Beyond the suspicious thyroid fine needle aspirate. A review

Fine needle aspiration (FNA) is currently the best diagnostic tool for thyroid nodules. However, the cytologic category of indeterminate or suspicious lesion, which is found in 10-15% of cases, remains a challenge. Since neither clinical presentation nor intraoperative frozen section is often helpful in differentiating these lesions and since surgical procedures for benign and malignant lesions differ, there is a clear need to develop ancillary tests. In this review we identify 12 potential markers of thyroid malignancy that have been examined in thyroid cytologic samples. Although many of these markers hold promise as adjuncts to FNA cytology, multicenter studies have often shown limitations in the predictive value of these assays due to lack of specificity, sensitivity or both. The recent development, however, of tissue microarray techniques to validate promising new markers suggests that improvements in the approach to indeterminate thyroid FNA samples may soon be at hand. This review presents a summary of the issues facing the development of a clinically useful diagnostic test in the differential diagnosis of thyroid nodules.     

Positive predictive value of fine needle aspiration cytology of breast lesions

The predictive value of fine needle aspiration (FNA) was assessed in 1,181 consecutive cases of breast lesions in which cytologic abnormalities were reported. The positive predictive value (PPV) of an FNA cytologic report of atypia, suspicious or positive was 0.49, 0.95 or 0.996, respectively. In the presence of a suspicious/positive report by both physical examination and mammography, the PPV of a cytologic report of suspicious was 0.99. The PPV was directly correlated with age, partly due to the incidence of fibroadenomas among younger patients; fibroadenomas were present in 53 of 146 cases with a false FNA report of atypia, in 10 of 19 cases with a false FNA report of suspicious and in 2 of 2 cases with a false FNA report of positive. Overall, 93 cases reported as benign by physical examination and mammography were biopsied on the basis of the FNA cytologic report; cancers were diagnosed in 33 of these 93 cases (6 cancers among 42 women less than 40 years old and 27 cancers among 51 women greater than 39 years old). The widespread use of FNA cytology to study breast lesions is thus recommended, without regard to patient age and even in the presence of clinically benign findings, since the increase in the rate of cancer detection is worth the excess of unnecessary biopsies. The predictive value of a positive report of FNA cytology, or even of a suspicious report in the presence of clinical suspicion, is so high that an intraoperative frozen section biopsy might be spared in such cases.     

Application of artificial neural network for classification of thyroid follicular tumors

OBJECTIVE: To analyze smears of 197 thyroid follicular tumors (adenoma and carcinoma). STUDY DESIGN: Several types of artificial neural networks (ANN) of various designs were used for diagnosis of thyroid follicular tumors. The typical complex of cytologic features, some nuclear morphometric parameters (area, perimeter, shape factor) and density features of chromatin texture (mean value and SD of gray levels) were defined for each tumor. RESULTS: The ANN was trained by means of cytologic features characteristic for a thyroid follicular adenoma and a follicular carcinoma. At subsequent testing, the correct cytologic diagnosis was established in 93% (25 of 27) of cases. The morphometry increased the accuracy of diagnosis for follicular tumors in up to 97% (75 of 78) of cases. ANN correctly distinguished an adenoma or a carcinoma in 87% (73 of 84) of cases when using color microscopic images of tumors. CONCLUSION: The usage of ANN has raised sensitivity of cytologic diagnosis of follicular tumors to 90%, compared with a usual cytologic method (sensitivity of 56%). The automatic classification of thyroid follicular tumors by means of ANN is prospective.     

