear features. On resection, DICER1-altered thyroid lesions include benign (50%), low-risk lesions (30%), or high-risk malignancies (20%).

The Evolving Role of Pathology in New Developments, Classification, Terminology, and Diagnosis of Pancreatobiliary Neoplasms.

Pancreatobiliary tract lesions are increasingly being discovered because of more sensitive imaging modalities. Magnetic resonance imaging has identified incidental pancreatic cysts in 13.5% of patients of progressively increasing age. Pancreatobiliary tissue is more accessible through endoscopic ultrasound and magnetic resonance imaging-guided biopsy procedures, and is now an integral part of pathologists' routine practice. Accordingly, several new tumor categories have been recently recognized, including intraductal tubulopapillary neoplasm, a new addition to tumoral intraepithelial neoplasms. Other entities have been reclassified, including the recent transition to 2-tiered grading of preinvasive neoplasms, as well as new perspectives on the distinctive biologic behavior of oncocytic intraductal papillary mucinous neoplasms (IPMNs) compared with other IPMN subtypes. This has led to proposals for revised staging of virtually every segment of the pancreatobiliary tree, with theranostic markers becoming an integral part of workup. Ki-67 is now an integral part of the classification of neuroendocrine tumors, with new definitions of "high-grade neuroendocrine carcinoma." Although bile duct brushings have opened new avenues for diagnosis, their sensitivity remains low and often requires concomitant fluorescent in situ hybridization to better define ambiguous cases. Various molecular pathways have been elucidated for pancreatic cysts, including KRAS for ductal neoplasia, GNAS for intestinal IPMNs, RNF3 for mucinous cysts, and VHL for serous cystic neoplasms, all key players in diagnostic workup. Integration of these updates into our understanding of pancreatobiliary disease requires active engagement of pathologists for appropriate specimen triage, judicious interpretation of results, and incorporation into reporting and staging. They also provide exciting opportunities for targeted therapy.

Cytopathologic diagnosis of oncocytic type intraductal papillary mucinous neoplasm: Criteria and clinical implications of accurate diagnosis.

BACKGROUND: Cytologic findings of pancreatic oncocytic-type intraductal papillary mucinous neoplasms (IPMNs)/intraductal oncocytic papillary neoplasms (IOPNs) are largely unknown. METHODS: Five IOPNs encountered by the authors were analyzed. RESULTS: Four IOPNs were located in the pancreatic head, and 1 was located in the pancreatic body/tail in 2 men and 3 women ages 56 to 84 years (mean age, 66 years). Radiologic diagnoses included pancreatic ductal adenocarcinoma (PDAC) in 2 patients, invasive cancer associated with IPMN in 1 patient, IPMN versus mucinous cystic neoplasm in 1 patient, and cystic mass in 1 patient. Cytologic findings included: hypercellular smears (4 of 5 cases) containing well formed clusters of oncocytic cells (5 of 5 cases) with prominent, slightly eccentric nucleoli (4 of 5 cases), predominantly arranged in sheets/papillary units (5 of 5 cases), with punched-out intercytoplasmic spaces (4 of 5 cases), and with occasional 3-dimensional groups and focal necrosis (3 of 5 cases). The intracytoplasmic mucin and thick extracellular mucin typical of other IPMNs were observed only in 2 cases and were very limited. The mean size on resection was 4.5 cm. Invasion was observed in 3 cases (0.1, 0.3, and 2.0 cm) of tubular-type IPMN. Initial cytologic evaluation was performed by the authors in 4 of 5 cases, which were diagnosed as IOPN (n = 3) and IPMN versus cystic PDAC (n = 1). One case was initially misdiagnosed as PDAC and, on resection, proved to be noninvasive IOPN. CONCLUSIONS: Cytologic features of IOPNs are classical, similar to their histologic counterparts, and differ significantly from other IPMN subtypes. Because of their highly complex appearance, they are often radiologically misdiagnosed as PDAC; thus, failure to recognize their characteristic features on fine-needle aspiration may lead to inappropriate treatment. Patients with IOPN have an incomparably better prognosis than patients with ordinary PDAC, even when their neoplasms are invasive.

Triple modality testing by endoscopic retrograde cholangiopancreatography for the diagnosis of cholangiocarcinoma.

