Cytopathology of follicular lesions of the thyroid gland

Fine needle biopsy is generally considered unreliable in the differential diagnosis of follicular lesions of the thyroid gland. To test this hypothesis, we correlated fine needle biopsy diagnoses with surgical diagnoses in 379 follicular lesions. From nuclear characteristics (especially size) and the architectural pattern of tissue fragments, the following observations were made. Differentiation of goiters (including hyperplastic ones) from neoplastic thyroid disease is quite accurate and no more than 1 to 2% of cancers should be missed. The specific cytologic diagnosis of follicular carcinoma is 75% accurate, and that of follicular variant of papillary carcinoma is over 95% accurate. Of histologically proved follicular carcinomas, almost three-quarters should be diagnosed as such or strongly suspected by fine needle biopsy. The remainder will be identified as cellular follicular adenomas, reaffirming the overlap of cytologic features of benign and malignant neoplastic disease. From cytologic and surgical pathologic data for each fine needle biopsy diagnosis of follicular lesion, a probability of cancer can be stated that is useful in management decisions.     

Follicular lesions of the thyroid: intraoperative cytology

The aim of this study is to evaluate the role and utility of intraoperative cytology in differentiating between follicular adenomas and non-neoplastic adenomatous nodules of the thyroid. We retrospectively reviewed the intraoperative cytologies of 36 adenomatous nodules and 19 follicular adenomas and evaluated several features. chi-square statistics were used to determine a statistically significant difference in cytologic scores between the two groups. We found significant differences in grading scores of the following parameters: follicular adenomas showed greater cellularity, greater follicle formation, larger nuclei, and more nuclear pleomorphism and overlap; adenomatous nodules showed more colloid and honeycomb arrangements. However, inspection of the data in graphic form showed a partial overlap in cytological features between the two groups: an adenomatous nodule revealing a microfollicular pattern histologically will cytologically display numerous follicles and scant colloid, giving a false impression of a neoplasm; while the smear of a macrofollicular adenoma is relatively hypocellular and contains abundant colloid, causing potential misdiagnosis as an adenomatous nodule. In conclusion, intraoperative cytologic examination can help to detect those follicular lesions more likely to be neoplastic, and a systematic approach is proposed when dealing with thyroid follicular lesions during intraoperative consultation in order to improve the diagnostic accuracy.     

Our approach to follicular-patterned lesions of the thyroid

Follicular-patterned lesions of the thyroid are common; these include hyperplastic/adenomatoid nodules, follicular adenoma, follicular carcinoma and follicular variants of papillary carcinoma. Most of these lesions can be diagnosed with ease; however, there is a controversial subgroup. In this review, we present our diagnostic approach based on our experience with the histological diagnosis of these tumours, which can help in appropriate clinical management.     

Handling of thyroid follicular patterned lesions

A novel scheme for the classification of well-differentiated thyroid tumors composed of follicular cells and having a follicular pattern of growth is presented. In addition to the two conventional categories, i.e., adenoma and carcinoma, this scheme includes a group of tumors “of uncertain malignant potential.”     

Cytopathologic analysis of thyroid lesions in the pediatric population

Fine-needle aspiration (FNA) of the thyroid is seldom performed in the pediatric population. Therefore, the clinical utility of thyroid FNA in this patient group has not been adequately addressed. A 15 yr retrospective review of the cytopathology archives at the participating institutions was performed to identify cases of thyroid FNA performed in pediatric patients. The medical records of these cases were reviewed, including the surgical pathology reports of those patients who had subsequently undergone surgical resection. One hundred one specimens from 82 patients were identified. Of these, 40 had a cytopathologic diagnosis of carcinoma, "suspicious" for carcinoma, neoplasm, or atypia, 48 were benign, and 13 were unsatisfactory. Of the 82 patients, 45 underwent partial or total thyroidectomy. Twenty-two (49%) of these were found to harbor a malignant neoplasm (18 papillary carcinomas). The diagnostic sensitivity for identifying a lesion was 87% (26/30) and the diagnostic specificity was 92% (47/51). There were four false-positives and four false-negatives in the review, yielding a positive predictive value of 87% and a negative predictive value of 92%. We conclude that FNA is a useful adjunct to the management of thyroid lesions in the pediatric population, with good diagnostic accuracy. Although thyroid neoplasms are relatively rare in children, our experience demonstrated that 40% of thyroid masses referred for FNA had an interpretation that caused concern, ranging from "atypical" to carcinoma. Additionally, a benign diagnosis by FNA may avoid unnecessary surgery with its potential complications, a significant consideration for this age group.     

