Constantine Theoharis

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

BACKGROUND Fine-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. PATIENTS AND METHODS A 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. RESULTS The 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. CONCLUSIONS These 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.

Thyroid follicular lesion of undetermined significance: Evaluation of the risk of malignancy using the two-tier sub-classification

The Bethesda 2007 Thyroid Cytology Classification defines follicular lesion of undetermined significance as a heterogeneous category of cases that are not convincingly benign nor sufficiently atypical for a diagnosis of follicular neoplasm or suspicious for malignancy. In our institution, we refer to these cases as indeterminate, and they are further sub‐classified into two: (1) low cellularity with predominant microfollicular architecture and absence of colloid (INa) and (2) nuclear features not characteristic of benign lesions (nuclear atypia) (INb). We reviewed these indeterminate cases to document the follow‐up trend using this two‐tier classification. A search of the cytology records was performed for the period between January 2008 and June 2009. All thyroid fine‐needle aspiration (FNA) cases were reviewed and the ones diagnosed as indeterminate were identified. Correlating follow‐up FNA and/or surgical pathology reports were reviewed. The percentage of cases showing a malignancy was calculated. One hundred and seventy‐one indeterminate cases were identified, representing 2.8% of the 6,205 thyroid FNA cases examined during the time under review (107 INa, 64 INb). Records of follow‐up procedures were available in 106 (61%) cases. Malignancy was identified in 27% of all indeterminate cases. This was disproportionately more in the INb (56%) compared to the INa (7%) cases. A diagnosis of “INa” does not carry the same implication as that of “INb”. The INb category needs a more aggressive follow‐up than the INa category and may justify an immediate referral for lobectomy. Despite the vague morphologic criteria for this diagnostic category, the indeterminate rate remains relatively low and falls within the NCI recommendation (<7%). Diagn. Cytopathol. 2011;.

BRAFV600E mutation in papillary thyroid microcarcinoma: a genotype-phenotype correlation.

BRAFV600E mutation has emerged as a marker of aggressive behavior in papillary thyroid carcinoma but its significance in microcarcinoma is not entirely clear. One-hundred and twenty-nine papillary thyroid microcarcinomas were tested for BRAFV600E mutation by single-strand conformation polymorphism, and their clinicopathologic features (age, sex, tumor size, multifocality, nodal metastases, histologic subtype, tumor cell morphology, architecture, tumor-associated stromal reaction, tumor interface to non-neoplastic thyroid (well circumscribed vs infiltrative), extrathyroidal extension, lymphovascular invasion, intratumoral multinucleated giant cells, and adjacent non-neoplastic thyroid pathology) were examined. Compared with tumors without the mutation (39/129, 30%), the mutated microcarcinomas (90/129, 70%) showed significantly higher prevalence of infiltrative tumor borders (78/90 vs 23/39, P=0.001), tumor-associated stromal desmoplasia/fibrosis and/or sclerosis (80/90 vs 25/39, P=0.002), classic nuclear features of papillary thyroid carcinoma (90/90 vs 35/39, P=0.008) and cystic change (43/90 vs 11/39, P=0.05). BRAFV600E mutation was more frequent in classic (75%), tall cell (91%), and other variants (>70%) than in follicular variant (21%) of papillary thyroid microcarcinoma. Tumors without the mutation were significantly more likely to be solid, well circumscribed, and lacked desmoplasia/fibrosis or sclerosis. However, on multivariate analysis, only the follicular variant of papillary microcarcinoma was significantly associated with the absence of mutation (odds ratio (95% confidence interval): 0.09 (0.01–0.54)). Lymph node metastases (n=24) were more frequent in microcarcinomas with mutation than without (21/24 vs 3/24, P=0.02). All patients with lateral cervical node metastasis (n=9), and all but one tumor with extrathyroidal extension (n=17/18) showed BRAFV600E mutation. No significant differences were noted in age, sex, tumor size, multifocality, lymphovascular invasion, psammoma bodies, stromal calcification, intratumoral multinucleated osteoclastic-type giant cells, and lymphocytic infiltration between the two groups of tumors. BRAFV600E mutation is an early event in thyroid carcinogenesis, and is associated with distinctive morphology and aggressive features even in papillary thyroid microcarcinomas.

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

BACKGROUND The 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. PATIENTS AND METHODS Cases 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. RESULTS One 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. CONCLUSIONS BRAF 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.