Value of the cytologic analysis of fine needle aspiration biopsy specimens in the diagnosis of pancreatic carcinomas

Between 1982 and 1986, 410 preoperative percutaneous fine needle aspiration (FNA) biopsies of the pancreas were performed on 316 patients clinically suspected of having a malignant pancreatic tumor. Of 58 patients with pancreatic carcinomas subsequently confirmed by histologic investigation, the FNA biopsy yielded a cytologically positive diagnosis of carcinoma in 39 cases (67.2%) and suspicious findings in another 5 cases (8.6%). In 14 cases of malignancy (24.1%), the FNA puncture failed to sample material from the tumor; hence, the cytologic evaluation yielded false-negative results. Of 21 patients with inflammatory disorders of the pancreas, cytologically suspicious cells were observed in 5 cases (23.8%); in none of those 5 cases did the histologic examination show any evidence of carcinoma. This indicates that caution should be taken not to cytologically over-diagnose cases of pancreatitis. On the whole, cytology proved to be a valuable method for the diagnosis of pancreatic carcinoma; it provided the highest rate of positive results in comparison with other modern clinical diagnostic methods. Furthermore, cytology may improve the diagnostic results even in those cases with clinically negative or merely suspicious findings. FNA punctures of the pancreas produced no serious complications in this series.     

Statistical analysis of fine needle aspiration cytology of the breast. A review of 678 cases plus 4,265 cases from the literature

Between 1979 and 1984, 678 breast fine needle aspiration (FNA) cytologic specimens were received in our laboratory; tissue follow-up was available for 159 cases (23%). The diagnoses rendered in cases with subsequent tissue study were benign (41%), insufficient (10.5%), atypical and/or suspicious for carcinoma (10.5%) and malignant (38%). Using the tissue diagnosis as the standard, there were four false-negative cytologic results and one false-positive result. Considering only cases with a definitive diagnosis of benign or malignant, the sensitivity of cytologic interpretation for diagnosing malignancy on adequate material was 94% while the specificity was 98%; the overall efficiency of the test was thus 96%. The predictive values were 98% for a positive test and 94% for a negative test. Of the total number of submitted cases, a correct and definitive diagnosis was rendered 76% of the time. Calculation of similar statistics from six other series in which the FNA cytologic diagnoses were compared with the histologic diagnoses yielded data almost identical to our findings. The high degree of uniformity in the data indicates that these statistical parameters can be used as standards for evaluating the efficiency of breast FNA cytology.     

Diagnostic pitfalls in the fine needle aspiration of thyroid nodules. A study of 555 cases in Chinese patients

The diagnostic value and limitations of fine needle aspiration (FNA) were determined by examining 555 palpable thyroid nodules in Chinese patients who had a definitive diagnosis established by thyroidectomy (529 cases) or large-needle biopsy (26 cases). Of the aspirates, 97.8% were satisfactory for cytologic examination. The overall malignancy rate was 20%. FNA detected 73 (74.5%) of 98 primary malignant tumors and 9 (90%) of 10 metastatic tumors. Diagnostic errors were most commonly due to inadequate specimens and cystic lesions. Cystic fluid, present in one-third of all lesions, was associated with a malignant nodule in 13% of the cases. FNA was most valuable for detecting papillary carcinomas; it may at times suggest the likelihood of a follicular carcinoma.     

Fine needle aspiration biopsy in the diagnosis of thyroid nodules

The fine needle aspiration (FNA) biopsies performed on thyroid nodules at Turku University Central Hospital from 1983 to 1988 were reviewed. Of the 1,054 total aspirated nodules, 194 were investigated histologically after thyroid surgery (191 cases) or at autopsy (3 cases). Two cases with an insufficient FNA sample, 4 with an incidental occult papillary carcinoma and 2 cases with carcinoma outside the nodule investigated by FNA biopsy were excluded from the series, leaving 186 histologically confirmed nodules in the final analysis. Three (3%) of the 107 cases with an FNA biopsy diagnosis of benign, 4 (8%) of the 52 with an FNA diagnosis of equivocal, 3 (20%) of the 15 with an FNA diagnosis of suspicious and all 12 (100%) with an FNA diagnosis of malignant were histologically malignant. If only an unequivocally malignant cytologic finding is considered positive, FNA biopsy had a diagnostic specificity of 100%, a sensitivity of 55% and an accuracy of 95% among the histologically confirmed cases. Follow-up revealed no cases of cancer among the 863 thyroids that were not explored surgically. It is concluded that FNA biopsy is a practical method with considerable diagnostic value in the evaluation of thyroid nodules.     