OBJECTIVES: Brush cytology has a low sensitivity for the diagnosis of cholangiocarcinoma. This study aimed to compare the standard approach (brush cytology) with a triple modality approach utilizing brush cytology, forceps biopsy and fluorescence in situ hybridization in terms of sensitivity and specificity for the diagnosis of cholangiocarcinoma. METHODS: In a retrospective study at a single academic center, 50 patients underwent triple modality testing. Additionally, 61 patients underwent brush cytology alone. Intervention was endoscopic retrograde cholangiopancreatography with brush cytology, fluorescence in situ hybridization, and forceps biopsy. The main outcome measures included sensitivity, specificity, positive predictive value and negative predictive value. RESULTS: Overall, 50 patients underwent triple tissue sampling, and 61 patients underwent brush cytology alone. Twenty-two patients were eventually diagnosed with cholangiocarcinoma. Brush cytology had a sensitivity of 42%, specificity of 100%, positive predictive value of 100% and negative predictive value of 88%. Triple tissue sampling had an overall sensitivity of 82%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 87%. Within the triple test group, brush cytology had a sensitivity of 27%, forceps biopsy had a sensitivity of 50%, and fluorescence in situ hybridization analysis had a sensitivity of 59%. CONCLUSIONS: A triple modality approach results in a marked increase in sensitivity for the diagnosis of cholangiocarcinoma compared with single modality testing such as brush cytology and should be considered in the evaluation of indeterminate or suspicious biliary strictures.

Health resource utilization and multidisciplinary impact of endoscopic ultrasonography in a tertiary referral medical center.

BACKGROUND: Endoscopic ultrasound (EUS) is a resource-intensive endoscopic procedure, but may result in high downstream health resource utilization and multispecialty impact. Our aim was to examine the downstream impact of EUS by specialty and by indication. METHODS: A retrospective chart review was performed at an academic medical center for patients for whom EUS represented the first point of contact at the study institution within a 20-month period. RESULTS: A total of 552 EUS procedures were reviewed and 208 represented the first point of contact. The most common principle indication involved the pancreas (n = 117, 56%). Downstream health utilization was calculated for an average of 313 days postprocedure (range: 35-632 days). Following unique referral for endoscopic ultrasound, 52% of the patients in the study were retained within the institution for further management and, of these, 34% had a major intervention in the form of surgery or chemoradiotherapy. Compared with other indications, patients presenting with a pancreatic mass were significantly more likely to remain in the study institution for further management (62% versus 39%, p = 0.005), were more likely to have a downstream surgery (29% versus 14%, p = 0.020) and were more likely to have downstream chemo-radiotherapy (11% versus 3%, p = 0.012). CONCLUSIONS: EUS represents a unique portal of entry into tertiary referral medical centers. First point of contact EUS referrals are associated with major downstream health resource utilization and significantly increased utilization for mass lesions of the pancreas.

Increased diagnostic yield of endoscopic ultrasound-guided fine needle aspirates with flow cytometry and immunohistochemistry.

Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is the most sensitive and specific test for establishing a tissue diagnosis for many gastrointestinal malignancies; however, cytologic morphology alone may not be definitive for subsets of tumors. Our aim was to quantify the impact of the broad application of flow cytometry (FC) and immunohistochemistry (IHC) on EUS-FNA diagnostic yield. A retrospective chart review was performed on EUS procedures at a tertiary referral, academic medical center. All EUS-FNA cases performed over a 21-month period were examined. Of 606 EUS procedures reviewed during the period of study, 264 utilized FNA. After pancreatic cyst cases were excluded, 235 EUS-FNA cases for 221 patients were selected for analysis. For cases with subsequent histological evaluation, including the subset utilizing FC/IHC, the sensitivity of EUS-FNA was 89%, specificity was 100%, and accuracy was 91%. One quarter (58/235, 25%) of the tissue specimens underwent further testing by FC/IHC. There were 48 definitive diagnoses made in the subset utilizing FC/IHC. In 20 of the 48 diagnoses (42%), FC/IHC was deemed critical to the diagnosis, and without FC/IHC testing in those cases, the overall sensitivity and accuracy of EUS-FNA would be reduced to 74 and 77%, respectively. FC/IHC allowed for six diagnoses rarely or not previously described by EUS-FNA. Application of FC/IHC improves characterization predominantly for nonadenocarcinoma tumor subtypes and may lead to a diagnostic result for tumors not previously characterized by EUS-FNA. With an adequate tissue sample, broad application of FC/IHC increases the diagnostic yield of EUS-FNA.

Mycophenolate mofetil for maintenance of remission in steroid-dependent autoimmune pancreatitis.

