Cytologic findings in the follicular variant of papillary carcinoma of the thyroid.

Fine needle aspirates from 8 thyroid papillary carcinomas, follicular variant, were studied. Histologically the tumors were composed exclusively of follicles (four cases) or an admixture of follicular and trabecular structures (four cases). Follicles were identified in smears from seven cases (87.5%) and sheets reminiscent of a trabecular pattern in one (12.5%). Colloid material presented as intraluminal (one case) or extraluminal, dense, round masses (six cases). Nuclear cytoplasmic inclusions occurred in seven (87.5%) of the cases. All these features have been described for follicular lesions or neoplasia together with occasional nuclear grooves, as occurred in two (25%) of the studied cases. In the other six (75%) cases, a moderate to high proportion of neoplastic cells with nuclear grooves facilitated the diagnosis of papillary carcinoma. Our findings suggest that a careful microscopic search for nuclear grooves should be attempted in aspirates yielding a diagnosis of follicular neoplasia that could otherwise be indistinguishable from the follicular variant of papillary carcinoma of the thyroid.     

Evaluating the diagnostic significance of nuclear grooves in thyroid fine needle aspirates with a semiquantitative approach

OBJECTIVE: To clarify the diagnostic significance of nuclear grooves in thyroid fine needle aspirates, to search for other associated nuclear features and to identify possible diagnostic pitfalls. STUDY DESIGN: In total, 67 fine needle aspiration cases were retrospectively reviewed for selected nuclear features, including grooves, intranuclear cytoplasmic invaginations, enlargement, pleomorphism and status of nucleoli. A semiquantitative method was used to estimate the percentage of nuclear grooves in 5 high-power fields with the most frequent nuclear grooves. RESULTS: Unequivocal intranuclear cytoplasmic invaginations were a specific diagnostic feature of papillary carcinoma. In the absence of intranuclear cytoplasmic invaginations, the presence of > or = 20% nuclear grooves was virtually diagnostic of thyroid neoplasms, predominantly papillary carcinoma. Less than 10% of nuclear grooves virtually eliminated the possibility of papillary carcinoma. However, 10-19% of nuclear grooves may be seen in papillary carcinoma and benign lesions; therefore, such cases fell into the diagnostic category of "atypical cytology" or "indeterminate" cytology. Nuclear enlargement with elongation was a readily identifiable feature usually associated with nuclear grooves. Significant pleomorphism was more commonly seen in papillary carcinoma than in benign lesions. CONCLUSION: A semiquantitative method is helpful when nuclear grooves are encountered in thyroid cytology in the absence of other diagnostic features. It can significantly improve the diagnostic specificity of nuclear grooves for 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.     

Posters. P13 Cytohistological correlation in 212 FNAs of thyroid: analysis of discordant cases

Aim To detect major pitafalls in thyroid FNA and to confirm its in a clinical sensitivity and specificity. Methods A total of 9251 fine needle aspirations biopsy carried out at Bellaria Hospital in Bologna from 1991 to 2000 by a pathologist in the FNA Clinic or by a clinician under ultrasonic guidance using a small needle (25–27 G); at least two passes have been made for each nodule. The specimen was considered satisfactory if at least five groups of follicular cells with at least 10 cells each, were seen. The cytological results were tiered in a four categories classification: inadequate, negative, suspicious and positive. Cyto‐histological correlations were available in 212 cases: 127 benign lesions and 85 malignant lesions. An analysis of false positive cases and false negative cases was performed and discordant case reviewed according to the flowing criteria: architecture, cellularity, colloid, pseudoinclusions, nuclear groovings, chromatin pattern, nuclear membrane, cytoplasm, naked nuclei and lymphocytes. Results Diagnostic distribution in 9251 FNAs from the thyroid: 88.6% negatives, 2.8 suspicious, 2.4% positives and 6.2% inadequates. Specificity was 85.8% and sensitivity was 78.8%. Among the 18 false negative cases eight were papillary microcarcinomas, four papillary carcinomas, five follicular carcinoma and one a Hurtle cell carcinoma. Four false positive cases were found: three reported as papillary carcinomas and one as carcinoma NOS. Review of false positives showed that in three cases the colloid was fluid, in three cases nuclear grooving was rare or absent, in two cases degenerative vacuoles at MGG were interpreted as nuclear inclusions and in three cases benign naked nuclei were present in the background. Review of false negatives confirmed lack of malignant features in 13 (eight papillary microcarcinomas and five follicular carcinomas), five were interpretation errors (three papillary carcinomas, one follicular, one Hurtle cell). Conclusion FNAC of the thyroid is a sensitive and specific method of assessment for thyroid nodules but false negative and false positive cases do occur. Use of all and only few criteria enhances diagnostic accuracy.     

