David Chhieng

The Bethesda thyroid fine-needle aspiration classification system: year 1 at an academic institution.

BACKGROUNDnFine-needle aspiration (FNA) may be the procedure of choice in the preoperative evaluation of thyroid nodules, yet it suffers as a modality both because of its inherent limitations as well as variability in its diagnostic terminology. The National Cancer Institute recently proposed a classification system. The objective of this study was to report our experience in using this new reporting system to review the distribution of diagnosis categories and to evaluate the specificity of the system based on the cytologic-histologic correlation.nnnPATIENTS AND METHODSnA total of 3207 thyroid nodules underwent FNA, that is, 3207 FNAs from 2468 patients were examined at our institution between January 1, 2008 and December 31, 2008. All FNAs were classified prospectively into unsatisfactory, benign, indeterminate (cells of undetermined significance), follicular neoplasm (FN), suspicious for malignancy, and positive for malignancy.nnnRESULTSnThe distribution of these categories from 3207 evaluated nodules was as follows: 11.1% unsatisfactory, 73.8% benign, 3.0% indeterminate, 5.5% FN, 1.3% suspicious, and 5.2% malignant. Of the 2468 sampled patients, 378 (15%) underwent thyroidectomy. The distribution of diagnoses of patients who underwent surgery was as follows: 10% unsatisfactory, 4.6% benign, 30.3% indeterminate, 61.4% FN, 76.9% suspicious, and 77.2% malignant. There was an excellent association between the categories and in predicting benign versus malignant thyroid nodules (p < 0.0001). However, the false-negative rate cannot be calculated because only a small number of patients with benign diagnosis underwent surgery. The false-positive rate was 2.2%; all were diagnosed as suspicious cytologically. Given that only 15% of the patients underwent surgery, at this time the sensitivity of thyroid FNA for diagnosing malignant thyroid nodules cannot be calculated, nor can the sensitivity of thyroid FNA as a screening test for all neoplasms be accurately estimated. The specificity for diagnosing malignant thyroid nodules was 93%, whereas the specificity as a screening test for all neoplasms was 68%. The positive predictive values for an FN, suspicious, and positive cytologic diagnosis were 34%, 87%, and 100%, respectively.nnnCONCLUSIONSnThese data demonstrate that the recently proposed classification system is excellent for reporting thyroid FNAs. Each diagnostic category conveys specific risks of malignancy, which offers guidance for patient management.

Reflex BRAF Testing in Thyroid Fine-Needle Aspiration Biopsy with Equivocal and Positive Interpretation: A Prospective Study

BACKGROUNDnThe BRAF V600E mutation has been reported in 50%-80% of papillary thyroid carcinoma (PTC) cases and is highly specific for PTC. Reflex BRAF testing may improve the diagnostic accuracy of thyroid fine-needle aspiration (FNA) tests having equivocal cytologic interpretations and provide prognostic information that helps guide management in patients with PTC.nnnPATIENTS AND METHODSnCases with equivocal thyroid FNA readings (indeterminate and suspicious for PTC) or a positive diagnosis for PTC and concomitant BRAF mutation analysis were included in this prospective study. BRAF mutation analysis was performed by polymerase chain reaction combined with single-strand conformation polymorphism gel electrophoresis using lavage fluid obtained from needle rinsing. The results of histopathologic follow-up were correlated with the cytologic interpretations and BRAF status.nnnRESULTSnOne hundred fifty-seven FNAs with equivocal or positive cytologic interpretations were eligible for the study. All but one (99.4%) FNAs were found to have sufficient DNA quality and quantity for the assay. Based on the follow-up diagnosis of nodules after surgical resection, the sensitivity for diagnosing PTC was 63.3% with cytology alone and 80.0% with the combination of cytology and BRAF testing, respectively. No false positives were noted with either cytology or BRAF mutation analysis. All PTCs with extrathyroidal extension and of tall-cell variant were postive for BRAF mutation.nnnCONCLUSIONSnBRAF V600E mutation analysis can be easily performed on cytologic preparation using lavage fluids obtained from needle rinsing. By combining morphologic evaluation and BRAF testing, there is a substantial improvement in the preoperative identification of PTC when compared with cytology alone. Patients with equivocal cytologic diagnosis and BRAF V600E mutation are candidates for total thyroidectomy ± central lymph node dissection.

Papillary thyroid carcinomas with and without BRAF V600E mutations are morphologically distinct.

