Invasion rather than nuclear features correlates with outcome in encapsulated follicular tumors: further evidence for the reclassification of the encapsulated papillary thyroid carcinoma follicular variant.

The prognosis of the encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) and its relationship to encapsulated follicular carcinoma (EFC) and follicular adenoma (FA) is subject to controversy. All EFVPTCs, EFCs, and FAs identified at a single institution between 1981 and 2003 were analyzed microscopically. A cohort of FAs from a different hospital was also examined. EFVPTCs were subdivided into noninvasive EFVPTC (NIEFVPTC) and invasive EFVPTC (IEFVPTC) displaying capsular/vascular invasion. There were 83 EFVPTCs (57 noninvasive, 26 invasive), 14 EFCs, and 52 FAs. Similar to FA, over a median follow-up of 9.5 years, none of the NIEFVPTCs manifested lymph node metastasis (LNM) or recurred. Furthermore, with a median follow-up of 10.5 years, none of 39 NIEFVPTCs without radioactive iodine therapy recurred. Four (15%) of 26 IEFVPTCs and none of 14 EFCs harbored distant metastasis (P = .29). There was no difference in LNM rate and degree of vascular or capsular invasion between IEFVPTC and EFC (P > .1). All 4 IEFVPTCs with adverse behavior presented with distant metastasis and no LNM. Sixteen percent of IEFVPTCs had poor outcome, whereas there was none in the NIEFVPTCs (P = .007). In conclusion, NIEFVPTC seems to behave similarly to FA, whereas IEFVPTC can metastasize and spread like EFC. Thus, invasion rather than nuclear features drives outcome in encapsulated follicular tumors. Non-IEFVPTC could be treated in a conservative manner sparing patients unnecessary total thyroidectomy and radioactive iodine therapy. The position of the EFVPTC in the classification of thyroid neoplasia should be reconsidered.

DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors.

CONTEXT: Nontoxic multinodular goiter (MNG) is frequently observed in the general population, but little is known about the underlying genetic susceptibility to this disease. Familial cases of MNG have been reported, and published reports describe 5 families that also contain at least 1 individual with a Sertoli-Leydig cell tumor of the ovary (SLCT). Germline mutations in DICER1, a gene that codes for an RNase III endoribonuclease, have been identified in families affected by pleuropulmonary blastoma (PPB), some of whom include cases of MNG and gonadal tumors such as SLCTs. OBJECTIVE: To determine whether familial MNG with or without SLCT in the absence of PPB was associated with mutations in DICER1. DESIGN, SETTING, AND PATIENTS: From September 2009 to September 2010, we screened 53 individuals from 2 MNG and 3 MNG/SLCT families at McGill University for mutations in DICER1. We investigated blood lymphocytes and MNG and SLCT tissue from family members for loss of the wild-type DICER1 allele (loss of heterozygosity), DICER1 expression, and microRNA (miRNA) dysregulation. MAIN OUTCOME MEASURE: Detection of germline DICER1 gene mutations in familial MNG with and without SLCT. RESULTS: We identified and characterized germline DICER1 mutations in 37 individuals from 5 families. Two mutations were predicted to be protein truncating, 2 resulted in in-frame deletions, and 1 was a missense mutation. Molecular analysis of the 3 SLCTs showed no loss of heterozygosity of DICER1, and immunohistochemical analysis in 2 samples showed strong expression of DICER1 in Sertoli cells but weak staining of Leydig cells. miRNA profiling of RNA from lymphoblastoid cell lines from both affected and unaffected members of the familial MNG cases revealed miRNA perturbations in DICER1 mutation carriers. CONCLUSIONS: DICER1 mutations are associated with both familial MNG and MNG with SLCT, independent of PPB. These germline DICER1 mutations are associated with dysregulation of miRNA expression patterns.

Thyroid cancer, thyroiditis and dietary iodine: a review based on the Salta, Argentina model.

Factors that should be considered when studying the effect of dietary iodine in the development of thyroid cancer include pathological criteria, diagnostic techniques, screening programs, radioactive fallout, and standard of medical care in the studied population. In most surveys, papillary carcinoma forms the largest group of thyroid malignancies, both before and after iodine prophylaxis where an increase in the papillary:follicular carcinoma ratio is also noted. Undifferentiated carcinomas decrease after salt prophylaxis. In Salta, Argentina, the increasing incidence of clinically significant papillary thyroid cancer and the decrease of undifferentiated carcinoma after iodine prophylaxis are probably due to better access to health centers and consequent earlier detection of differentiated precursor tumors. Autoimmune focal and diffuse or Hashimoto's thyroiditis are linked to dietary iodine. Pathological studies made in different regions indicate that these types of thyroiditis occur more frequently in areas of iodine sufficiency than in areas of iodine deficiency, and increase after iodine prophylaxis both in non-goitrous and iodine-deficient areas like Salta, Argentina. An increase of lymphocytic thyroiditis could be linked to an increased incidence of primary thyroid lymphoma, and thyroiditis is more commonly associated with papillary carcinoma than with other types of thyroid follicular or C-cell derived carcinomas regardless of iodine intake.

