Scott L. Boerner

Hyalinizing Trabecular Tumor of the Thyroid: A Variant of Papillary Carcinoma Proved By Molecular Genetics

Hyalinizing trabecular tumors of the thyroid are interesting but uncommon neoplasms. They have been classified as benign hyalinizing trabecular adenomas or malignant hyalinizing trabecular carcinomas. They share both epidemiologic and morphologic features with papillary carcinoma, and there has been much speculation about the relationship between these two entities. Because RET/PTC gene rearrangements are specific to papillary thyroid carcinoma, the authors examined the presence of RET/PTC-1, -2, and -3 in eight hyalinizing trabecular tumors using reverse transcription–polymerase chain reaction with Southern hybridization and immunohistochemistry. They detected the presence of a RET/PTC gene rearrangement in six of the eight hyalinizing trabecular tumors. This confirms the long-standing suspicion that hyalinizing trabecular tumors do indeed represent a morphologic variant of papillary carcinoma.

Lung cancer screening using low-dose computed tomography in at-risk individuals: The Toronto experience

OBJECTIVE The Department of Medical Imaging at the University Health Network in Toronto is performing a lung cancer screening study, utilizing low-dose computed tomography (LDCT) as the modality. Baseline and annual repeat results are reported on the first 3352 participants, enrolled between June 2003 and May 2007. METHODS Enrollment was limited to those aged 50 years or older, with a smoking history of at least 10 pack-years, no previous cancer and general good health. A helical low-dose CT (LDCT) of the chest was performed using 120kVp, 40-60mA, images were reconstructed with 1-1.25mm overlapping slices. The primary objectives were the detection of parenchymal nodules and diagnosis of early stage lung cancer. Baseline LDCTs were termed positive if at least one indeterminate non-calcified nodule 5mm or larger in size, or non-solid nodule 8mm or larger in size was identified. Follow up periods for individuals with a positive baseline LDCT were determined by nodule characteristics. RESULTS The median age at baseline was 60 years (range 50-83), with a median of 30 pack-years of cigarette smoking (range 10-189). Baseline CT evaluations were positive in 600 (18%) participants. To date, 2686 (80%) of the participants have returned for at least one annual repeat screening LDCT. Biopsies have been recommended for 82 participants since the study began, and 64 have been diagnosed with screen-detected cancer (62 lung, two plasmacytoma of the rib). A total of 65 lung cancers have been diagnosed (62 screen-detected, 3 interim), 57 are NSCLC (82% with known stage are stage I or II) and the rate of surgical resection was 80%. Sensitivity and specificity of the protocol in successfully diagnosing early stage lung cancers were 87.7% and 99.3%, respectively. CONCLUSIONS Data indicate that LDCT can identify small lung cancers in an at-risk population. The diagnostic algorithm results in few false-positive invasive procedures. Most cancers are detected at an early stage, where the cancer is resectable with a greater potential for cure. Long-term follow up of lung cancer cases will be carried out to determine survival.

Cutaneous manifestations of thyroid cancer: a report of four cases and review of the literature

Cutaneous metastases from thyroid carcinoma are rare. This report describes four cases of thyroid carcinoma metastatic to the skin. Two cases were medullary carcinoma and two were papillary thyroid carcinoma. In two cases, skin metastases were the presenting feature of the underlying thyroid carcinoma. Examination of the skin lesions by conventional light microscopy suggested the possibility of metastatic carcinoma and immunohistochemical tests confirmed the diagnosis. Subsequent investigations identified primary thyroid lesions. In two cases, the skin metastasis was the first evidence of the recurrence of known thyroid carcinoma. These cases identify a novel presentation of thyroid carcinoma.

Phase II Study of Preoperative Gefitinib in Clinical Stage I Non–Small-Cell Lung Cancer