Papillary carcinoma of the thyroid gland. Analysis of 94 cases with preoperative fine needle aspiration cytologic examination

From 1979 to 1983, 94 papillary carcinomas of the thyroid gland were examined histologically in our institute after a preoperative cytologic examination. Material for cytologic examination was obtained using fine needle aspiration (FNA) biopsy. Eighty-five (90.4%) of the 94 examined cytologic smears were representative. Among these 85 cases suspicion for malignancy or malignancy itself was found in 64 cases (75.3%). The remaining 21 smears, classified as cytologically not as suspect for malignancy, were reclassified and the previous diagnosis had to be revised in one case. In the other 20 cases no clue for malignancy could be demonstrated even after reexamination. In the 85 cases with representative cytologic findings, tumor size was determined on surgical material, in order to establish how many carcinomas with a diameter less than 3 cm could not be reached by FNA biopsy. Except for one case, all carcinomas with negative preoperative cytologic findings had a diameter less than or equal to 3 cm. The question arising is the possibility of improving the accuracy of FNA biopsy in tumor detection within cold nodules of the thyroid by combined use of scintigraphy and ultrasound-guided FNA biopsy.     

Thyroid Cytology and Risk of Thyroid Cancer: Differences Among Indeterminate Specimens

ObjectiveTo assess the potential for stratification of indeterminate cytologic findings on fine-needle aspiration (FNA) of thyroid nodules in an effort to improve therapeutic strategies.MethodsWe attempted to determine the malignant risk associated with various indeterminate FNA cytologic patterns by correlation of specimens with the final histologic diagnosis. For this analysis, we identified 294 computerized medical records of surgically treated thyroid nodules during a 5-year period at our institution with the corresponding FNA cytology reports available.ResultsOf the 294 surgical cases, 162 with a positive or indeterminate cytologic report were selected, reviewed, and classified. Of 52 patients with positive cytologic findings on FNA, 51 (98%) had a final histologic report of a malignant thyroid nodule. Of 110 patients with indeterminate specimens, 30 (27%) had a final histologic diagnosis of thyroid carcinoma. The presence of nuclear atypia was predictive of thyroid carcinoma in 75% of patients, a Hürthle cell cytologic pattern was associated with a malignant thyroid nodule in 33%, and a hypercellular smear was suggestive of malignant involvement in 26% of cases. The lowest rate of malignant potential was associated with cytologic microfollicular and scant colloid alone subtype (6%).ConclusionThe results of this study show that indeterminate thyroid cytologic specimens can be subdivided into groups with different malignant risks. A microfollicular cytologic pattern in the absence of a hypercellular smear or nuclear atypia does not support a recommendation of surgical treatment. A malignant cytologic diagnosis has a high positive predictive value for detection of thyroid cancer. (Endocr Pract. 2004;10:330-334)     

Clinicopathologic analysis of fine needle aspiration cytology of the thyroid. A review of 1,613 cases and correlation with histopathologic diagnoses

OBJECTIVE: To evaluate the accuracy of fine needle aspiration (FNA) of thyroid lesions at our institution and to ascertain its usefulness in determining the therapeutic approach. STUDY DESIGN: The authors reviewed the results of 1,613 cases of FNA cytology of thyroid nodules performed from 1999 to 2001 at the Department of Pathology, Chonnam National University Hospital. Cytologic diagnoses were compared with histologic diagnoses in 207 cases that included both FNA and thyroid surgery. RESULTS: The sensitivity for the detection of neoplasms (carcinoma and follicular adenoma) was 78.4% and the specificity 98.2%. A false positive diagnosis was made in 1 case (1.8%) and false negative ones in 28 cases (21.5%). The diagnostic accuracy was 84.4%, with a positive predictive value of 99.0% and negative predictive value of 66.3%. The predictive value of a cytologic diagnosis was 100% in papillary carcinoma. CONCLUSION: FNA is a useful test in determining the therapeutic approach of thyroid lesions.     