BRAF Mutation Testing of Thyroid Fine-Needle Aspiration Specimens Enhances the Predictability of Malignancy in Thyroid Follicular Lesions of Undetermined Significance

Background/Objective: The Bethesda 2007 Thyroid Cytology Classification defines atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) as a heterogeneous category of cases that are neither convincingly benign nor sufficiently atypical for a diagnosis of follicular neoplasm or suspicious for malignancy. At our institution, we refer to these cases as ‘indeterminate’ and they are further subclassified into two categories. BRAF mutation occurs in 40–60% of papillary thyroid carcinoma (PTC). In this study, we examined cases in the AUS/FLUS category in correlation with BRAF mutation analysis and surgical pathology outcome. Study Design: Thyroid fine-needle aspiration (FNA) cytology specimens interpreted as ‘indeterminate’ were selected from our files, and available remnants of thin-layer processed specimens were used for BRAF mutation analysis. Surgical pathology reports were reviewed for the final outcomes in these patients. Results: Of the 84 indeterminate cases with BRAF mutation analysis, only 49 had follow-up with surgical intervention. Sixteen cases had BRAF mutation. All of the BRAF-positive cases had a final diagnosis of PTC. Conclusions: The sensitivity and specificity of BRAF mutation in detecting PTC in FNA specimens with indeterminate diagnosis was 59.3 and 100%, respectively, while the positive and negative predictive values were 100 and 65.6%, respectively. The limited data supports the use of BRAF mutation analysis to predict the risk of malignancy in patients with indeterminate thyroid FNAs.

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 
(2012) Histopathology 60, 1052–1059

The molecular diagnosis and management of thyroid neoplasms.

Purpose of review The molecular work-up of thyroid nodules on fine needle aspiration (FNA) cytology samples has given clinicians a new level of diagnostic information. We focus this review on the molecular techniques used in the diagnosis of thyroid cancer, especially BRAF, and the resulting management considerations that are raised. Recent findings BRAF testing offers both diagnostic and prognostic information; it has been used along with the Bethesda Thyroid FNA Classification System to offer preoperative guidance in the management of thyroid nodules. Various authors have successfully utilized molecular panels on cytologic specimens including mutations and rearrangements such as RAS and RET/PTC. Preoperative mutation detection allows initial management decisions to be made with a greater clinical confidence. Summary BRAF molecular testing holds promise as a possible diagnostic tool for indeterminate FNAs, and as a determinant for planning initial clinical management of thyroid nodules. Further developments in the molecular approach to thyroid cancer are expected to allow greater individualization of patient care.

Endoscopic ultrasound-guided fine-needle aspiration diagnosis of Merkel cell carcinoma metastatic to the pancreas.

Merkel cell carcinoma (MCC) is a rare and highly aggressive primary neuroendocrine carcinoma of the skin with a high propensity for local, regional, and distant spread. Distant metastasis of MCC to the pancreas is uncommonly seen and may impose a diagnostic challenge cytologically. Here we report a case of MCC with pancreatic metastasis, which was diagnosed by endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA). The aspirates revealed both single and clustered epithelial cells with scant cytoplasm and round nuclei with stippled chromatin and inconspicuous nucleoli. Immunocytochemically, the tumor cells were positive for CK20, synaptophysin, CD56, and CD117. The neoplastic cells were also identified by flow cytometry as non‐hematopoietic cells which were positive for CD56 and negative for CD45. To our knowledge, this is only the second case report of MCC metastatic to the pancreas diagnosed by EUS‐FNA. There have been several reports of MCC metastatic to the pancreas diagnosed only at the time of surgical resection. However, a preoperative diagnosis allows for appropriate management while sparing a patient the morbidity of unnecessary procedures. Diagn. Cytopathol. 2014;247–252.

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

BACKGROUND Fine-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. METHODS Fourteen 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. RESULTS The 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 3.5 cm (median 0.7 cm). 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 1.6 cm) had no residual malignant cells and no additional carcinoma leading to a final diagnosis of negative for malignancy. CONCLUSIONS US-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.

Insular variant of poorly differentiated thyroid carcinoma.

OBJECTIVE To present a case of an insular variant of poorly differentiated thyroid carcinoma (PDTC) and to review the literature related to diagnosis, natural history, and treatment of this unusual form of thyroid cancer. METHODS We present the clinical, laboratory, and pathologic findings of the study patient and review English-language literature related to PDTC published between 1970 and the present. RESULTS PDTC is a controversial and rare epithelial thyroid cancer, intermediate between differentiated thyroid carcinoma and anaplastic thyroid carcinoma that exhibits increased aggressiveness, propensity to local recurrence, distant metastases, and increased mortality. PDTC warrants aggressive management with total thyroidectomy followed by radioactive iodine ablation and potentially additional therapy for residual or recurrent disease. Some carcinomas do not take up radioactive iodine, and dedifferentiated clones of distant metastases may evolve. It is unclear whether chemotherapy is beneficial. Use of additional imaging modalities, including positron emission tomography, 18-fludeoxyglucose positron emission tomography/computed tomography, 18-fludeoxyglucose positron emission tomography/computed tomography/magnetic resonance imaging, (124)I positron emission tomography/computed tomography, positron emission tomography/magnetic resonance imaging fusion studies, and recombinant human thyrotropin-stimulated radioactive iodine uptake for cancer surveillance are discussed. CONCLUSIONS PDTC is an unusual and aggressive form of thyroid cancer. Fine-needle aspiration cytology may not yield sufficient information to specifically diagnose PDTC. Aggressive management with total thyroidectomy and neck dissection followed by high-dose radioactive iodine remnant ablation is standard. Iodine I 131 whole body scanning is often the initial test for tumor surveillance, with other imaging modalities applied as needed.