Finkelstein A, Levy G H, Hui P, Prasad A, Virk R, Chhieng D C, Carling T, Roman S A, Sosa J A, Udelsman R, Theoharis C G & Prasad M L u2028(2012) Histopathology 60, 1052–1059

The Effect of Neoadjuvant Chemotherapy on Histologic Grade, Hormone Receptor Status, and Her2/neu Status in Breast Carcinoma

Abstract:u2002 The use of neoadjuvant chemotherapy prior to surgical resection for breast cancer is no longer restricted to patients with locally advanced disease. As preoperative treatment becomes more common, the question arises whether or not such therapy changes important tumor characteristics. The objective of our study is to compare histological grade, hormone receptor status, and HER2/neu expression pre‐ and post‐therapy patients receiving preoperative neo‐adjuvant chemotherapy. Forty patients status post‐neoadjuvant treatment who had available archived pathologic material pre‐ and post‐therapy were identified. Glass slides were reviewed retrospectively, and tumor grade, hormone receptor status, and HER2/neu expression were compared between the pre‐ and post‐therapy specimens. No significant differences were noted between the pre‐ and post‐specimens for two of the three parameters comprising the modified Bloom–Richardson grade, including degree of tubule formation (pu2003=u20030.062) and nuclear pleomorphism (pu2003=u20030.086). For mitotic activity, a decrease in score was observed between pre‐ and post‐therapy specimens which was statistically significant (pu2003=u20030.021). However, there was no significant difference in the overall modified Bloom–Richardson grade (pu2003=u20030.118). Information was available regarding hormone receptor and HER2/neu status in 26 patients (65%). There was no significant difference between pre‐ and post‐treatment specimens for hormone receptor status. However, there were more patients with HER2/neu overexpression after receiving neoadjuvant therapy (pu2003=u20030.027). Neoadjuvant therapy resulted in a significant decrease in mitotic count and an increase in the proportion of patients with Her2/neu overexpression. No significant changes were noted for the degree of tubule formation, nuclear pleomorphism, overall Bloom–Richardson score, and hormone receptor status. However, small sample size may be a limitation of these results.

Optimal Surgical Management of Well-Differentiated Thyroid Cancer Arising in Struma Ovarii: A Series of 4 Patients and a Review of 53 Reported Cases

BACKGROUNDnWell-differentiated thyroid cancer arising in struma ovarii is rare. The optimal management of this entity remains undefined. Unilateral cystectomy, unilateral salpingo-oophorectomy (USO), or total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH/BSO), in addition to total thyroidectomy and radioactive iodine (RAI) ablation, have been employed by various groups. We hypothesized that in patients with thyroid cancer arising within struma ovarii, pelvic surgery alone would be sufficient, provided there is no evidence of gross extra-ovarian extension.nnnMETHODSnWe review a series of four patients from a single institution and 53 cases from the literature, comparing the extent of treatment and outcomes. Our literature review focused on low-risk patients with struma ovarii confined to the ovary, without evidence of gross extra-ovarian spread or distant metastases. Cumulative recurrence rate was determined by using the Kaplan-Meier method.nnnRESULTSnWe report the treatment of four patients with well-differentiated thyroid cancer arising within struma ovarii. Patients underwent USO, BSO, or TAH/BSO. One patient underwent prophylactic total thyroidectomy in anticipation of RAI treatment, and was found to have a synchronous papillary thyroid carcinoma. All patients clinically remain without evidence of disease at a median follow-up of 9 (range 0.8-13) years. Treatment strategies in 53 cases from a review of the literature varied. The pooled cumulative recurrence rate of 57 cases with struma ovarii confined to the ovary was 7.5% at 25 years.nnnCONCLUSIONSnThyroid cancer arising in struma ovarii is rare. Controversy exists regarding the extent of pelvic resection and management of the thyroid gland. In our series of four patients, all patients are alive without evidence of disease, and the 25-year recurrence rate of 57 cases was low (7.5%), despite a variety of approaches to surgical resection and adjuvant treatment. Extensive pelvic surgery and prophylactic total thyroidectomy to facilitate RAI therapy may be reserved for patients with gross extra-ovarian extension or distant metastases.

Mucinous Expression in Benign and Neoplastic Glandular Lesions of the Uterine Cervix

