Follicular variant of papillary thyroid carcinoma: diagnostic limitations of fine needle aspiration cytology

OBJECTIVE: To study the diagnostic sensitivity and specificity of fine needle aspiration cytology (FNAC) offollicular variant of papillary thyroid carcinoma (FVPTC). STUDY DESIGN: The study group consisted of 390 papillary thyroid carcinoma (PTC) cases diagnosed histologically with thyroidectomy specimens. The FNAC and histopathologic classification were compared in terms of the appearance of FVPTC and non-FVPTC statistically with the chi squared test. Also, several features of the cytologic smears of FVPTC were reviewed. RESULTS: Twelve of the 390 PTC cases were classified as FVPTC histologically. Five of the 12 cases were also reported as FVPTC in the diagnosis by FNAC and the other 7 as the usual type of PTC (UTPTC). There was 1 case classified as UVPTC histologically but FVPTC cytologically. If we use histologic diagnosis as the gold standard, the sensitivity and specificity of FNAC diagnosis of FVPTC were 42% and 83%, respectively. CONCLUSION: FNAC may be a good tool for diagnosing PTC, but it is unreliable to differentiate between FVPTC and UTPTC.     

Cribriform-morular variant of papillary thyroid carcinoma. Report of a case showing morules with peculiar nuclear clearing

BACKGROUND: There have been only 4 reported cases of cribriform-morular variant of papillary thyroid carcinoma (CMVPTC) with cytologic findings from fine needle aspiration. In these reports, the cytologic findings do not fully reflect the histologic characteristics of this entity. We report a case of CMVPTC in which a cribriform pattern without colloid and epithelial morules with peculiar nuclear clearing (PNC) were present in smears, thus fulfilling the criteria for a cytologic diagnosis of CMVPTC. Protein truncation tests for APC molecule abnormality indicated the presence of germline mutation in the patient's APC gene. CASE: A 30-year-old woman had multiple thyroid tumors. Aspiration cytology revealed a large number of round to spindle-shaped atypical-cells showing sheet-like, cribriform, follicular, whorl-like and solid, 3-dimensional arrangements. The cribriform and follicular arrangements did not contain colloid in the lumen. The powdery chromatin pattern characteristic of papillary carcinoma was not observed, but there were scattered intranuclear cytoplasmic pseudoinclusions and grooved nuclei. The nuclei of the atypical cells presenting in the whorl formations showed enlargement, thickened nuclear membranes and entirely clear contents, consistent with PNC. Hyalinelike necrotic cells were also observed in the cell clusters or in the background. Histologic and immunohistochemical findings were typical of CMVPTC. CONCLUSION: The cribriform pattern without colloid, fascicular or whorl formation of spindle cells, and morules with PNC are identifiable on cytologic smears and are sufficiently distinctive to allow a cytologic diagnosis of CMVPTC.     

Diagnostic value of qualitative and quantitative variables in thyroid lesions

Two hundred and thirty-three thyroid lesions were studied by fine needle aspiration (FNA) cytology using standard cytologic criteria available in the literature. These included 114 cases of nodular colloid goitre (NCG), 47 cases of Hashimoto's thyroiditis (HT), 12 follicular adenomas (FAd), five cases of subacute thyroiditis and three cases of thyrotoxicosis among the benign lesions. The malignant lesions seen were 30 cases of papillary carcinoma (PCa), 16 follicular carcinomas (FCa), three cases with double lesions, e.g. papillary carcinoma with coexisting NCG, and three of papillary carcinoma with HT. Emphasis was given to eight qualitative and quantitative (morphometric) variables in these various thyroid lesions. Cell measurements were done using a Visopan Lux projection microscope. The three qualitative variables included type of nuclear membrane (regular/irregular), type of nuclear chromatin and the presence or absence of conspicuous nucleoli. The quantitative variables studied were nuclear diameter, nuclear area, cytoplasmic diameter, cytoplasmic area & N/C ratio. Statistical analysis was performed in order to know whether the standard cytologic criteria used at FNA cytology in the literature (increased cellularity, microfollicles, increased N/C ratio, absence of significant haemosiderin-laden macrophages and scanty colloid) could differentiate a follicular adenoma from a follicular carcinoma. A statistical analysis was also performed to establish the utility of the qualitative and quantitative variables. The results showed that none of the standard cytologic criteria applied could differentiate follicular adenoma from a follicular carcinoma. With regard to qualitative variables, irregularity of nuclear membrane and presence of conspicuous nucleoli were most significant in papillary carcinoma, followed by follicular carcinoma, then by follicular adenoma; these features being hardly evident in nodular colloid goitre and Hashimoto's thyroiditis. A coarse nuclear chromatin was most significant in follicular carcinomas followed by follicular adenomas. It was less obvious in the benign conditions, but more prominent in Hashimoto's thyroiditis compared with a goitre. It was also not obvious in a papillary carcinoma. Of the quantitative variables, all measurements were greatest in PCa > FCa > FAd > NCG = HT. When differentiating follicular adenoma from follicular carcinoma the qualitative variables of significance were the presence or absence of nucleoli, the chromatin pattern and regularity/irregularity of nuclear membrane; the nuclear area was the most important feature among quantitative variables.     