Asymptomatic intrathyroidal parathyroid adenoma. Report of a case with a cytologic differential diagnosis including thyroid neoplasms

BACKGROUND: Intrathyroidal parathyroid neoplasms (IPNs) are uncommon tumors with an indolent clinical course. When asymptomatic, they can be incorrectly diagnosed as thyroid neoplasms on fine needle aspiration biopsy (FNAB), leading to inappropriate surgical treatment. CASE: A case of unsuspected IPN occurred in which the cytologic picture mimicked that of a thyroid neoplasm. The histologic specimen of the total thyroidectomy showed 2 adjacent intrathyroidal nodules morphologically and immunohistochemically corresponding to a parathyroid adenoma. CONCLUSION: The incidence of IPN remains controversial, especially in asymptomatic patients. On FNAB it is a possible cause of inappropriate surgery for a suspicious thyroid neoplasm (follicular or medullary carcinoma). Immunostaining for parathormone on the cytologic smear is valuable in establishing the correct preoperative diagnosis when the morphologic features are strongly suggestive of IPN.     

Fine needle aspiration of the hot thyroid nodule

The use of fine needle aspiration (FNA) cytology in the evaluation of solitary hot thyroid nodules was examined in 24 patients. Satisfactory FNA specimens were obtained from 22 patients. None of the cytologic samples was considered malignant or suspicious for malignancy. The cytologic findings were indeterminate in one instance--a smear with follicular features. The smears from the other 21 patients were judged to be benign. If FNA had been used as the initial diagnostic step, the need for a thyroid scan would thus perhaps have been avoided in 21 of the 24 patients. These results support the idea that FNA is the most effective procedure in the evaluation of the solitary thyroid nodule, whether functional or not.     

Galectin-3 is not useful in thyroid FNA

INTRODUCTION: Previous studies have suggested that galectin-3 immunohistochemistry may be useful in the fine needle aspiration (FNA) diagnosis of thyroid carcinoma as it has been reported to selectively stain carcinomas and not adenomas or goitres. METHODS: Fifty-one patients were included in a prospective study of galectin-3 in thyroid FNA; 88.2% were female and 11.8% male, mean age 53 years, range 25-87 years. Cell blocks were prepared and stained for galectin-3 if any cells were present in needle washings from the respective FNAs. RESULTS: Twelve of 51 (23.5%) of cell blocks contained epithelial cells. One benign and one inadequate FNA were negative for galectin-3 staining. One of five non-diagnostic FNA cases, a papillary carcinoma on final histology showed positive staining. Four follicular neoplasm/suspicious of carcinoma cases showed negative staining. One malignant FNA case, a papillary carcinoma showed positive staining with galectin-3 but three further carcinomas, two papillary and one follicular were galectin-3 negative. CONCLUSION: Galectin-3 immunohistochemistry does not appear to be a useful adjunct to diagnosis in thyroid FNA as it does not reliably distinguish malignant and benign lesions. Many thyroid aspirates are of low cellularity and are not suitable for cell block immunohistochemistry.     

Intraoperative cytologic diagnosis of unsuspected cardiac myxoma: a case report

BACKGROUND: Atrial myxoma is the most common primary intracardiac tumor. The diagnosis is generally primary intracardiac tumor, based on classical clinical findings coupled with echocardiographic or magnetic resonance image findings demonstrating a cardiac mass. CASE: Unsuspected atrial myxoma was found in a woman who had been diagnosed with invasive lobular carcinoma of the breast. The echocardiographic findings in the presence of fever favored a clinical working diagnosis of infective endocarditis complicating a suspected cardiac metastasis. While intraoperative frozen section examination could not rule out metastatic invasive lobular carcinoma, cytologic touch imprint findings were diagnostic of myxoma. This appears to be the first report of concurrent breast carcinoma and atrial myxoma. To our knowledge, this is also the first report of intraoperative cytologic diagnosis of cardiac myxoma. CONCLUSION: In myxoma cases with a complicated clinical setting in which frozen section examination may be equivocal, intraoperative cytologic examination may be a useful diagnostic tool.     