CONTEXTnMucins are glycoproteins produced by both normal and neoplastic glandular epithelial cells including endocervix.nnnOBJECTIVEnTo determine the expression of mucins in uterine cervical glandular lesions and whether mucin expression correlates with the nature and origin of the glandular lesions.nnnDESIGNnAntibodies to MUC1, MUC2, MUC4, and MUC5AC were applied on 52 cases including 14 endocervical adenocarcinomas (including 4 adenosquamous carcinomas), 9 endometrial carcinomas (8 endometrioid adenocarcinomas and 1 adenosquamous carcinoma), 8 adenocarcinoma in situ (AIS), 2 glandular dysplasias, 6 tubal metaplasias, 10 microglandular hyperplasias, and 3 normal endocervix. The presence of any staining was considered positive.nnnRESULTSnAll benign endocervical epithelia, including tubal metaplasia and microglandular hyperplasia, expressed MUC1, MUC4, and MUC5AC but not MUC2. Almost all endocervical AIS and carcinomas and all endometrial adenocarcinomas expressed MUC1; the exceptions were 2 cases of endocervical adenocarcinoma and 1 case of adenosquamous carcinoma of the endocervix. MUC2 staining was noted in 25%, 40%, and 22% of AIS, endocervical adenocarcinomas, and endometrial adenocarcinomas, respectively. About 38% of AIS, 75% of endocervical adenocarcinomas, and 44% of endometrial adenocarcinomas expressed MUC4. Half of AIS, most of endocervical adenocarcinomas, and 22% of endometrial adenocarcinomas expressed MUC5AC. The difference in MUC4 and MUC5AC expression between benign endocervical lesions and AIS and the difference in MUC5AC expression between endocervical and endometrial neoplasms were statistically significant.nnnCONCLUSIONSnMucin expressions differed among benign endocervical lesions and AIS and among endocervical and endometrial malignancies. These results suggest that mucin staining may potentially be helpful in differentiating various uterine cervical glandular lesions.

A Comparison of the Roche Cobas HPV Test With the Hybrid Capture 2 Test for the Detection of High-Risk Human Papillomavirus Genotypes

CONTEXTnAll Food and Drug Administration-approved methods in the United States for human papillomavirus testing including the Hybrid Capture 2 human papillomavirus assay and the Roche cobas human papillomavirus test are approved for cytology specimens collected into ThinPrep media but not for specimens collected into SurePath solution.nnnOBJECTIVEnTo compare the performance of the Roche cobas and Hybrid Capture 2 tests for the detection of high-risk human papillomavirus using both ThinPrep and SurePath preparations as part of a validation study.nnnDESIGNnOne thousand three hundred seventy-one liquid-based cytology samples, including 1122 SurePath and 249 ThinPrep specimens, were tested for high-risk human papillomavirus DNA using the Roche cobas human papillomavirus test and the Hybrid Capture 2 human papillomavirus assay. For cases with discrepant results, confirmatory testing was performed using Linear Array human papillomavirus testing.nnnRESULTSnOne hundred and fifty-six (11.38%) and 184 (13.42%) of the 1371 specimens tested positive for high-risk human papillomavirus DNA using the Hybrid Capture 2 human papillomavirus assay and Roche cobas human papillomavirus assay, respectively. In addition, 1289 (94.0%) of 1371 specimens demonstrated concordant high-risk human papillomavirus results with a κ value of 0.72 (95% confidence interval, 065-0.78). There was no statistically significant difference in the percentage of positive high-risk human papillomavirus results between the 2 liquid-based preparations with either assay. Discordant results between the 2 assays were noted in 82 of 1371 cases (6%). Twenty-seven of 82 cases (32.9%) were Hybrid Capture 2 positive/Roche cobas negative and 55 of 82 cases (67.1%) were Roche cobas positive/Hybrid Capture 2 negative. Two of 20 Hybrid Capture 2-positive/Roche cobas-negative cases (10%) and 26 of 37 Roche cobas-positive/Hybrid Capture 2-negative cases (70%) tested positive for high-risk human papillomavirus by Linear Array.nnnCONCLUSIONSnBoth assays showed good agreement and excellent specificity with either ThinPrep or SurePath preparations. The number of discordant results was relatively small. The performance of both assays was similar for ThinPrep specimens, but the Roche cobas test demonstrated higher sensitivity with SurePath specimens.

Vanishing Thyroid Tumors: A Diagnostic Dilemma After Ultrasonography-Guided Fine-Needle Aspiration

BACKGROUNDnFine-needle aspiration (FNA) is the most accurate and cost-effective method for evaluating thyroid nodules. However, FNA-induced secondary changes completely replacing thyroid tumors (vanishing tumors) may create a novel problem. In this study, we highlight the diagnostic and management issues associated with the unintended consequences of ultrasonography (US)-guided FNA.nnnMETHODSnFourteen thyroid glands (11 women and 3 men, ages 33-64 years) with vanishing tumors were prospectively identified between 2009 and 2012 upon surgical resection. Cytology and histopathology slides were reviewed, and second opinions were obtained when necessary.nnnRESULTSnThe cytology of the 14 vanishing tumors was suspicious/positive for papillary thyroid carcinoma (PTC) in 5, indeterminate (atypia of unknown significance) in 5, benign in 2, follicular neoplasm in 1, and nondiagnostic in 1 nodule. Upon thyroidectomy, the vanishing tumors ranged in size from 0.4 to 3.5u2009cm (median 0.7u2009cm). Microscopically, the nodules showed cystic degeneration, organizing hemorrhage, granulation tissue, fibrosis, and microcalcifications. In seven tumors, a few residual malignant cells (PTC in five) or residual benign follicles (hemorrhagic cyst in two) at the periphery of the vanishing tumors helped with the final diagnosis. The remaining seven tumors were completely replaced by FNA-induced secondary changes, and had the cytology diagnosis of benign in one, follicular neoplasm in one, and suspicious/positive for PTC in five. Of the latter five, two showed additional separate foci of PTC, while three vanishing tumors (0.5, 1.2, and 1.6u2009cm) had no residual malignant cells and no additional carcinoma leading to a final diagnosis of negative for malignancy.nnnCONCLUSIONSnUS-guided FNA may lead to complete obliteration of thyroid nodules, rendering final diagnosis upon thyroidectomy difficult or impossible. In these unusual circumstances, the possibility that the surgical pathology may be nonrepresentative should be considered if the cytologic features on FNA are sufficient by themselves to support a definitive diagnosis of PTC.