Columnar cell variant of papillary thyroid carcinoma. Report of a case with cytologic findings

BACKGROUND: The columnar and tall cell variants of papillary thyroid carcinoma (PTC) are uncommon variants and have generally been regarded as more aggressive forms in comparison to the more common classic papillary and follicular subtypes. Cytologic diagnosis of these rare variants is elusive since the characteristic nuclear features of the usual papillary thyroid carcinoma are very often absent or inconspicuous. We present a case of the columnar cell variant of PTC in a young woman that demonstrates the diagnostic challenge. CASE: A 24-year-old woman presented with a solitary, 3-cm mass in the left aspect of the thyroid. The aspirate consisted of a moderately cellular sampling of sheets, papillary clusters and microfollicles of cells with oval nuclei and uniform, finely granular chromatin. These cells were arranged in a peudostratified manner around well-defined fibrovascular cores. There were no intranuclear inclusions or well-defined nuclear grooves in the cells of the aspirate. There was also absence of colloid despite the presence of well-formed follicles. The resected thyroid revealed a columnar cell variant of PTC. CONCLUSION: The cytologic features of columnar cell-type PTC are at variance with those of classic PTC and are elusive in fine needle aspiration cytology. It is the lack of classic cytologic features of PTC that is distinctly apparent, yet it is the monomorphism of cells in the aspirate, their papillary configuration and their pseudostratification in well-formed fibrovascular cores that are the keys to the diagnosis. Immunohistochemical staining to rule out other thyroid neoplasms can be performed to aid in the diagnosis.     

Nuclear grooves in the aspiration cytology of papillary carcinoma of the thyroid

Nuclear grooving has recently been shown to be a useful morphologic feature in the diagnosis of papillary carcinoma of the thyroid in tissue sections and imprint smears. In order to assess the diagnostic value of nuclear grooving in cytologic specimens, the presence of this feature was evaluated in fine needle aspirates from 20 papillary carcinomas of the thyroid, 10 follicular adenomas, 3 follicular carcinomas, 1 medullary carcinoma, 10 nodular goiters and 4 cases of Hashimoto's thyroiditis. In each case, 30 random high-power fields (HPFs), or all fields in less cellular smears, were examined, and the percentage of the fields in which nuclear grooving could be seen was recorded. Seventeen of 20 papillary carcinomas (85%) showed nuclear grooves in more than 25% of the HPFs examined; in the remaining three cases, grooves were observed in less than 25% of the HPFs. In control cases (all other thyroid lesions), nuclear grooves either were absent or were present in less than 25% of the HPFs examined. These findings suggest that nuclear grooving, when seen in abundance, can be considered a reliable criterion for the diagnosis of papillary carcinoma in fine needle aspiration cytology of the thyroid. The presence of occasional grooves, however, should be regarded as a nonspecific finding.     

