Syndecan-1 expression in thyroid carcinoma: stromal expression followed by epithelial expression is significantly correlated with dedifferentiation

AIM: To investigate the expression of syndecan-1 in thyroid neoplasia. Syndecan-1 is a proteoglycan regulating cell adhesion. Previous studies have demonstrated that decreased expression of syndecan-1 is linked to malignant progression. METHODS AND RESULTS: Syndecan-1 expression in thyroid neoplasia was studied immunohistochemically. Syndecan-1 was expressed in stromal cells as well as neoplastic epithelial cells. Stromal syndecan-1 expression was observed more frequently in papillary carcinomas larger than 10 mm in size than in microcarcinomas and in widely invasive than in minimally invasive follicular carcinomas. Furthermore, poorly differentiated carcinomas showed this phenomenon more than well-differentiated carcinomas, but the expression in undifferentiated carcinomas was similar to that of poorly differentiated carcinomas. Epithelial syndecan-1 expression was more frequently observed in anaplastic (undifferentiated) carcinomas than in papillary and follicular carcinomas. No significant difference in epithelial expression was found between well and poorly differentiated carcinomas, but undifferentiated carcinomas expressed epithelial syndecan-1 more frequently than did poorly differentiated carcinomas. CONCLUSIONS: These results are in contrast to those previously reported for carcinomas at other sites. It is suggested that the role of syndecan-1 in thyroid carcinomas might be unique. Stromal syndecan-1 expression followed by its epithelial expression is significantly related to progression, including dedifferentiation of thyroid carcinoma.     

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.     

Frequency of medullary thyroid carcinoma in an endemic goiter area

A series of 41 poorly differentiated follicular carcinomas of the thyroid gland without histopathological features of medullary or papillary carcinoma and 9 cases of undifferentiated thyroid carcinoma of the small cell type (diagnosed between 1967 and 1983) were investigated immunohistochemically. Two poorly differentiated follicular carcinomas showed a considerable number of calcitonin-positive cells in addition to the weakly thyroglobulin-positive tumor cells. One of these cases revealed several areas with calcitonin-positive tumor cells with additional squamous metaplasia with keratinization. No medullary carcinomas could be demonstrated among the 9 cases previously diagnosed as undifferentiated thyroid carcinomas of the small cell type. From the epidemiological point of view the application of immunohistochemistry does not significantly increase the proportion of medullary carcinomas detected in our endemic goiter area. The incidence of medullary carcinoma remains surprisingly low when compared with nonendemic areas.     

An immunohistochemical analysis of cyclin D1, p53, and p21waf1/cip1 proteins in tumors originating from the follicular epithelium of the thyroid gland

This study aimed at clarifying the factors closely related to the tumor progression of thyroid neoplasms. We examined the immunoreactivity of cyclin D1, p53, and p21waf1/cip1 proteins in 179 thyroid tumors originating from the follicular epithelium using an immunohistochemical technique. Cyclin D1 positivity was frequent in well-differentiated thyroid carcinomas (39/122 cases), but it was rarely seen in follicular adenomas (1/33 cases), (p < 0.05). Positivity for p53 was more frequent in poorly differentiated carcinomas (7/19 cases) and undifferentiated carcinomas (4/5 cases) than in well-differentiated carcinomas (14/122 cases) (p < 0,05, respectively). P21waf1/cip1 positivity was more frequent in well-differentiated thyroid carcinomas (43/122 cases) than in follicular adenomas (4/33 cases) (p < 0.05). Regarding the relationships of these proteins, co-positivity for cyclin D1 and p53 was observed more often in poorly differentiated carcinomas (5/7 cases) than in well-differentiated carcinomas (7/39 cases) (p < 0.05). Most cases with cyclin D1 positivity did not show p21waf1/cip1 expression in poorly differentiated carcinomas (6/7 cases). Three cases examined showed co-positivity of p53 and p21waf1/cip1. Our results suggest that cyclin D1 is invoved in thyroid oncogenesis. Moreover, p53 might be closely related to the development of poorly differentiated carcinomas and undifferentiated carcinomas originating from well-differentiated carcinomas.     

Differential expression of galectin-1 and galectin-3 in thyroid tumors. Potential diagnostic implications.