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.     

Nuclear grooves in cytologic preparations. A study of the utility of this feature in the diagnosis of papillary carcinoma

The sensitivity and specificity of nuclear grooves and inclusions for papillary carcinoma was investigated in 32 touch preparations and 69 fine needle aspiration cytologic preparations of the thyroid. Ultrastructurally, these grooves and inclusions are cytoplasmic invaginations into the nucleus. Overall, 100% of the papillary carcinomas contained nuclear grooves while only 70% contained inclusions. Grooves, however, could be seen in 70% of nonpapillary neoplasms and in 56% of nonneoplastic conditions of the thyroid, albeit generally fewer in number and often not as distinct. Inclusions were present in 13% of nonpapillary neoplasms and were absent in nonneoplastic conditions. Some nuclei on cytologic preparations contain lines that are probably artifacts of chromatin alignment and do not represent true nuclear grooves. Since such lines may be indistinguishable from true grooves, grooves should be used cautiously and in conjunction with other criteria in the diagnosis of papillary carcinoma.     

The potential value of the demonstration of thyroglobulin by immunoperoxidase techniques in fine needle aspiration cytology

The peroxidase-antiperoxidase method for the demonstration of thyroglobulin was performed on 30 fine needle aspiration smears. All of the benign thyroid lesions plus the papillary and follicular carcinomas of the thyroid were positive for thyroglobulin. Two cases of metastatic thyroid carcinoma in lymph nodes were also positive. Medullary carcinoma of the thyroid and ten control smears from various other tissues were negative. This proves the sensitivity and the specificity of the method, which may be used in routine cytology and may add to the accuracy of diagnosing metastatic tumors suspected of being of thyroid origin. The intranuclear cytoplasmic vacuoles in papillary carcinoma of the thyroid were negative for thyroglobulin. This unexpected finding is demonstrated, and a possible explanation is offered.     

Nuclear grooves. How specific are they?

OBJECTIVE: To study the significance of nuclear grooves in thyroid and extrathyroid benign and malignant lesions. STUDY DESIGN: In this retrospective study, 26 cases were selected randomly, consisting of papillary carcinoma of the thyroid (7), papillary adenocarcinoma (9), normal cervical smear (5) and benign bronchioalveolar lavage (BAL) (5). In all cases hematoxylin and eosin- and Papanicolaou-stained smears were studied for nuclear grooves. RESULTS: Except for one case of papillary adenocarcinoma, nuclear grooves were discernible in all cases. The highest number of nuclear grooves was seen in normal cervical smears, followed by papillary carcinoma of the thyroid, papillary adenocarcinoma and BAL smears. CONCLUSION: The number of grooves did not correlate with either benign or malignant conditions. These findings cast serious doubt about the diagnostic significance of nuclear grooves. Probably nuclear grooves are nonspecific findings and should be considered only in association with other diagnostic features.     

Computerized morphometric study on fine needle aspirates of cellular follicular lesions of the thyroid

OBJECTIVE: To investigate the value of computerized nuclear morphometry in the differential diagnosis of cellular follicular lesions of the thyroid cytologically diagnosed on fine needle aspiration (FNA) smears. STUDY DESIGN: Sixty cases of FNA thyroid smears were cytologically diagnosed and classified as follows: 30 cases of follicular carcinoma, 20 cases of cellular hyperplastic nodules and 10 cases of follicular adenoma. Using an image analysis system, two morphometric variables, nuclear area and major axis length of the nucleus, were measured for each case. RESULTS: For both nuclear morphometric variables, statistical differences were found between carcinomas and hyperplastic nodules as well as between carcinomas and adenomas. No statistical differences were found between the nuclear variables in either hyperplastic nodules or adenomas. CONCLUSION: The results confirm the aim of our study, to establish nuclear morphometry by computerized image analysis as an additional tool in the differential diagnosis of thyroid follicular lesions cytologically diagnosed on FNA smears.     

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 of follicular variant of papillary carcinoma of thyroid

In this retrospective study, we tried to ascertain the fine needle aspiration cytology (FNAC) features of six histopathologically proven cases of the follicular variant of papillary carcinoma of thyroid (FVPCT). These proven cases were diagnosed from 1998-2000. May-Grunwald-Giemsa and haematoxylin & eosin stained FNAC smears were studied independently by two observers (MP and PD) for detailed cytological features. A comparison of the cytological features was undertaken with those reported in the literature. There were six cases of which only one case was diagnosed as FVPCT while the other five cases were diagnosed as follicular neoplasm (four cases) and neoplasm unclassifiable (one case) on FNAC smears. All these cases showed abundant cellularity with a prominent follicular pattern. No papillae were identified in any of the cases. Syncytial clusters (five cases), nuclear grooves (six cases), nuclear inclusions (one case) and chewing gum colloid (three cases) were noted in variable proportions. We suggest that a differential diagnosis of FVPCT should be considered if the cytology smears show abundant cellularity, syncytial clusters and follicular arrangement along with thick colloid.     