Systemic corticosteroids represent the standard treatment for autoimmune pancreatitis with IgG4-associated cholangitis. For steroid-dependent disease, azathioprine has been used for maintenance of remission. Mycophenolate mofetil has been used for transplant immunosuppression and more recently for autoimmune hepatitis; however, there are no case reports to date on the use of mycophenolate mofetil in adult patients with autoimmune pancreatitis. A patient with IgG4-mediated autoimmune pancreatitis and IgG4-associated cholangitis refractory to steroids and intolerant of azathioprine was treated with mycophenolate mofetil, which inhibits de novo guanosine synthesis and blockade of both B and T lymphocyte production. Introduction of mycophenolate mofetil and uptitration to 1000 mg by mouth twice daily over a treatment period of 4 mo was associated with improvement in the patient's energy level and blood glucose control and was not associated with any adverse events. The patient was managed without a biliary stent. However, there was a return of symptoms, jaundice, increase in transaminases, and hyperbilirubinemia when the prednisone dose reached 11 mg per day. In the first report of mycophenolate mofetil use in an adult patient with IgG4-associated autoimmune pancreatitis and IgG4-associated cholangitis, the introduction of mycophenolate mofetil was safe and well-tolerated without adverse events, but it did not enable discontinuation of the steroids. Mycophenolate mofetil and other immunomodulatory therapies should continue to be studied for maintenance of remission in the large subset of patients with refractory or recurrent autoimmune pancreatitis.

Detection of recurrent prostate carcinoma with anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid PET/CT and 111In-capromab pendetide SPECT/CT.

PURPOSE: To compare the diagnostic performance of the synthetic amino acid analog radiotracer anti-1-amino-3-fluorine 18-fluorocyclobutane-1-carboxylic acid (anti-3-(18)F-FACBC) with that of indium 111 ((111)In)-capromab pendetide in the detection of recurrent prostate carcinoma. MATERIALS AND METHODS: This prospective study was approved by the institutional review board and complied with HIPAA guidelines. Written informed consent was obtained. Fifty patients (mean age, 68.3 years ± 8.1 [standard deviation]; age range, 50-90 years) were included in the study on the basis of the following criteria: (a) Recurrence of prostate carcinoma was suspected after definitive therapy for localized disease, (b) bone scans were negative, and (c) anti-3-(18)F-FACBC positron emission tomography (PET)/computed tomography (CT) and (111)In-capromab pendetide single photon emission computed tomography (SPECT)/CT were performed within 6 weeks of each other. Studies were evaluated by two experienced interpreters for abnormal uptake suspicious for recurrent disease in the prostate bed and extraprostatic locations. The reference standard was a combination of tissue correlation, imaging, laboratory, and clinical data. Diagnostic performance measures were calculated and tests of the statistical significance of differences determined by using the McNemar χ(2) test as well as approximate tests based on the difference between two proportions. RESULTS: For disease detection in the prostate bed, anti-3-(18)F-FACBC had a sensitivity of 89% (32 of 36 patients; 95% confidence interval [CI]: 74%, 97%), specificity of 67% (eight of 12 patients; 95% CI: 35%, 90%), and accuracy of 83% (40 of 48 patients; 95% CI: 70%, 93%). (111)In-capromab pendetide had a sensitivity of 69% (25 of 36 patients; 95% CI: 52%, 84%), specificity of 58% (seven of 12 patients; 95% CI: 28%, 85%), and accuracy of 67% (32 of 48 patients; 95% CI: 52%, 80%). In the detection of extraprostatic recurrence, anti-3-(18)F-FACBC had a sensitivity of 100% (10 of 10 patients; 95% CI: 69%, 100%), specificity of 100% (seven of seven patients; 95% CI: 59%, 100%), and accuracy of 100% (17 of 17 patients; 95% CI: 80%, 100%). (111)In-capromab pendetide had a sensitivity of 10% (one of 10 patients; 95% CI: 0%, 45%), specificity of 100% (seven of seven patients; 95% CI: 59%, 100%), and accuracy of 47% (eight of 17 patients; 95% CI: 23%, 72%). CONCLUSION: anti-3-(18)F-FACBC PET/CT was more sensitive than (111)In-capromab pendetide SPECT/CT in the detection of recurrent prostate carcinoma and is highly accurate in the differentiation of prostatic from extraprostatic disease. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11102023/-/DC1.

High-grade, nonmyogenic pulmonary artery sarcoma: rare findings on coronary angiography.