Carcinoma of the thyroid gland, the most frequently diagnosed endocrine malignancy, is often associated with early regional metastases. With the exception of papillary carcinoma, distinguishing benign from malignant thyroid neoplasms in the absence of metastatic disease is difficult. Recently, the vertebrate lectins galectin-1 and galectin-3 have been implicated in the regulation of cellular growth, differentiation, and malignant transformation of a variety of tissues. To determine whether these galectins have a role in thyroid neoplasia, we analyzed 32 specimens from thyroid malignancies (16 papillary, 7 follicular, 8 medullary carcinomas, and 1 metastasis to lymph node), 10 benign thyroid adenomas, 1 nodular goiter, and 33 specimens from adjacent normal thyroid tissue for the expression of galectin-1 and galectin-3 with immunohistochemical and immunoblotting techniques utilizing anti-galectin antibodies. All thyroid malignancies of epithelial origin (ie, papillary and follicular carcinomas) and a metastatic lymph node from a papillary carcinoma expressed high levels of both galectin-1 and galectin-3. The medullary thyroid carcinomas, which are of parafollicular C cell origin, showed a weaker and variable expression of these galectins. In contrast, neither benign thyroid adenomas nor adjacent normal thyroid tissue expressed galectin-1 or galectin-3. These results suggest that galectin-1 and galectin-3 may be associated with malignant transformation of thyroid epithelium and may potentially serve as markers for distinguishing benign thyroid adenomas from differentiated thyroid carcinomas.     

Hypermethylation of the CDKN2/p16INK4A promotor in thyroid carcinogenesis

Functional inactivation of the p16INK4A gene has been reported to be involved in the development of a variety of human malignancies. In thyroid carcinomas, mutations of the p16INK4A gene or homozygous deletions of the gene locus 9p21 are rare. This study investigated whether p16INK4A promotor methylation is an alternative mechanism for p16INK4A gene inactivation during thyroid carcinogenesis. A methylation-specific polymerase chain reaction protocol was applied. A total of 77 thyroid tumor specimens, including 18 follicular adenomas, 18 follicular carcinomas, 16 papillary carcinomas, 12 poorly differentiated carcinomas, and 13 undifferentiated carcinomas were analyzed longitudinally. In addition, 15 tumor-free thyroid tissues were investigated. The p16INK4A promotor status was compared with p16INK4A protein expression and patient-specific data. p16INK4A promotor hypermethylation was detected in 13% of non-tumorous tissue; in 33% of follicular adenomas; in 44% of papillary carcinomas; in 50% of follicular carcinomas; in 75% of poorly differentiated carcinomas; and in 85% of undifferentiated carcinomas. With the exception of two cases, the p16INK4A protein was lost as a result of promotor hypermethylation. Comparing the methylation status with tumor stage, no correlation was found. However, lymph node and distant metastasis status showed a statistically significant prevalence for the p16INK4A promotor methylation (p = 0.035). There was no association between p16INK4A promotor methylation and age and sex. These results suggest that hypermethylation of the p16INK4A promotor region is a frequent and an early event during thyroid carcinogenesis and is associated with tumor progression and dedifferentiation.     

Cyclooxygenase-2 in normal,hyperplastic and neoplastic follicular cells of the human thyroid gland

This study was undertaken to investigate cyclooxygenase-2 (COX-2) expression in follicular cells of the human thyroid. COX-2 expression was studied immunohistochemically in a total of 174 samples. COX-2 immunoreactivity was confined to the cell cytoplasm with the nuclei remaining unlabelled. COX-2 expression was observed in five cases (17.2%) of normal follicular cells and in one case (16.6%) of solid cell nests. Follicular carcinoma expressed COX-2 more frequently than follicular adenoma (93.4% vs 21.1%) (p0.001). A higher percentage of cases of papillary microcarcinomas up-regulated COX-2 in comparison with all papillary carcinomas (p0.05). However, we could not establish any relationships among COX-2, patients ages or lymph node metastases in papillary carcinomas. COX-2 expression was found in 12 (92.3%) poorly differentiated carcinomas and in 13 (92.8%) undifferentiated carcinomas. We found that COX-2 is not always useful as a marker of malignancy. Our results suggest that COX-2 plays a role in progression of all thyroid carcinomas, but in papillary carcinomas, seems more important only in the early stages. COX-2 expression in the undifferentiated carcinoma deserves special consideration due to its prognosis and to the fact that selective COX-2 inhibitors were found to enhance tumour response to radiation in some studies.     