Fine needle aspiration cytology of follicular variant of papillary carcinoma of the thyroid: Morphologic pointers to its diagnosis

OBJECTIVE: To study the cytomorphologic features of 59 cases of histologically proven follicular variant of papillary carcinoma (FVPC), compare them to those described in the literature and highlight cytologic features that may aid in the preoperative diagnosis. STUDY DESIGN: Aspiration smears from 59 histologically proven cases of FVPC were examined independently by 2 observers, and a detailed cytologic evaluation was done for architectural, cytologic and nuclear features. surgical RESULTS: On initial cytology of the 59 cases, 36 (61%) were diagnosed aspapillary carcinoma, and 17 of these were subtyped as FVPC. On reviewing the smears, 50 cases were diagnosed as papillary carcinoma, and 33 of them were typed as FVPC; however, 4 cases were diagnosed as benign lesions. Most smears showed moderate to high cellularity, with 55 cases (93%) showing syncytial clusters and 48 (81%) showing microfollicular architecture. Chromatin clearing and nuclear grooves were seen in 55 (93.2%) and 54 (91.52%) cases but were easily detected in only 36 (61%) and 44 (74%) cases, respectively. Thick colloid was identified in 28 cases, and 3 of these cases also showed thin colloid in the background. CONCLUSION: Our findings suggest that syncytial clusters, microfollicular architecture, chromatin clearing and nuclear grooves are strong morphologic pointers to the diagnosis of FVPC.     

A low-power, "architectural," clue to the follicular variant of papillary thyroid adenocarcinoma in aspiration biopsy

OBJECTIVE: To search for low-power, or "architectural," clues to the diagnosis of the follicular variant of papillary thyroid adenocarcinoma (FVP) in Diff-Quik-stained aspiration biopsy smears in order to aid in the rapid diagnosis of FVP, especially as a complement to frozen sections. STUDY DESIGN: The smears of 23 cases, each with tissue-proven FVP, were compared to those of 23 cases of classic papillary thyroid adenocarcinoma (PTA), 23 cases of tissue-proven follicular neoplasms (FN) (i.e., adenoma or well-differentiated adenocarcinoma) and 23 samples of colloid nodules (CN). The low-power (10x) features of the four groups were studied and compared. RESULTS: Our study showed that FVP exhibited monolayered cellular sheets with branched, irregular contours, which can be distinguished from the uniform microfollicles with smooth contours formed in FN and the large, round or oval monolayered sheets of follicular cells found in CN. FVP shared all of the features of classic PTA except for the larger, complex sheets of epithelial cells and psammoma bodies found in the latter. CONCLUSION: The branched sheets of epithelial cells evident during low-power examination of Diff-Quick-stained smears of thyroid aspirates are a ready first clue to the rapid diagnosis of FVP. The diagnosis can be confirmed by subsequent careful evaluation of nuclei in Papanicolaou-stained smears and sections of tissue.     

Distinction between colloid nodules and follicular neoplasms of the thyroid. Further observations on cell blocks

The differentiation between colloid nodules and follicular neoplasms may be difficult in lesions yielding only microfollicles by fine needle aspiration (FNA). In a retrospective study of 35 follicular lesions, the FNA smears and cell blocks and the excised specimens were reviewed for possible distinguishing features. Columnar cells lining follicles and prominent sinusoidal stroma were seen only in follicular neoplasms; these were more easily appreciated in the cell blocks. Nuclear features and fibrosis were not helpful because they were found in both groups of lesions. Attention to the nuclear morphology was important, however, for the diagnosis of the follicular variant of papillary carcinoma. A repeat FNA might be helpful in obtaining hyperplastic papillae and fragments of dilated follicles for a diagnosis of colloid nodule in half of the cases. A few lesions with predominant microfollicular patterns were even problematic to diagnose on the excised specimens.     

Benign follicular thyroid lesions versus follicular variant of papillary carcinoma: differentiation by architectural pattern

Differentiation between benign and malignant follicular lesions is one of the difficult diagnostic areas in thyroid fine needle aspiration (FNA). Nuclear criteria are usually used to distinguish between them. In this study the microarchitectural pattern of common benign follicular lesions, namely nodular hyperplasia (NH) and follicular adenoma (FA) were analysed in comparison with those of follicular variant of papillary carcinoma (FVPC) in order to aid in their differentiation. The FNA smears of histologically proven cases of FVPC, NH and FA were reviewed and compared. The microarchitectural features of FVPC, NH and FA were described. Three cytological features--multi-layered rosettes, branching monolayered sheets and balls of thick pinkish colloid--were exclusively observed in FVPC. Hyperplastic papillae with intact follicles and colloid were frequently seen in NH, 83% and 100%, respectively. Albeit less frequently, they were also noted in FVPC, 25% and 75% of cases, respectively. These overlapping features make the distinction between FVPC and NH sometimes difficult; however, assessing the smears for the specific features of FVPC may help in their differentiation. None of the aforementioned microscopic findings with the exception of the seldom presence of colloid were documented in FA. The crowded clusters of follicular cells were seen both in FA and FVPC; however, they were complex and branching in the latter and round to oval in the former. Finally, smears with good recovery of material are indispensable for the identification of these helpful microarchitectural patterns.     