Pulmonary artery sarcomas are exceptionally rare, and they are often misdiagnosed as chronic pulmonary thromboemboli. Early and accurate diagnosis is crucial to the prognosis of patients who have pulmonary artery sarcomas.Herein, we describe the case of a 74-year-old man who presented with dyspnea and was initially thought to have a pulmonary embolus. Anticoagulation with unfractionated heparin was ineffective. Rare angiographic findings during routine cardiac catheterization led to the diagnosis of a high-grade, nonmyogenic, primary pulmonary artery sarcoma. This case illustrates the usefulness of angiographic findings as an adjunct to conventional diagnostic methods in correctly identifying this rare, aggressive malignancy.

Detection of circulating tumor cells in human peripheral blood using surface-enhanced Raman scattering nanoparticles.

The detection and characterization of circulating tumor cells (CTC) holds great promise for personalizing medicine and optimizing systemic therapy. However, low specificity, low sensitivity, and the time consuming nature of current approaches have impeded clinical adoption. Here we report a new method using surface-enhanced Raman spectroscopy (SERS) to directly measure targeted CTCs in the presence of white blood cells. SERS nanoparticles with epidermal growth factor peptide as a targeting ligand have successfully identified CTCs in the peripheral blood of 19 patients with squamous cell carcinoma of the head and neck (SCCHN), with a range of 1 to 720 CTCs per milliliter of whole blood. Our technique may provide an important new clinical tool for management of patients with SCCHN and other cancers.

Pilot evaluation of anti-1-amino-2-[18F] fluorocyclopentane-1-carboxylic acid (anti-2-[18F] FACPC) PET-CT in recurrent prostate carcinoma.

PURPOSE: Anti-1-amino-2-[(18)F]fluorocyclopentane-1-carboxylic acid (anti-2-[(18)F]FACPC) is an unnatural alicyclic amino acid radiotracer with high uptake in the DU-145 prostate cancer cell line in vitro. Our goal was to determine if anti-2-[(18)F]FACPC is useful in the detection of prostate carcinoma. PROCEDURES: Five patients with elevated PSA (1.1-20.5 ng/mL) after curative therapy for prostate carcinoma underwent 60 min dynamic positron emission tomography (PET) of the pelvis after IV injection of 193-340 MBq of anti-2-[(18)F]FACPC. Uptake was compared against PET scans in the same patients with the leucine analog, anti-1-amino-3-[(18)F]fluorocyclobutane-1-carboxylic acid (anti-[(18)F]FACBC), at similar time points and validated via pathology, clinical, and imaging follow-up. RESULTS: At 5 min, average (±SD) SUVmax of malignant lesions is 4.1(±1.3) for anti-2-[(18)F] FACPC and 4.3(±1.1) for anti-[(18)F]FACBC. Yet, blood pool activity at 5 min is significantly higher for anti-2-[(18)F]FACPC with average (±SD) lesion/blood pool SUVmax/SUVmean ratio of 1.4 (±0.5) vs. 3.0 (±0.9) for anti-[(18)F]FACBC. At 20 min, average (±SD) SUVmax of malignant lesions is 2.6 (±1.0) for anti-2-[(18)F]FACPC and 3.4 (±0.8) for anti-[(18)F]FACBC. Yet, bladder activity at 20 min is significantly more intense for anti-2-[(18)F] FACPC with average (±SD) lesion/bladder SUVmax/SUVmean ratio of 0.3 (±0.8) vs. 2.3 (±1.4) for anti-[(18)F]FACBC. CONCLUSIONS: While prostate bed lesions are visible on early imaging with anti-2-[(18)F]FACPC, there is high blood pool activity obscuring nodes. As blood pool fades, nodal uptake decreases and high bladder activity then obscures pelvic structures. Compared with anti-[(18)F]FACBC, imaging characteristics for anti-2-[(18)F]FACPC are unfavorable for pelvic recurrent prostate carcinoma detection.

Pseudoangiomatous stromal hyperplasia. A case for bilateral mastectomy in a 12-year-old girl.

Pseudoangiomatous stromal hyperplasia (PASH) is a benign proliferation of breast stromal cells with a complex pattern of interanastomosing spaces lined by myofibroblasts and is most commonly seen in women of child-bearing age. PASH is a frequent incidental microscopic finding in breast biopsies. Nodular PASH, however, resulting in a clinically appreciable mass and rapid growth is a rare entity, with only four such patients cited in the literature. Surgical excision results in a cure in the majority of cases, with a recurrence rate of approximately 7-22%. We report a case of a 12-year-old girl with nodular PASH who presented with bilateral breast enlargement refractory to surgical excisions, eventually requiring bilateral mastectomies. To our knowledge, our patient is the youngest patient to have nodular PASH and to undergo bilateral mastectomies.