Immunohistochemical detection of p53 in differentiated, poorly differentiated and undifferentiated carcinomas of the thyroid

In an attempt to find whether or not p53 immunoreactivity in the thyroid gland is restricted to undifferentiated carcinomas and to evaluate the putative prognostic usefulness of its detection, we investigated p53 immunoreactivity in a series of 14 benign thyroid lesions and 65 thyroid carcinomas (12 papillary; six minimally invasive follicular; four widely invasive follicular; 31 poorly differentiated and 12 undifferentiated tumours). Unequivocal nuclear immunostaining for p53 was observed in two widely invasive follicular carcinoma (20.0%), five poorly differentiated carcinomas (16.1%) and in 10 undifferentiated carcinomas (83.3%). The percentage of immunoreactive cells was much smaller in the former groups than in undifferentiated carcinomas. Despite a trend to a more aggressive behaviour of the p53 immunoreactive cases no significant differences in the outcome of patients with positive and negative tumours was found when the comparison was made within each category of carcinomas. We conclude that p53 immunoreactivity can be detected both in undifferentiated carcinomas and in some differentiated and poorly differentiated thyroid carcinomas. Larger series of cases are necessary to evaluate the prognostic usefulness of this finding.     

An Immunohistochemical Analysis of Cyclin D1, p53, and p21 Proteins in Tumors Originating fromthe Follicular Epithelium of the Thyroid Gland*

This study aimed at clarifying the factors closely related to the tumor progression of thyroid neoplasms. We examined the immunoreactivity of cyclin D1, p53, and p21^waf1/cip1 proteins in 179 thyroid tumors originating from the follicular epithelium using an immunohistochemical technique. Cyclin D1 positivity was frequent in well-differentiated thyroid carcinomas (39/122 cases), but it was rarely seen in follicular adenomas (1/33 cases), (p < 0.05). Positivity for p53 was more frequent in poorly differentiated carcinomas (7/19 cases) and undifferentiated carcinomas (4/5 cases) than in well-differentiated carcinomas (14/122 cases) (p < 0,05, respectively). P21^wafl/cip1 positivity was more frequent in well-differentiated thyroid carcinomas (43/122 cases) than in follicular adenomas (4/33 cases) (p < 0.05). Regarding the relationships of these proteins, co-positivity for cyclin D1 and p53 was observed more often in poorly differentiated carcinomas (5/7 cases) than in well-differentiated carcinomas (7/39 cases) (p < 0.05). Most cases with cyclin D1 positivity did not show p21^waf1/cip1 expression in poorly differentiated carcinomas (6/7 cases). Three cases examined showed co-positivity of p53 and p21^waf1/cip1.Our results suggest that cyclin D1 is invoved in thyroid oncogenesis. Moreover, p53 might be closely related to the development of poorly differentiated carcinomas and undifferentiated carcinomas originating from well-differentiated carcinomas.     

Distribution of Leu-7 antigen (HNK-1) in thyroid tumors: its usefulness as a diagnostic marker for follicular and papillary carcinomas.

The reactivity of the anti-Leu-7 monoclonal antibody was tested in 39 neoplastic and nonneoplastic thyroid tissue specimens. These included eight colloid goiters, 14 follicular adenomas, nine papillary carcinomas, five follicular carcinomas, two medullary carcinomas, and one metastatic follicular carcinoma in bone. We observed strong cytoplasmic and/or cell membrane positivity in all follicular and papillary carcinomas, in both primary and metastatic tumors. However, the medullary thyroid carcinomas tested were negative. We also observed weak and only occasional staining with anti-Leu-7 antibody in colloid goiter and follicular adenomas. The staining in the benign thyroid lesions was usually focal, less than 10% of the cells; however, in cases of follicular and papillary carcinomas, both in primary and metastatic tumors, the staining was diffuse and strong. Some of the colloid material in colloid goiters and follicular adenomas showed faint homogenous staining with anti-Leu-7 antibody. Our findings suggest that anti-Leu-7 monoclonal antibody is a marker that may facilitate the differentiation between benign and malignant thyroid lesions, with the exception of medullary carcinoma. In addition, caution should be taken when using this antibody to diagnose metastatic lesions, as other metastatic carcinomas have also been reported to be positive. This antibody should be used in conjunction with a panel of antisera to complement a morphologic diagnosis.     