What if Many Follicular Variant Papillary Thyroid Carcinomas are not Malignant? a Review of Follicular Variant Papillary Thyroid Carcinoma and a Proposal for a New Classification

ObjectivesTo review the relevant literature concerning follicular variant of papillary thyroid carcinoma (FVPTC) with an emphasis on the heterogeneity of this disorder and to propose a new classification for FVPTC on the basis of molecular diagnostics and apply the classification to a typical case.MethodsEnglish-language articles pertaining to FVPTC published between January 1990 and December 2010 were reviewed.ResultsFVPTC is particularly vexing. The criteria for diagnosing FVPTC appear to have changed over the years. Pathologists often disagree about the diagnosis of FVPTC. The clinical behavior of these tumors is variable. Molecular diagnostic studies suggest that FVPTC represents a heterogeneous group of disorders rather than a single entity.ConclusionsOn the basis of the available data, it is proposed that individual cases of FVPTC be reclassified as papillary thyroid carcinoma, follicular thyroid carcinoma, or follicular adenomas, after appropriate molecularbiologic studies have been completed. Long-term followup studies to validate this classification are necessary. (Endocr Pract. 2011;17:768-787)     

Morphometric image analysis of follicular lesions of the thyroid

OBJECTIVE: To determine the role of image morphometry in distinguishing various follicular lesions of the thyroid in cytologic smears. STUDY DESIGN: Archival fine needle aspiration smears of 10 cases each of follicular hyperplasia, follicular adenoma, follicular carcinoma and follicular variant of papillary carcinoma were used for the study. All cases were histopathologically proven. At least 100 random nuclei from each case were subjected to analysis with an image cytometer. Area, convex area, length, width, perimeter, convex perimeter and roundness of nuclei were measured using a 40 x objective (1 pixel = 0.446 micron). RESULTS: ANOVA showed that all the nuclear variables studied were significantly different (P < .05) in follicular hyperplasia as compared to follicular carcinoma and papillary carcinoma. All nuclear variables except roundness were also significantly different (P < .05) between follicular hyperplasia and follicular adenoma. However, between follicular adenoma, follicular carcinoma and papillary carcinoma there was considerable overlap of nuclear morphometric parameters. CONCLUSION: Image morphometry may help to distinguish nonneoplastic follicular lesions (hyperplasia) from neoplastic lesions (adenomas and carcinomas). However, to distinguish benign from malignant follicular lesions, image morphometry might not improve the accuracy of standard cytologic examination.     

Aspiration cytology of the oncocytic variant of papillary adenocarcinoma of the thyroid gland

OBJECTIVE: To study the cytologic features of the oncocytic variant of papillary adenocarcinoma of the thyroid gland to distinguish this subtype from other oncocytic lesions of the thyroid. STUDY DESIGN: We reviewed the smears from aspiration biopsies of 6 proven cases of oncocytic variant of papillary adenocarcinoma and compared their cytologic features with smears from 19 oncocytic follicular neoplasms (11 adenocarcinomas and 8 adenomas). Smears were stained with a modified Giemsa stain (Diff-Quik). RESULTS: All smears were cellular. Colloid was variable but more abundant in cases of the oncocytic variant of papillary adenocarcinoma. The cells in papillary adenocarcinoma had round to ovoid, overlapped nuclei; prominent intranuclear inclusions; and "grooves." Nucleoli were generally absent. In oncocytic follicular neoplasms, the cells had round nuclei and prominent nucleoli. Nuclear inclusions and grooves were seen but were not as prevalent as in papillary adenocarcinomas. CONCLUSION: The oncocytic variant of papillary adenocarcinoma of the thyroid gland can be distinguished from other oncocytic lesions by fine needle aspiration biopsy, whereas the absence of prominent nucleoli in oncocytes favors the diagnosis of an oncocytic papillary adenocarcinoma.     