Intraoperative Diagnostic Strategy to Distinguish Parathyroid Adenomas from Metastatic Thyroid Cancer

ObjectiveTo report the limitations of frozen section examination and the value of intraoperative tissue aspiration for parathyroid hormone assay to distinguish parathyroid adenomas from metastatic thyroid carcinoma.MethodsWe describe 2 patients with a biochemical diagnosis of primary hyperparathyroidism who underwent intraoperative frozen section analysis of suspected parathyroid tumors. Parathyroid gland aspiration for parathyroid hormone was also performed for confirmation.ResultsThe intraoperative frozen section examination of the suspected parathyroid tumors inaccurately identified the tumors as follicular carcinomas. The parathyroid gland aspirate, however, accurately substantiated the presence of parathyroid adenomas, rather than follicular cancers.ConclusionAspiration of a suspected parathyroid tumor for parathyroid hormone assay accurately determines whether a nodule is a parathyroid gland and facilitates intraoperative decision making, especially when frozen section diagnosis is misleading. (Endocr Pract. 2009; 15:454-457)     

Learning vector quantizer in the investigation of thyroid lesions

OBJECTIVE: To investigate the capability of the learning vector quantizer (LVQ) in the discrimination of benign from malignant thyroid lesions. STUDY DESIGN: The study was performed on May-Grünwald-Giemsa-stained smears taken by fine needle aspiration (FNA). Using a custom image analysis system, 25 features that describe the size, shape and texture of approximately 100 nuclei were measured from each case. Statistical features were extracted from each case, and a linear regression analysis was performed to detect the statistically significant features. The cases were distributed by category, as follows: 100 cases of goiter and follicular adenomas, 11 cases of follicular carcinoma, 35 cases of papillary carcinoma, 24 cases of oncocytic adenoma, 8 cases of oncocytic carcinoma and 20 cases of Hashimoto thyroiditis. About 30% of the cases from each class were used for training two LVQ classifiers. The remaining 139 cases, out of a total of 198, were used as the test set. A classifier was used to discriminate into four classes and a second into two classes. RESULTS: The application of LVQ neural networks allows good discrimination between benign and malignant lesions (O.A. = 97.8). However, reliable discrimination of the cytologic types of the lesions was not obtained. CONCLUSION: These results indicate that the use of neural networks combined with image morphometry may offer useful information on the potential for malignancy of thyroid lesions and may improve the diagnostic accuracy of FNA of the thyroid gland, especially in cases of follicular neoplasms classified as suspicious for malignancy and in cases of oncocytic tumors.     

Intraoperative imprint cytology of the thyroid gland with computer-assisted morphometric analysis of cell clusters

Imprint preparations were used in addition to frozen sections in the intraoperative diagnosis of 37 cases of benign and malignant lesions of the thyroid gland, including adenomatous goiter, follicular adenoma, follicular carcinoma and papillary carcinoma. In the imprints, the cytologic features specific for carcinoma, as compared with benign lesions, were (1) the folding of the nuclear contour, (2) the increased density of the cytoplasmic matrix and (3) the frequent appearance of cell clusters of larger size. The size and frequency of cell clusters were morphometrically analyzed by a computer image analyzer. There was an increasing number of large clusters, plus the appearance of clusters of more than 300 micron in diameter, in both follicular and papillary carcinoma. In benign lesions, on the contrary, the majority of cells were isolated or in small clusters, the diameter of which never exceeded 300 micron in diameter. These results demonstrate that (1) the imprint cytology of the thyroid gland is useful in making a rapid intraoperative diagnosis and (2) the introduction of computer-assisted quantitative analysis is of practical value in the diagnosis of malignancy.     