S-100 protein+ dendritic cells and CD34+ dendritic interstitial cells in thyroid lesions

Dendritic cells (DCs) are antigen-presenting cells and mature from precursor CD34⁺ stromal cells (dendritic interstitial cells [DICs]) or monocytes. The aim of the present study was to gain insight into the local immune response to various thyroid lesions. We investigated, immunohistochemically, the presence of S-100⁺ DCs and CD34⁺ DICs in 13 papillary carcinomas, 10 follicular carcinomas, 7 follicular adenomas, 1 Hurthle cell carcinoma, 1 Hurthle cell adenoma, 2 medullary carcinomas, 6 undifferentiated carcinomas, and 3 nodular goiters. Dense infiltrates of S-100⁺ DCs were noted in the majority of papillary carcinomas (mean: 66.4), while moderate infiltrates were observed in follicular adenomas (mean: 23.3), follicular carcinomas (mean: 23.5), and undifferentiated carcinomas (mean: 31.6). The remaining lesions showed slight infiltrates of scattered DCs. DICs were noted exclusively in neoplastic lesions, specifically at the periphery and within the tumor capsule. The increased number of DCs in papillary carcinomas is possibly correlated with their good prognosis. The specific distribution of DICs suggests a possible contribution to growth regulation of thyroid neoplasms.     

Cytokeratin 19 and galectin-3 immunohistochemistry in the differential diagnosis of solitary thyroid nodules

AIMS: The immunohistochemical expression of cytokeratin 19 (CK 19) and galectin-3 was evaluated in 69 thyroid lesions to assess their potential as markers in the diagnosis and classification of thyroid malignancy. The following were studied: 26 cases of papillary carcinoma, 12 of follicular carcinoma, 20 follicular adenomas, two medullary carcinomas, one anaplastic carcinoma and eight multinodular goitres. METHODS AND RESULTS: Formalin-fixed paraffin-embedded thyroid tissues were stained immunohistochemically for both CK 19 and galectin-3. CK 19 expression was found in all 26 papillary carcinomas, five of 12 follicular carcinomas, two of two medullary carcinomas and one case of anaplastic carcinoma. Only five of 20 follicular adenomas were positive for CK 19, and this was in a focal distribution. Two of eight multinodular goitres stained focally positive. Galectin-3 expression was found in 22 of 26 papillary carcinomas, 12 of 12 follicular carcinomas and one of two cases of medullary carcinoma. Only two of 20 follicular adenomas were positive. Three of eight multinodular goitres showed focal galectin-3 expression. CONCLUSIONS: Our findings suggest that the immunohistochemical localization of CK 19 and of galectin-3 is a useful adjunct to the histopathological diagnosis of a solitary thyroid lesion. The expression of CK 19 favours a diagnosis of papillary carcinoma in all its variant patterns. Galectin-3 may serve as a marker for the recognition of follicular carcinoma, particularly the minimally invasive form.     

Enhanced B-Raf protein expression is independent of V600E mutant status in thyroid carcinomas