A logistic model for thyroid lesions

A stepwise logistic regression analysis was performed in 27 cases of papillary carcinoma thyroid (PC), 20 follicular neoplasms (FN), 30 cases of Grave's disease (GD), and 40 cases of colloid adenomatous goitre (CAG). The three most important variables in predicting PC were papillary clusters, dense cytoplasm, and intranuclear cytoplasmic inclusions, whereas the predictors of FN were high cellularity combined with a prominent acinar pattern. A few cases of GD and CAG showed a cytologic overlap with PC and FN, respectively. Regression analysis established high cellularity, fire flare appearance, and epitheloid granulomas as reliable predictors of GD, whereas abundant colloid with or without foam cells and follicles associated with colloid (FAC) were important variables in CAG.     

Intraoperative assessment of thyroid and parathyroid lesions

The value of intraoperative frozen section analysis of thyroid nodules and of parathyroid lesions continues to change as new and ancillary techniques (both preopearative and intraoperative) become widely used, eg, fine needle aspiration, new radiologic scan techniques, rapid hormone assays. This articles reviews the use of frozen section diagnosis in the evaluation of thyroid and parathyroid lesions, presents the current literature and the author's experiences, and proposes a practical approach to these cases.     

Immunohistochemical expression of CXCR4 in thyroid carcinomas and thyroid benign lesions

In different tumor entities, expression of the chemokine receptor 4 (CXCR4) has been linked to tumor dissemination and poor prognosis. The aim of this study was to examine the immunohistochemical expression of CXCR4 in thyroid carcinomas and thyroid benign lesions. Using monoclonal anti-CXCR4 antibody, we performed immunohistochemical staining on tissue sections from 134 cases obtained from Ruijin Hospital affiliated with Shanghai Jiaotong University School of Medicine (Shanghai, China) between 2000 and 2007. In our study, the CXCR4 expression of the thyroid carcinoma group (including 16 papillary thyroid carcinomas, 18 follicular thyroid carcinomas, 9 poorly differentiated thyroid carcinomas, and 7 medullary thyroid carcinomas) was found to be higher than in the benign lesion group (including 19 cases of Hashimoto's thyroiditis, 15 nodular goiters, and 50 follicular adenomas) (p < 0.0001). Within the carcinoma group, the more malignant thyroid carcinoma group (including 9 poorly differentiated thyroid carcinomas and 7 medullary thyroid carcinomas) showed a higher ratio of CXCR4 positivity compared to the less malignant thyroid carcinoma group (including 16 papillary thyroid carcinomas and 18 follicular thyroid carcinomas) (p < 0.0001). Our study suggests that CXCR4 expression might be a frequent and cancer-specific event in thyroid carcinoma, and it might be involved in malignancy transformation during the progression of thyroid carcinoma.     

Fine-needle aspiration in the evaluation of thyroid lesions in children

The role of fine-needle aspiration (FNA) cytology in the evaluation of thyroid lesions in not as well established in children when compared with adults. Hence we aimed to ascertain the utility and limitations of FNA in childhood thyroid lesions. This was a retrospective analysis of all thyroid FNA performed in children less than 14 years of age over a 4-year period (2005-2009). Histopathological follow-up was available in six cases. A total of 77 cases were included in the analysis. The most common cytological diagnosis was lymphocytic thyroiditis (49.3%), followed by colloid goiter (18.2%), hyperplasia (10.4%), and benign aspirate (7.8%); malignancy was identified in six cases (7.8%). Of these six cases, three were papillary thyroid carcinoma. There was one false-positive case reported as a Hurthle-cell neoplasm, which on histology showed Hashimoto's thyroiditis. One case each of rhabdomyosarcoma and spindle epithelial tumor with thymus like differentiation was wrongly diagnosed as thyroid neoplasm, NOS, and medullary carcinoma (spindle variant), respectively. The overall diagnostic accuracy was 98.6% with 100% sensitivity, 98.6% specificity, 80% positive predictive value, and 100% negative predictive value. FNA is extremely valuable in the initial evaluation of thyroid swelling in children. Rare neoplasms masquerading as thyroid nodules in children can pose difficulties in diagnosis; however, papillary carcinoma is easily recognized. In lymphocytic thyroiditis, it provides a tissue diagnosis, thereby avoiding more invasive procedure for merely diagnostic purposes.     