Sensitivity and specificity of fine needle aspiration cytology in the diagnosis of tumors of the thyroid gland

A study of the preoperative fine needle aspiration cytologies in consecutive patients with primary malignant tumors (203 cases) or benign thyroid tumors (217 cases) showed a sensitivity of 0.57 and a specificity of 0.98. The sensitivity of FNA cytology in medullary and undifferentiated carcinomas was 0.82 and 0.84, respectively; none of these were microscopically misdiagnosed. The sensitivity was only 0.58 for papillary carcinomas (excluding occult carcinoma) and 0.42 for follicular carcinoma. Four reasons for these low sensitivities were identified: tumors missed at aspiration, microscopic misinterpretations, diagnoses of cellular atypia and indeterminate diagnoses. Reevaluation of the false diagnoses once more emphasized the problem of distinguishing follicular adenomas from follicular carcinomas. Microscopically undiagnosed papillary carcinomas were either the result of misinterpretations of the characteristic cytomorphologic features or of the smears being misdiagnosed as showing cellular atypia when papillary formations were missing and only one or two of the other cellular criteria were evident. The specificity of FNA cytology of thyroid tumors was found to be high enough to permit surgical intervention after a cytodiagnosis of malignancy.     

Necrotic Debris In Thyroid Aspirates: A Feature of Follicular Carcinoma of the Thyroid

Fine needle aspirates from 44 follicular thyroid tumours (30 adenomas, 14 carcinomas) have been studied. All aspirates contained neoplastic cells in follicular and trabecular arrangements. The individual tumour cells showed varying degrees of anisonucleosis and nuclear pleomorphism. Colloid was scanty or absent from all smears. Granular or filamentous necrotic material was observed in both biopsies and smears from one moderately and two poorly differentiated follicular carcinomas, but in none of the adenomas. This suggests that necrotic debris may be a feature of follicular carcinoma of the thyroid.     

Cytopathology of the tall cell variant of thyroid papillary carcinoma.

The tall cell variant of thyroid papillary carcinoma differs from classic papillary carcinoma in its more aggressive clinical behavior, cell type (columnar amphophilic to oxyphilic) and higher frequency of stromal lymphoid infiltrate. A retrospective study of three such cases was made, with an emphasis given to the utility of fine needle aspiration cytology in their identification. Aspirates revealed papillary fronds and cyanophilic and oxyphilic neoplastic cells with a high proportion of nuclear grooves and cytoplasmic inclusions. These nuclear details allowed a specific diagnosis of papillary carcinoma with oxyphil cells as compared to oxyphilic cell follicular tumors. Smears from two cases showed, in addition, lymphoid cells and multinucleate giant cells. In them a diagnosis of coexisting Hashimoto's disease, granulomatous thyroiditis or inflammatory tumor stroma could not be excluded cytologically.     

Fine needle aspirates of follicular lesions of the thyroid gland. The intermediate-type smear

In order to evaluate fine needle aspirates of thyroid lesions with features intermediate between those of follicular neoplasms and colloid nodules, 38 aspirates in which a definitive diagnosis had not been made were reviewed. On review, ten aspirates were excluded from the "intermediate" category; seven were reclassified as unsatisfactory and one as a cellular colloid nodule. Two papillary carcinomas showed a complex pattern not identified in smears from other lesions; these aspirates were also classified separately for independent evaluation. The remaining 28 aspirates were characterized by syncytial-type tissue fragments with mild nuclear atypia. The association of syncytial-type tissue fragments and orderly sheets and fragments forming a honeycomb pattern in the same aspirate indicated a colloid nodule, though a two-disease process could not be excluded. Of the aspirates containing only syncytial-type tissue fragments, 50% were from adenomas, 25% were from carcinomas, and 25% were from colloid nodules. Criteria to distinguish between the various follicular lesions were not identified in these smears.     

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.     