BRAF (7q24) encodes a serine/threonine protein kinase, and its expression level varies in different tissues. Although a high prevalence of BRAF mutation has been suggested as an important event in thyroid tumorigenesis, little is known about the expression pattern of B-Raf in the thyroid. Thus, we examined the expression of B-Raf in various neoplastic and nonneoplastic thyroid tissues and compared it with BRAF mutational status. Normal and hyperplastic thyroid tissues showed focal and faint immunoreactivity for B-Raf, especially in cuboidal follicular cells of small follicles. In contrast, diffuse expression of B-Raf was observed in follicular adenomas and well-differentiated carcinomas. The missense point mutation BRAF(V600E) was identified in 42% (13/31 cases) of papillary carcinomas and 33% (5/15 cases) of undifferentiated carcinomas but not in normal thyroid tissues, nodular hyperplasia, follicular adenomas, or follicular carcinomas. The immunohistochemical expression of B-Raf did not correlate with BRAF mutational status. Moreover, Western blotting revealed that B-Raf expression in thyroid carcinoma cell lines was also independent of BRAF mutation. Serum or fibroblast growth factor-1 stimulation further activates ERK1/2 in heterozygous BRAF(V600E)-positive carcinoma cells as well as BRAF(V600E) mutation-negative carcinoma cells. In conclusion, heterogeneous focal expression of wild-type B-Raf in nonneoplastic tissues may play a role in the growth or functional activity of thyroid follicular cells. In contrast, diffuse expression of wild-type and/or mutant B-Raf may be involved in the tumorigenic process resulting in activation of the mitogen-activated protein kinase signaling pathway in cooperation with other genetic abnormalities and activation of ligand-receptor signaling pathways.     

Retinoblastoma expression in thyroid neoplasms.

Retinoblastoma (Rb) mutation in thyroid neoplasia has been identified in a few molecular studies; however, the utility of Rb immunohistochemistry in distinguishing benign and malignant thyroid lesions has not been documented in formalin-fixed, paraffin-embedded tissues. The present study investigated Rb immunohistochemistry in a series of 111 formalin-fixed, paraffin-embedded benign and malignant thyroid lesions. All of the major histologic subtypes were included to detect any heterogeneity in Rb-1 expression that might influence the diagnostic utility of this technique or further elucidate the pathogenesis of thyroid neoplasia among the categories. Altogether, 34 follicular adenomas, 9 follicular carcinomas, 7 Hürthle cell adenomas, 5 Hürthle cell carcinomas, 23 papillary carcinomas (8 of which were follicular variants), 4 insular carcinomas, 4 anaplastic carcinomas, 6 medullary carcinomas, and 19 nodular goiters were analyzed. Avidinbiotin immunohistochemistry was performed using the Dako Rb-1 clone. Pronase digestion was introduced into the epitope retrieval protocol to eliminate false-positive cytoplasmic stainig. Nuclear immunoreactivity was assessed as positive if 10% or more of thyroid epithelial nuclei stained positively, and conversely as negative. The majority of benign non-Hürthle thyroid lesions, whether hyperplastic or neoplastic, retained Rb nuclear immunopositivity in most cells (51 of 53 cases [96%]). Conversely, malignant thyroid neoplasms lacked Rb immunoreactivity in the majority (42 of 51 cases [82%]), including all papillary carcinomas (23 of 23) and almost all follicular carcinomas (8 of 9 [89%]). Virtually all Hürthle cell neoplasms were negative (11 of 12 [92%]), whether benign or malignant. In conclusion, Rb immunohistochemistry can aid in the distinction between benign and malignant thyroid lesions in conjunction with morphology. This seems to be most applicable to the often problematic differentiation between follicular adenoma and the follicular variant of papillary carcinoma (P < .0001; sensitivity and specificity, 100%) or minimally invasive follicular carcinoma (P = .0007; sensitivity, 89%; specificity, 100%).     

Histological and functional correlation of thyroid carcinoma by immunohistochemistry

40 cases of thyroid carcinoma comprising of 22 follicular, 11 papillary, 4 medullary, 2 anaplastic and 1 medullary carcinoma with focal areas of papillary differentiation were selected for this immunohistochemical study for the presence of thyroglobulin, calcitonin and somatostatin. As per the functional classification recommended by Otto L Jungberg, 22 cases were well differentiated, 13 were of intermediate differentiation with 3 poorly differentiated cases. 2 cases of anaplastic carcinoma were negative for all the 3 markers. Correlation between functional classification and histological pattern show 77% of the well differentiated type to be of follicular pattern with the rest consisting of papillary carcinoma. In the intermediate type 38.4% were follicular carcinoma, 15.3% medullary carcinoma and the rest, papillary carcinoma. Poorly differentiated type consisted of 2 medullary carcinomas. Contrary to previous reports, functional differentiation did not always correlate with histological pattern.     