Fine needle aspiration cytologic study of the solitary thyroid nodule. Profile of 308 cases with histologic correlation

The cytologic features and diagnoses of 308 solitary thyroid nodules subjected to fine needle aspiration (FNA) are presented and correlated with the histopathology. The findings reconfirmed the overall utility of FNA cytology in the differentiation of benign from neoplastic lesions and in the specific diagnosis of most types of thyroid lesions. The difficulty in the diagnosis of follicular carcinoma and in its differentiation from follicular adenoma is highlighted. Of note was the finding of Hürthle-cell populations in several types of lesions, which represents a potential diagnostic problem; this potential difficulty was lessened by sampling two or three areas within a nodule, thus obtaining a more truly representative specimen.     

Membrane connectivity estimated by digital image analysis of HER2 immunohistochemistry is concordant with visual scoring and fluorescence in situ hybridization results: algorithm evaluation on breast cancer tissue microarrays

Because metaplastic carcinoma of the breast encompasses a great variety of histopathology, diagnostic challenges abound, especially within the realm of cytology. The authors compiled and studied an eight-case series comprised of metaplastic breast carcinomas and lesions initially suspicious cytologically for metaplastic carcinoma in order to assess the degree of cytologic-histologic correlation and to identify recurring problematic themes surrounding the cytology-based diagnosis of this neoplasm. The cytologic and histologic slides from eight cases suspicious for metaplastic breast carcinoma diagnosed by fine needle aspiration (FNA) were collected and analyzed through a seven-year retrospective search of case files at our institution. Based on cytologic characteristics, the cases were separated into three groups. Group 1 consisted of three cases presenting with poorly differentiated adenocarcinoma and squamoid components on FNA. Group 2 was composed of two cases that featured a monophasic, malignant ductal cell population on cytology, while the cytologic specimens for the third group of cases presented with a mesenchymal component with or without a malignant glandular constituent. Cytologic-histologic correlation was present in two of three cases demonstrating a mesenchymal component, and there was 100% sensitivity in the cytologic detection of those mesenchymal elements. However, in only one of three cases was there an accurate cytologic diagnosis of metaplastic carcinoma when squamoid changes were present on FNA. Both cases demonstrating only malignant glandular elements on cytologic specimens revealed an additional component of malignant squamous differentiation upon the examination of mastectomy-derived tissue. These results indicate that squamous-like changes identified on FNA should be interpreted with caution and that sampling error remains a problematic recurrence in cytology. Regardless, there appears to be promise concerning the accurate cytologic diagnosis of metaplastic carcinoma when the lesion is characterized by a mesenchymal component. A study implementing a larger case number is essential in determining the significance of these findings.     

Hyalinizing trabecular tumor in a background of lymphocytic thyroiditis: a challenging neoplasm of the thyroid

ObjectiveTo describe a case of hyalinizing trabecular tumor (HTT) in a background of lymphocytic thyroiditis that was misdiagnosed as papillary thyroid carcinoma (PTC) based on fine-needle aspiration (FNA) cytologic findings and overtreated with total thyroidectomy.MethodsWe present a case report, including the imaging and pathologic findings, of a 68-year-old woman who presented with a multinodular goiter that was suspicious for PTC.ResultsOn the basis of FNA cytologic findings, she underwent a total thyroidectomy, and histologic examination of the thyroid gland revealed HTT in a background of lymphocytic thyroiditis. Radioiodine treatment was not administered because of the tumor’s low risk profile. No metastatic foci were established under nonsuppressive levothyroxine therapy after 3 years of follow-up.ConclusionsHTT is a challenging entity because of the uncertainty of its nature, the diagnostic challenges,and the mimicry of other types of thyroid tumors. In order to avoid overtreatment, endocrinologists and thyroid surgeons should be aware of the features of HTT, and suspicious cases should be evaluated by experienced cytopathologists. (Endocr Pract. 2011;17:e140-e143)