PURPOSE Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have proven efficacy in advanced non-small-cell lung cancer (NSCLC). Their role in early-stage NSCLC has not been established. Our purpose was to explore the use of preoperative gefitinib in clinical stage I NSCLC to assess tumor response, toxicity, and clinical and molecular predictors of response. PATIENTS AND METHODS Patients received gefitinib 250 mg/d for up to 28 days, followed by mediastinoscopy and surgical resection in an open-label, single-arm study. Tumor response was evaluated by Response Evaluation Criteria in Solid Tumors. Blood samples and tumor biopsies were collected and analyzed for transforming growth factor alpha level, EGFR protein expression, EGFR gene copy number, and EGFR (exon 19 to 21) and KRAS mutations. RESULTS Thirty-six patients completed preoperative treatment (median duration, 28 days; range, 27 to 30 days). Median follow-up time is 2.1 years (range, 0.86 to 3.46 years). Three patients experienced grade 3 toxicities (rash, diarrhea, and elevated ALT). Tumors demonstrated EGFR-positive protein expression in 83%, high gene copy number in 59%, EGFR mutations in 17%, and KRAS mutations in 17%. Tumor shrinkage was more frequent among women and nonsmokers. Partial response was seen in four patients (11%), and disease progression was seen in three patients (9%). The strongest predictor of response was EGFR mutation. CONCLUSION Preoperative window therapy with gefitinib is a safe and feasible regimen in early NSCLC and provides a trial design that may better inform predictors of treatment response or sensitivity.

Characteristics of Apparently False-Negative Digene Hybrid Capture 2 High-Risk HPV DNA Testing

This study characterized cases with a negative high-risk Hybrid Capture 2 (HRHC2; Digene, Gaithersburg, MD) test result with concurrent or follow-up biopsy-confirmed high-grade cervical intraepithelial neoplasia (CIN 2/3). From 2,306 HRHC2 tests, 10 negative results were identified with CIN 2/3 (false-negative rate, 4.5%). The majority of the patients had abnormal colposcopic findings and high-grade squamous intraepithelial lesion (HSIL) shown by concurrent cytologic examination, although with few abnormal cells. No trend was evident in the location of the dysplastic epithelium or overall lesion size. In 4 tests, the relative light units over cutoff was more than 0.4 but less than 1.0, suggesting that low quantities of human papillomavirus (HPV) DNA were present in the sample. The negative predictive value for HRHC2 testing may be compromised when the copy number of the HPV DNA is low, and a negative HRHC2 test result may be falsely negative in patients with abnormal colposcopic findings or concurrent cytologic findings showing HSIL.

Targeted use of fluorescence in situ hybridization (FISH) in cytospin preparations: results of 298 fine needle aspirates of B-cell non-Hodgkin lymphoma.

Fluorescence in situ hybridization (FISH) results from fine needle aspirates (FNA) of B‐cell non‐Hodgkin lymphomas (NHLs) were reviewed to 1) investigate the value added by using specific gene rearrangement probes to lymphoma diagnosis, prognosis, and subtyping; and 2) evaluate the prevalence of cytogenetic alterations other than specific translocations.

Sample Features Associated with Success Rates in Population-Based EGFR Mutation Testing

Introduction: Epidermal growth factor receptor (EGFR) mutation testing has become critical in the treatment of patients with advanced non–small-cell lung cancer. This study involves a large cohort and epidemiologically unselected series of EGFR mutation testing for patients with nonsquamous non–small-cell lung cancer in a North American population to determine sample-related factors that influence success in clinical EGFR testing. Methods: Data from consecutive cases of Canadian province-wide testing at a centralized diagnostic laboratory for a 24-month period were reviewed. Samples were tested for exon-19 deletion and exon-21 L858R mutations using a validated polymerase chain reaction method with 1% to 5% detection sensitivity. Results: From 2651 samples submitted, 2404 samples were tested with 2293 samples eligible for analysis (1780 histology and 513 cytology specimens). The overall test-failure rate was 5.4% with overall mutation rate of 20.6%. No significant differences in the failure rate, mutation rate, or mutation type were found between histology and cytology samples. Although tumor cellularity was significantly associated with test-success or mutation rates in histology and cytology specimens, respectively, mutations could be detected in all specimen types. Significant rates of EGFR mutation were detected in cases with thyroid transcription factor (TTF)-1–negative immunohistochemistry (6.7%) and mucinous component (9.0%). Conclusions: EGFR mutation testing should be attempted in any specimen, whether histologic or cytologic. Samples should not be excluded from testing based on TTF-1 status or histologic features. Pathologists should report the amount of available tumor for testing. However, suboptimal samples with a negative EGFR mutation result should be considered for repeat testing with an alternate sample.

Cyto-histologic agreement in pathologic subtyping of non small cell lung carcinoma: review of 602 fine needle aspirates with follow-up surgical specimens over a nine year period and analysis of factors underlying failure to subtype.