Follicular thyroid neoplasm: clinicopathologic features suggesting malignancy

Thyroid follicular neoplasms are the most common tumors of the thyroid. The criterion for their malignancy is evidence of capsular or vascular invasion, which makes preoperative diagnosis difficult. The poorly differentiated thyroid carcinoma entity was introduced by World Health Organization in its 2004 classification with an incidence still poorly known. We found 356 follicular neoplasms treated between 1990 and 2006. Among these tumor patients, adenomas were more common in women than in men (3.6:1), but carcinomas differed little with respect to gender (1.2:1). All follicular carcinomas (n=39), atypical adenomas (n=6), and oxyphilic adenomas (n=15) were included in the study, as well as 30 consecutive conventional follicular adenomas. Five tumors were reclassified as poorly differentiated follicular thyroid carcinomas, representing 13% of carcinomas in this unselected material. Predictors of malignancy were high proliferation index (PI) by MIB-1 (p<0.001), large tumor size (p<0.001), and old age (p=0.006). High PI was also a marker of worse prognosis in malignant tumors. Oxyphilic tumor cells were more frequent in carcinomas than in adenomas; however, among carcinomas, they were non-prognostic. Probability for malignancy is thus greater in a male patient with a large oxyphilic follicular neoplasm. The PI requires evaluation in all follicular thyroid carcinomas to identify poorly differentiated tumors with worse prognosis.     

Askenazi (Hurtle) cell tumors of the thyroid

Oncocytic adenomas have primarily follicular structure; trabeculas, solid areas, necrosis are rare. They may possess malignant potential as their malignant transformation occurs in 35% cases against 5% in adenomas of follicular cells. Oncocytic follicular carcinomas can be hardly distinguished from oncocytic adenomas. Tumors larger than 4-5 cm in diameter are considered to be malignant. Main difference with adenomas is invasion into the capsule surrounding thyroid or into the vessels. They can be well or poorly differentiated or anaplastic. Oncocytic papillary carcinoma and oncocytic medullary carcinoma are rare. The clinical course of oncocytic tumors is more aggressive than that of tumors from follicular cells. Of key importance in differential diagnosis is electron microscopy (EM) and immunohistochemistry with antimitochondrial antibodies. EM may be also useful in determination of the degree of oncocytic tumors maturation.     

Dipeptidyl aminopeptidase IV in the cytologic diagnosis of thyroid carcinoma

Recently, the demonstration of DAP IV activity in thyroid cells aspirates has been proposed as an useful tool for the diagnosis of malignancy. We have studied the enzymatic activity of DAP IV, using the modified method of Lodja, in a series of 336 selected aspirates of the thyroid gland with the following cytologic diagnosis: 236 nodular hyperplasias, 60 follicular proliferations, eight Hashimoto's thyroiditis, eight Hürthle-cell proliferations, 20 papillary carcinomas, two anaplastic carcinomas, and two medullary carcinomas. The results were subjectively evaluated on the basis of staining intensity and extension in a minimum of 200 cells. Strong-to-moderate enzymatic activity with an extension of more than 40% of the cells were exclusively seen in follicular-cell derived carcinomas (papillary carcinoma, Hürthle-cell carcinoma, and follicular carcinoma). Medullary carcinoma, anaplastic carcinoma, and benign conditions were negative or weakly stained. Cytohistologic correlation in 88 patients operated on showed the following results: 26 nodular hyperplasia (18 nodular hyperplasia and eight follicular adenomas), 36 follicular proliferation (24 nodular hyperplasia, six, adenomas, three papillary carcinomas, three follicular carcinomas), two Hürthle-cell proliferation (one Hürthle-cell adenoma and one Hürthle-cell carcinoma), 20 papillary carcinomas, two medullary carcinomas, and two anaplastic carcinomas. DAP IV staining was moderate to strong and extensive in all malignant tumors initially diagnosed as follicular or Hürthle-cell proliferations. We conclude that DAP IV activity is present in malignant differentiated thyroid tumors of follicular cells (papillary carcinoma, follicular carcinoma, Hürthle-cell carcinoma), but it is identified neither in medullary carcinoma nor in anaplastic carcinoma. Therefore, its usefulness is restricted to the diagnosis of follicular-cell malignancies. Diagn. Cytopathol. 1998;19:4–8. © 1998 Wiley-Liss, Inc.