Fine needle aspiration cytology in a case of diffuse sclerosing carcinoma of the thyroid

The fine needle aspiration (FNA) cytologic findings in a rare case of bilateral diffuse sclerosing carcinoma of the thyroid are described. Along with a generally papillary architecture, the FNA biopsy smears showed a number of features not usually seen in thyroid carcinomas: psammoma bodies, an abundance of squamous metaplasia and a dense inflammatory component. The FNA diagnosis was multifocal papillary carcinoma with squamous metaplasia; histopathologic examination made the final diagnosis.     

Cytologic features of hyalinizing trabecular adenoma of the thyroid

OBJECTIVE: To clarify the cytologic findings of hyalinizing trabecular adenoma (HTA) in order to reduce erroneous diagnoses of papillary carcinoma. STUDY DESIGN: Review of aspiration cytologic smears of 16 HTA cases and comparison with those of 20 papillary carcinoma cases. RESULTS: The smears from HTA were slightly cellular, and 5 of 16 cases were insufficient for evaluation. Vague, curved nuclear palisading, radiating arrangement surrounding hyaline materials and yellow bodies were observed in 9 (81.8%) of 11 cases that had sufficient material. The tumor cells were mainly spindled; elongated, polygonal and stellate cells were also seen. In 9 of 11 cases, tumor cells with cytoplasmic processes were occasionally observed. The cytoplasm was faintly stained and somewhat filamentous. The cell border was indistinct. Neither papillary nor follicular structures were seen. Intranuclear cytoplasmic inclusions were identified in 100% of HTA and 75% of papillary carcinomas. The incidences of nuclear grooves in HTA and papillary carcinoma were 81.8% and 100%, respectively. CONCLUSION: Cytologic findings indicating HTA are vague, curved nuclear palsiading; radiating arrangement surrounding hyaline material; elongated cells; cell processes; ill-defined cell border; faintly stained and filamentous cytoplasm; yellow bodies; and hyaline material in the background. All are useful cytologic characteristics in distinguishing HTA from papillary carcinoma. A lack of papillary architecture and sheetlike arrangement may also suggest HTA rather than papillary carcinoma.     

Expression of CD44 and cyclin D1 in fine needle aspiration cytology of papillary thyroid carcinoma

OBJECTIVE: To compare the expression pattern of CD44 and cyclin D1 immunostaining in fine needle aspiration specimens of papillary carcinoma of the thyroid and nonpapillary lesions. STUDY DESIGN: The study was performed on 80 fine needle aspiration cytologic smears of thyroid lesion retrospectively using monoclonal antibodies and on histologic material from a proportion of cases. RESULTS: Most papillary carcinomas expressed intense cell membrane or diffuse cytoplasmic staining for CD44 (97.8%). Focal immunoreactivity was observed in follicular neoplasms (28.5%) and nodular goiter (4.7%). There was no difference in CD44 immunostaining between follicular carcinoma and adenoma. Cyclin D1 was expressed in the nuclei of most papillary carcinomas (79.2%). Focal nuclear immunoreactivity was noted in nodular goiters (23.5%) and follicular neoplasms (10%). In resected specimens, all papillary carcinomas (19 cases) showed intense membranous or granular CD44 immunoreactivity. Focal cyclin D1 expression was noted in 52.6%. There was no difference in CD44 and cyclin D1 expression between the group of papillary carcinomas with regional lymph node metastasis as compared to those without metastasis. Positive staining for both CD44 and cyclin D1 would strongly favor papillary carcinoma, although further studies on cytologic material are necessary to verify this diagnostic approach. CONCLUSION: Most papillary carcinomas express CD44 and cyclin D1, whereas it is less common in follicular neoplasms and nodular goiter. This may be helpful in diagnostically difficult cases.     

Follicular variant of papillary thyroid carcinoma – a cytological study

The cytological diagnosis of classical papillary carcinoma is easily established based on the characteristic architectural and nuclear features. However, the follicular variant of papillary thyroid carcinoma(FVPTC) poses a diagnostic challenge. In this study we analysed the cytological features of 14 histopathologically proven cases of FVPTC. We inferred that a combination of architectural features such as follicles and syncytial clusters and nuclear features, viz grooves, pseudoinclusions and enlarged nuclei with fine chromatin, were helpful in establishing the diagnosis. It is hence suggested that based on the combination of the aforesaid features a diagnosis of FVPTC be offered whenever it is possible. This helps in patient management, obviating the need for a second surgical intervention.     