Ki-67 and AgNOR proliferative markers as diagnostic adjuncts to fine needle aspiration cytology of thyroid follicular lesions

OBJECTIVE: To differentiate hyperplastic nodules (HPN), follicular adenoma (FA) and follicular carcinoma (FCA) of the thyroid by cytomorphologic features combined with argyrophilic nucleolar organizer regions (AgNORs) and Ki-67 proliferative markers on fine needle aspiration cytology. STUDY DESIGN: Cytomorphologic patterns, along with two proliferation markers, Ki-67 and AgNORs, in fine needle aspirates of 123 histologically confirmed cases of thyroid follicular lesions, including 39 hyperplastic nodules, 70 follicular adenomas and 14 cases of follicular carcinomas, were recorded. RESULTS: Mean AgNOR (mAgNOR) counts and Ki-67 labelling index (LI) were consistently higher in FCA in comparison to FA and HPN irrespective of the cytologic patterns in fine needle aspiration smears. Between benign and malignant lesions, an overlap of 1.83% at the cutoff point of 4.0 was observed in cases of mAgNORs, whereas it was 11.09% at a cutoff of 5.0 in cases of Ki-67 LI. CONCLUSION: mAgNOR counting in fine needle aspiration smears is more sensitive, simple and cost effective as compared to Ki-67 LI for differentiating between benign and malignant thyroid follicular neoplasms.     

Solitary nodular goiter. Review of cytomorphologic features in 441 cases.

OBJECTIVE: To study the cytomorphologic features of solitary nodular goiters (SNG). STUDY DESIGN: May-Grünwald-Giemsa-stained smears in 441 SNG diagnosed by ultrasonography and fine needle aspiration (FNA) and found to have optimum cellular material at review were subjected to detailed cytologic assessment. The age of the patients ranged from 11 to 75 years, with a median of 35. Male: female ratio was 69:372. The parameters for cytologic assessment included cellularity, colloid content, acinar formation, papillary formation, intranuclear cytoplasmic inclusions, nuclear grooves, marginal vacuoles, Hürthle cells and various inflammatory cells. Histopathology reports on thyroidectomy specimens were available in 27 cases from two Delhi hospitals. RESULTS: Hyperplastic nodules (68 cases) differed significantly from colloid goiters (269 cases) by having more cases with excessive cellularity, acinar formation and marginal vacuoles (P < .001). There was also a significant difference with respect to papillary formation and moderate-to-excessive colloid content (P < .001). As compared to hyperplastic nodules, neoplasms (60 cases) had a significantly higher number of cases with papillary formation, intranuclear inclusions and nuclear grooves but lower number of cases with marginal vacuoles (P < .01-.001). Among neoplasms, usual papillary carcinoma (19 cases) differed from follicular neoplasms (20 cases) with respect to acinar formation, papillary formation and nuclear grooves (P < .001). A significant difference was also observed with respect to colloid content and nuclear inclusions. Follicular variant of papillary carcinomas (FVPC) (10 cases) emerged as a distinct cytologic entity following review and differed from usual papillary carcinomas in having a higher number of cases with acinar formation, tubular formation and marginal vacuoles (P < .01-.001) and lower number of cases with nuclear grooves (P = .05). FVPC also differed from follicular neoplasms with respect to papillary formation, tubular formation, intranuclear inclusions and nuclear grooves (P < .01-.001). Overall cytohistologic agreement was achieved in 24 of 27 (88.9%) cases. CONCLUSION: Detailed cytologic assessment of FNA smears-in SNG was helpful in highlighting parameters that differentiate between various types of goiters.     

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 biopsy of the thyroid. Differential diagnosis by videoplan image analysis

Fine needle aspiration biopsy of cold thyroid nodules has become increasingly popular in determining neoplastic versus nonneoplastic conditions. The differential diagnosis between follicular adenoma and low-grade follicular carcinoma has not been consistently attainable, however; adenomatous goiter also may present problems in diagnosis, while papillary carcinoma seldom proves to be a difficult diagnosis. Image analysis, utilizing the Videoplan image analysis system, was performed on fine needle aspiration biopsy smears from these four types of nodules. The nuclear area, maximum diameter, minimal diameter and approximation to a circle were determined for 25 randomly selected cells with intact nuclei in each smear. These values were calculated with a range and standard deviation and were graphed for each parameter by case category. Cytoplasmic measurements could not be performed due to the absence of definite cytoplasmic boundaries. There was no significant difference in mean nuclear area between follicular adenoma, follicular carcinoma and adenomatous goiter. Papillary carcinoma was the only lesion to show any difference with this single parameter. The mean of maximum and minimum diameter and approximation to a circle were similar for all the types of thyroid masses examined in this study. The Videoplan image analysis system provided an efficient and accurate means of obtaining the nuclear measurements and calculating the statistics. These data illustrate that a differential diagnosis between follicular adenoma, follicular carcinoma and adenomatous goiter, while difficult by light microscopy, is not aided by image analysis of individual cell nuclei.