BACKGROUND The differential therapeutic efficacy and toxicity of targeted therapies has made subtyping of non-small lung cancer (NSCLC) mandatory. This study aimed to review the accuracy of NSCLC subtyping using lung fine needle aspirates (FNAs) in two periods (before and after the introduction of targeted therapy), checking the reasons for failure and the impact of the use of immunohistochemistry (IHC). METHODS An electronic search retrieved all NSCLC FNAs with a corresponding surgical specimen from 2001 to 2009. NSCLC, NOS (not otherwise specified) cases from 2005 to 2009 (after targeted therapy) were reviewed to determine reasons for failure in subtyping and to further subtype based solely on cytomorphology. The number of cases in which IHC was performed and the antibodies used were also recorded. RESULTS Cytohistological agreement of 602 lung FNAs (341 adenocarcinomas, 93 squamous cell carcinomas and 168 NSCLC, NOS) was achieved in 93.80%. There was a significant decrease in the percentage of cases not subtyped in the period after the introduction of targeted therapy (35.07% versus 24.57%). Final percentage of cases not subtyped after morphological review was 17.03%. IHC was performed in 157 cases, with an increased use in recent years. The number of antibodies did not influence the overall success in subtyping and an average of 3 markers was used. Most frequent antibodies used were TTF-1, CK7, high molecular weight keratin and p63. More than half of cases not subtyped even after IHC corresponded to poorly or undifferentiated neoplasms in the surgical specimens. For the NSCLC, NOS which IHC was not performed, a cell block was produced in 106 cases (75.71%). Review of the cell block slides from 2005 to 2009 showed that the majority (70.7%) had rare, few or no tumor cells. CONCLUSIONS Specific subtyping can be achieved in a high proportion of lung FNAs with high accuracy. The percentage of NSCLC, NOS has significantly decreased in recent years together with a trend for an increased use of IHC as well as increased number of cell blocks produced. An average of 3 IHC markers was used for subtyping and the number of markers did not influence the overall subtyping.

CT Screening for Lung Cancer: Implication of Lung Biopsy Recommendations

OBJECTIVE The purpose of this article is to address the implications of invasive diagnostic procedures recommended by a lung cancer screening protocol. In particular, we assess how many invasive procedures were recommended for benign nodules. MATERIALS AND METHODS Between 2003 and 2009, 4782 high-risk current and former smokers were enrolled in a lung cancer screening study. A helical low-dose CT of the chest was performed. Morphologic features targeted were parenchymal nodules. The indication for biopsy was made according to the diagnostic algorithm provided by the International Early Lung Cancer Action Program. We recorded the time points of biopsy recommendation; shape, size, and growth of nodules; types of diagnostic procedures; complication rates; and final pathologic diagnosis. RESULTS A total of 128 diagnostic biopsies were recommended for suspicious nodules, and 127 biopsies were performed, including 110 percutaneous CT-guided fine-needle aspiration biopsies (FNABs), nine video-assisted thoracoscopic surgery (VATS) resections, seven bronchoscopies, and one ultrasound-guided biopsy of a lymph node. Of 110 FNABs, 24 had unsatisfactory results, 13 of which were referred for secondary diagnostic VATS resection. The indication for biopsy was made on the basis of shape in 48% of cases (62/128), growth on follow-up in 40% of cases (51/128), and the appearance of new nodules in 12% of cases (15/128). In total, 104 of 124 biopsies (84%) were correctly indicated (true-positive recommendation) for malignancy, 20 were benign (false-positive) (16%), and final results are pending for four cases. The overall false-positive recommendation rate was 0.42% (20/4782); 11.6% of FNABs (16/128) and 3.6% of VATS (5/128) revealed benign nodules, corresponding to an overall false-positive rate of 0.33% for FNAB (16/4782) and 0.10% for VATS (5/4782). CONCLUSION The recommended biopsy procedures for screen-detected suspicious pulmonary nodules resulted in a low intervention rate for benign nodules. This rate is minimal when we followed a research protocol that relies on shape and growth.

The use of FTA cards for preserving unfixed cytological material for high-throughput molecular analysis

Novel high‐throughput molecular technologies have made the collection and storage of cells and small tissue specimens a critical issue. The FTA card provides an alternative to cryopreservation for biobanking fresh unfixed cells. The current study compared the quality and integrity of the DNA obtained from 2 types of FTA cards (Classic and Elute) using 2 different extraction protocols (“Classic” and “Elute”) and assessed the feasibility of performing multiplex mutational screening using fine‐needle aspiration (FNA) biopsy samples.