Intranuclear vacuoles in nonpapillary carcinoma of the thyroid. A report of three cases

Three cases of nonpapillary carcinoma of the thyroid are reported in which intranuclear vacuoles or (pseudo)inclusions were observed in fine needle aspiration smears. Two of the cases had medullary carcinoma; one had a poorly differentiated follicular carcinoma. The cytologic, histologic and ultrastructural appearances of intranuclear vacuoles and of the so-called ground-glass nuclei of papillary carcinoma are described, and the diagnostic significance of these findings is discussed briefly. Intranuclear vacuoles are distinct and different from ground-glass nuclei.     

Cytopathology of papillary carcinoma of the thyroid by fine needle aspiration

To delineate the cytologic presentation of papillary carcinoma of the thyroid, the fine needle aspiration smears were studied from 87 surgically proven cases. Six diagnostically useful findings were identified: papillary fronds, monolayered sheets, tissue fragments, intranuclear cytoplasmic inclusions, psammoma bodies and multinucleated giant cells. From 1,500 smears on "cold" nodules of the thyroid, 6 known false-negative and 4 false-positive diagnoses for papillary carcinoma were made. The estimated accuracy of the fine needle aspirate diagnosis of papillary carcinoma is 94%.     

Fine-needle aspiration of mucin-producing thyroid tumors

Objective: Mucin-producing thyroid tumors are extremely rare. Nonetheless, we have encountered three such cases in fine-needle aspiration. We report the cytologic and histologic findings and review the literature. Study Design: Cytologic features were studied on direct smears using Romanovsky stain to detect background substance and Papanicolaou stain to analyze nuclear and cytoplasmic features. The cytologic features were correlated with histology. Mucin was demonstrated by mucicarmine, Alcian Blue/PAS, and Alcian Blue (pH 2.5). Results: The cytologic features related to mucin include: (1) thick luminal mucin globules and signet ring cells aspirated from an 83-year-old woman with a 3-cm signet ring cell follicular adenoma, (2) abundant fluffy mucin containing signet ring cells in cohesive fragments aspirated from a 75-year-old man with the bilateral signet ring cell follicular variant of papillary carcinoma, which is the first case in the English literature, and (3) abundant thin mucoid mucin aspirated from the lymph node of an 86-year-old woman with a 5-cm mucinous poorly differentiated thyroid carcinoma. Conclusion: The occurrence of mucin in thyroid fine-needle aspiration does not necessarily indicate metastasis, and the presence of mucin in cervical lymph nodes does not exclude the thyroid gland as a possible primary.     

Adenoid cystic pattern in follicular variant of papillary thyroid carcinoma: a report of four cases

S. Mandal, and S. Jain
Adenoid cystic pattern in follicular variant of papillary thyroid carcinoma: a report of four cases Objective: An adenoid cystic pattern in thyroid tumours is a rare finding that may be seen in papillary carcinoma of thyroid (PCT), the follicular variant of PCT (FV‐PCT), a rare cribriform‐morular variant of papillary carcinoma of thyroid (CMV‐PCT) and follicular carcinoma. There is little published cytological literature describing these patterns. We report four cases of PCT with this unusual pattern. Methods: Fine needle aspiration (FNA) cytology was performed on four patients with a neck lump using a 22‐G needle; smears were stained with Giemsa and Papanicolaou stains. Immunocytochemical staining for thyroglobulin was done in all cases. Results: The patients were female and ranged in age from 18 to 46 years. They presented with a gradually increasing mass in the neck. FNA smears in all cases showed nuclear features of PCT. There were also prominent follicular areas with hyaline globules in some of the cell clusters reminiscent of adenoid cystic carcinoma and, in places, morula‐like groups of neoplastic cells were also seen. Immunocytochemistry for thyroglobulin was positive in all cases but negative in the hyaline globules. Conclusions: Adenoid cystic areas with morula‐like groups in PCT are a rare finding. Cytopathologists and clinicians should be aware of these distinct features in thyroid tumours to avoid diagnosing metastatic adenoid cystic carcinoma. It is also important to rule out CMV‐PCT since that variant is mostly associated with familial adenomatous polyposis, although sporadic occurrence is known.