Utility of frozen section analysis on follicular lesions of the thyroid

The experience of one surgeon (R.H.) with intraoperative frozen sections (FS) performed on thyroid nodules over a 10-year period was studied to assess the utility of FS in follicular thyroid lesions. One hundred and ten patients with dominant or solitary nodules demonstrating a follicular growth pattern were evaluated. The FS slides and subsequently the permanent sections of the nodules were reviewed by the pathologists in the study (M.P.B., VAL.) without knowledge of the original diagnoses. Our results indicate: (1) if the FS was definitively benign (58 patients), the final diagnosis was benign [these lesions consisted of adenomatous nodule, nodular goiter, follicular adenoma, and Hürthle cell adenoma); (2) if an FS diagnosis of malignancy was rendered (4 patients), it was confirmed on permanent sections (follicular variant of papillary carcinoma in all 4); and (3) if the FS diagnosis was deferred (48 patients), the final diagnosis was benign in all but 10 (21 %) (of these 10, 6 had minimally invasive follicular carcinoma [2 of the Hürthle cell type], and 4 had follicular variants of papillary carcinoma). Overall, sensitivity, specificity, and accuracy rates for FS diagnoses were 29, 100, and 91%. Because unilateral lobectomy may be acceptable therapy for well-differentiated thyroid cancers, and because the efficiency of FS evaluation in diagnosing malignancy is low (only 4 malignancies of 110 total patients were diagnosed at FS, or 3.6% overall), we conclude that in this era of cost-containment, FS is not useful in the evaluation of follicular thyroid nodules identified preoperatively as follicular lesions by fine-needle aspiration cytology. Several recommendations concerning the 3 categories of FS diagnosis (i.e., definitively benign, definitively malignant—especially the follicular variant of papillary carcinoma—and deferred) are also put forward.     

Unusual non-neoplastic lesions in the "surgical pathology" of the thyroid

This review aims to describe and assist in the categorization of most of the unusual non-neoplastic conditions, encountered in the surgical pathology of the thyroid. The conditions included are: normal intrathyroidal vestigial tissues/structures (i.e. rests of the ultimobranchial body and thyroglossal duct) and their relevant pathological derivatives (ultimobranchial body cyst, intrathyroidal lymphoepithelial cyst, thyroglossal duct cyst); mature intrathyroidal heterologous tissues/organs of either metaplastic or heterotopic origin (adipose tissue, striated skeletal muscle, cartilage, parathyroid glands, thymus, salivary gland tissue) and their relevant pseudotumoural lesions; varieties of metaplastic and non-metaplastic morphologic changes of the thyroid follicular epithelium (oncocytic, clear cell/signet ring cell, darkly pigmented cell, mucinous (myxoid), squamous, spindle cell); amyloid goiter; some reactive and/or degenerative cytologic and nuclear atypicalities (nuclear pseudoclearing and cell pleomorphism) as well as some hyperplastic or peculiar growth patterns (capsular pseudoinvasion; vascular invasion; papillary carcinoma-like and paraganglioma-like patterns) of benign conditions mimicking neoplasia; and finally. some pseudotumoural lesions of the stroma (pseudoangiosarcomatous vascular proliferation, and post-fine-needle aspiration spindle cell nodule). The pathogenetic mechanism, the morphologic interpretation, and the differential diagnosis of each of the above-listed conditions are discussed and pertinent illustrations for many of them are also provided. Lesions of thyroid tissue situated outside of the gland itself are not discussed.     

Comparative ultrastructure of thyroid,tongue and eyelid lesions in the neuroma phenotype of medullary carcinoma of the thyroid

Summary Electron-microscopic and histochemical studies of thyroid tumor, tongue neuromas and eyelid neuromas from the lesions of a patient with medullary thyroid carcinoma were compared. In the thyroid tumor, a significant number of the C cells showed heterogeneity of granule types; no C cells, however, were identified in the tongue and eyelid neuromas. Amyloid was clearly shown by Congo red staining in the thyroid neoplasm and in the tongue neuromas. In all tissues, amyloid fibrils were found to be ultrastructurally closely associated with fibroblasts. These fingings suggest that the fibroblast rather than the C cell may have played the important role in the deposition of amyloid in this patient's thyroid carcinoma.The authors wish to thank Dr. Lloyd Bartlett, Department of Surgery, University of Manitoba for permission to study the case and for the provision of surgical specimens.     