Proteomic analysis of cerebrospinal fluid discriminates malignant and nonmalignant disease of the central nervous system and identifies specific protein markers.

CNS diseases are often accompanied by changes in the protein composition of cerebrospinal fluid (CSF). SELDI-TOF-MS provides an approach for identifying specific protein markers of disease in biological fluids. We compared the CSF proteomes from patients with neoplastic and reactive/inflammatory CNS diseases to identify potential biomarkers. SELDI-TOF-MS was performed on CSF derived from lumbar puncture of 32 patients, including 10 with CNS malignancies, 12 with inflammatory or reactive conditions, and 10 with unknown CNS disease. Using the SAX-2 (strong anionic exchange) chip, we uncovered three conserved protein peak ranges within each disease category. For neoplastic diseases, we identified conserved peaks at 7.5-8.0 kDa (9/10 samples), 15.1-15.9 kDa (8/10 samples), and 30.0-32.0 kDa (5/10 samples). In reactive/inflammatory diseases, conserved peaks were found at 6.7-7.1 kDa (10/12 samples), 11.5-11.9 kDa (12/12 samples), and 13.3-13.7 kDa (9/12 samples). A protein from the 30.0 to 32.0 kDa peak range found in neoplastic CSF was identified by MALDI analysis as carbonic anhydrase, a protein overexpressed in many malignancies including high-grade gliomas. Similarly, cystatin C was identified in the 13.3-13.7 kDa peak range in non-neoplastic CSF and was most prominent in inflammatory conditions. Our approach provides a rational basis for identifying biomarkers that could be used for detection, diagnosis, and monitoring of CNS diseases.

Real-time detection of gene expression in cancer cells using molecular beacon imaging: new strategies for cancer research.

Development of novel approaches for quantitative analysis of gene expression in intact tumor cells should provide new means for cancer detection and for studying the response of cancer cells to biological and therapeutic reagents. We developed procedures for detecting the levels of expression of multiple genes in fixed as well as viable cells using molecular beacon imaging technology. We found that simultaneous delivery of molecular beacons targeting survivin and cyclin D1 mRNAs produced strong fluorescence in breast cancer but not in normal breast cells. Importantly, fluorescence intensity correlated well with the level of gene expression in the cells detected by real-time reverse transcription-PCR or Western blot analysis. We further show that molecular beacons can detect changes of survivin gene expression in viable cancer cells following epidermal growth factor stimulation, docetaxel treatment, and overexpression of p53 gene. Thus, molecular beacon imaging is a simple and specific method for detecting gene expression in cancer cells. It has great potential for cancer detection and drug development.

Angiogenic and lymphangiogenic microvessel density in breast carcinoma: correlation with clinicopathologic parameters and VEGF-family gene expression.

Angiogenesis and lymphangiogenesis are essential for breast cancer progression and are regulated by vascular endothelial growth factors (VEGF). To determine clinical and molecular correlates of these processes, we measured blood and lymphatic vascular microvessel density in 29 invasive carcinomas (22 ductal, six lobular, one papillary), using the vascular marker CD31 and the novel lymphatic marker D2-40. Microvessel density was assessed microscopically and by image cytometry, and was compared with tumor histology, grade, stage, lymph node metastasis, hormone receptors, HER2/neu status, and expression of VEGF, VEGF-C and VEGF-D by immunohistochemistry or quantitative RT-PCR. Strong correlation was observed between visual and image cytometric microvessel density using D2-40 but not CD31 (P=0.016 and 0.1521, respectively). Image cytometric CD31 microvessel density correlated with tumor size, grade, stage and lymph node metastasis (P=0.0001, 0.0107, 0.0035 and 0.0395, respectively). D2-40 microvessel density correlated with tumor stage (P=0.0123 by image cytometry) and lymph node metastasis (P=0.0558 by microscopy). Immunohistochemical VEGF signal in peritumoral blood vessels correlated with image cytometric CD31 and D2-40 microvessel density (P=0.022 and 0.0012, respectively), consistent with the role of VEGF in blood and lymphatic vascular growth. Intratumoral VEGF-C and VEGF-D expression by quantitative RT-PCR correlated with D2-40 (P=0.0291 by image cytometry) but not with CD31 microvessel density, which could suggest a selective role of VEGF-C and VEGF-D in lymphangiogenesis. CD31 and D2-40 microvessel density correlated significantly with several prognostic factors, including lymph node metastasis. Thus, measurements of angiogenesis and lymphangiogenesis may have utility for breast cancer pathology, particularly for estimation of metastatic risk.