Assessment of Biomarker Expression in Predicting Pathologic Response to Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer

To the Editor: The use of neoadjuvant chemotherapy has become the standard of care in the management of patients with locally advanced breast carcinoma. The response rate of the primary tumors following neoadjuvant chemotherapy is variable (1–4). Therefore, it would be beneficial to identify patients who would not respond to the neoadjuvant chemotherapy to avoid unnecessary side effects. Evaluating biomarker expression profiles prior to and after neoadjuvant chemotherapy may prove to be useful in determining the response of breast tumours to neoadjuvant chemotherapy. We have conducted a pilot study to examine the expression of selected biomarkers as potential predictors of response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. Twenty-two women (7 Caucasians and 15 AfricanAmericans) with locally advanced breast cancer (stage II or III) received 8 weeks treatment of docetaxel (38 mg ⁄ m ⁄ week). After completing docetaxel therapy, all except two patients also underwent 3 cycles of doxorubicin (75 mg ⁄ m ⁄ 21 days). Biopsies were obtained before neoadjuvant chemotherapy and after the treatment of docetaxel. All patients underwent surgical resection of the primary tumour and lymph node dissection. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue using antibodies against oestrogen ⁄ progesterone receptors (ER ⁄ PR), Ki-67, p27, p185, Bcl-2, Bax, TGF-alpha, EGFR and p53. The degree of staining was expressed using a semiquantitative scoring system which took into account of both the intensity and proportion of positive staining cells. All patients except one demonstrated responses to neoadjuvant chemotherapy, eight were complete responders (no invasive or in situ cancer present on surgical resection) and 13 were partial responders (‡25% reduction in tumour size). Among the patients with complete pathologic response, there was a substantial decrease in the immunoscores of Ki-67 between preand postchemotherapy samples; however, the difference did not reach statistical significance (Wilcoxon test, p = 0.08). There were no statistically significant differences in the immunoscores of the remaining markers before and after neoadjuvant chemotherapy. Patients who demonstrated complete pathologic response had significantly lower Ki-67 and Bax expression prior to therapy when compared with patients who had only partial or no pathologic response. (Wilcoxon test, Ki-67: p = 0.03 and Bax: p = 0.05 respectively). No statistically significant differences in the pretreatment expression of other markers were observed between the two groups of patients. Our results suggest that baseline expression of both Ki-67 and Bax may serve as important predictors of tumour responsiveness to neoadjuvant chemotherapy. In addition, there is also indication that a substantial decrease in Ki-67 expression may serve as a surrogate marker for complete pathologic response to neoadjuvant chemotherapy.

Anal High-Grade Squamous Intraepithelial Lesions in Human Immunodeficiency Virus–Infected Men

ObjectivesnAnorectal cytology (ARC) is a widely used screening tool for anal cancer in human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). Its diagnostic accuracy needs to be improved, especially for high-grade squamous intraepithelial lesions (HSILs).nnnMethodsnUsing 100 HIV+u2009MSM with biopsy-proven anal HSILs, we correlated histologic/cytologic findings.nnnResultsnUpon review, HSIL cells were present in 58 cytology samples and absent in 42. Positive samples were higher in cellularity and contained transformation zones ( P u2009<u2009.05). Cytology was able to predict HSILs in 36%, 48%, 68%, and 78% of patients with one, two, three, and four or moreu2009high-grade lesions. HSIL cells were identified in all cytology samples initially reported as HSILs or atypical squamous cells, cannot exclude HSIL and in 34 samples reported as low-grade squamous intraepithelial lesions or less. Notably, among this last category, 15 (44%) were keratinized-type HSILs.nnnConclusionsnOur findings should improve the ARC detection rate for anal HSILs, helping to implement ARC as the primary screening tool for anal cancer.