Analysis of inconclusive fine-needle aspiration of thyroid follicular lesions

To evaluate all inconclusive fine-needle aspiration biopsy (FNAB) specimens from thyroid follicular lesions with subsequent histologic diagnosis at St John Hospital and Medical Center, Detroit, MI. The criterion for specimen adequacy used in our institution was also reexamined to determine whether it was too stringent. We reviewed 45 inconclusive FNAB samples. Only cases that underwent surgical intervention were considered. Specimen adequacy was determined by the presence of at least 8–10 tissue fragments of well-preserved follicular epithelium on at least two slides; each tissue fragment should have a minimum of 8–10 cells. Different cytologic characteristics—cellularity, cellular architecture, nuclear pleomorphism, inclusion/grooves, chromatin, Hürthle cell change, lymphocytes, macrophages, colloid, and multinucleated giant cells—were scored and compared with final surgical diagnosis. The surgical procedure performed was also analyzed. Review of these 45 surgical specimens found 28 (62.2%) multinodular goiters, 14 (31.1%) nodular hyperplasias, 2 (4.4%) follicular adenomas, and one (2.2%) with invasive follicular carcinoma. Forty-three (95.6%) of these cases were female and 2 (4.4%) were male. Cytologic review showed 2 acellular samples, 10 cases containing macrophages only, 10 aspirates with macrophages and an inadequate number of follicular cells, and 23 specimens with an inadequate number of follicular cells. Twenty-three patients underwent total thyroidectomy; 20, lobectomy; and 2, isthumusectomy. Almost 98% of the patients with inconclusive FNAB had benign lesions. This finding encouraged us to continue using our criteria for adequacy because of the importance of a negative report. Patients in our series, who underwent thyroidectomy after an inconclusive or nondiagnostic aspirate, had a malignancy rate of 2.2%, which was no worse than patients with a benign preoperative diagnosis. A balanced approach with careful follow-up for nondiagnostic cytology is prudent.     

Keratin subsets in papillary and follicular thyroid lesions

 Previous studies indicate that keratins 7, 8 and 18 are present in all thyroid papillary and follicular lesions, but the distribution of other keratins has been incompletely characterized. The profile of individual keratin (K) polypeptides was evaluated immunohistochemically in over 200 non-neoplastic and neoplastic thyroid papillary and follicular lesions. Monoclonal antibodies to K19, K17, K16, K5/6 and K10 were applied in paraffin sections of formaldehyde-fixed tissue. K19 was present variably, often only focally in goitres, and was present only sporadically in papillary hyperplasia. However, K19 was strongly and uniformly expressed in virtually all papillary carcinomas, indicating differential diagnostic usefulness in differentiating papillary hyperplasia and papillary carcinoma. About half of the follicular carcinomas (defined as tumours strictly excluding the follicular variant of papillary carcinoma) were also strongly K19-positive, suggesting that K19 patterns are not reliable in differentiating papillary and follicular carcinoma. K17 and K5/6 were present in cysts and squamous metaplasia of goitres, and focally in papillary but only exceptionally in follicular carcinoma in areas of squamous differentiation and tumour cells in desmoplastic stroma. K16 in turn was present only focally in well-developed squamous metaplasia in goitres but was not found in differentiated thyroid carcinomas. K10, a high-molecular-weight keratin typical of epidermal differentiation, was identified neither in non-neoplastic nor in neoplastic differentiated thyroid lesions, including squamous metaplasia. These results indicate that papillary carcinomas differ from other differentiated thyroid tumours in their varying, usually focal, expression of stratified epithelial keratins that are partly but not exclusively related to squamous differentiation in such lesions. However, papillary carcinomas do not express truly epidermally restricted keratins; their previously described reactivity with polyclonal ”epidermal keratin” antibodies most probably results from the reactivity of such antibodies with K19. Received: 14 April 1997 / Accepted: 28 May 1997