Accuracy of aspiration cytology in thyroid cancer: a study in 1 institution.

OBJECTIVE: To evaluate sensitivity of fine needle aspiration cytology in diagnosing malignancy in histologically proven thyroid cancers. STUDY DESIGN: We analyzed the results of 335 smears from clinically significant and histologically proven primary thyroid cancers obtained from 9,115 aspirates, taking into account the pathologist's experience. RESULTS: The sensitivity for diagnosing thyroid malignancy in general was 88.0% (range, 82.6-97.2% from less to more experienced pathologist, respectively). It was higher for papillary (mean, 91.9%) and medullary (mean, 95.4%) carcinomas than for follicular cancer (mean, 50.0%). Biopsy showed thyroid cancer in 27.4% suspicious (range, 22.9-33.3%), 4.4% indeterminate (range, 1.9-6.6%) and 4.1% negative (range, 0-6.6%) smears. CONCLUSION: The more experienced the pathologist, the higher the sensitivity rate for recognizing thyroid cancer in general and by histologic type on aspirates despite some limitations of the method in identifying follicular carcinoma. We recommend thyroidectomy for patients with positive smears and follow-up for patients with benign, indeterminate and suspicious cytology, provided that the cytologic specimens were reviewed by an experienced pathologist.

Observer variation in the diagnosis of follicular variant of papillary thyroid carcinoma.

The histopathologic diagnosis of follicular variant of papillary thyroid carcinoma (FVPCA) can be difficult. Recent reports have suggested that this neoplasm may be frequently overdiagnosed by pathologists. We examined the observer variation in the diagnosis of FVPCA in 87 tumors by 10 experienced thyroid pathologists. The criteria that the reviewers considered most helpful for making a diagnosis of FVPCA were also assessed. A concordant diagnosis of FVPCA was made by all 10 reviewers with a cumulative frequency of 39%. In this series, 24.1% of the patients had metastatic disease (n = 21). In the cases with metastatic disease, a diagnosis of FVPCA was made by all 10 reviewers with a cumulative frequency of 66.7%, and 7 of the reviewers made a diagnosis of FVPCA with a cumulative frequency of 100%. The most important criteria used to diagnose FVPCA included the presence of cytoplasmic invaginations into the nucleus (pseudo-inclusions), abundant nuclear grooves, and ground glass nuclei. These results suggest that although the diagnosis of FVPCA is variable even among experienced thyroid pathologists, most reviewers agreed on this diagnosis for patients with metastatic disease. The use of well-defined histopathologic features should improve the consistency in diagnosing FVPCA. Since most cases with metastatic disease had obvious invasion, caution should be used in making a diagnosis of FVPCA in the absence of the major histopathologic features or clear-cut invasive growth.

Thyroid implants after surgery and blunt trauma.

The differential diagnosis of thyroid tissue found laterally in the neck includes several conditions: lymph node deposits of thyroid carcinoma, "benign metastatic thyroidosis," detached thyroid nodules, and true ectopic thyroid tissue. We have studied nine cases with thyroid deposits in the soft tissues of the neck that do not conform to these diagnoses. We present evidence that they represent surgical or traumatic implantation of thyroid neoplasms. Eight of the nine cases presented one to 26 years after initial surgery. Adequate information of the operative procedure was available in seven cases, one patient underwent subtotal lobectomy and six subtotal thyroidectomy for a nodular gland. The nodules occurred within the operation field with no evidence that they were within lymph nodes. In six cases, birefringent particles consistent with talc from the earlier operation were found adjacent to the nodules. Three cases showed implants of colloid nodules, three of follicular adenoma, one of oncocytic (Hürthle) cell adenoma and one of follicular carcinoma. In the ninth case, infiltrating thyroid tissue in muscle and fibrous tissue presented 3 years after major blunt trauma to the neck. The tissue resembled that in a disrupted thyroid nodule present in the gland itself and was regarded as traumatically implanted. The observation that surgery or trauma to a nodular thyroid can occasionally lead to multiple subcutaneous thyroid implants has implication for management of thyroid disease. Therapy may be difficult; recurrence followed surgical removal of the nodules in three cases, and radioiodine may be a more effective therapy. Recognition of this entity is important for accurate pathologic diagnosis. It is apparently limited to implantation of tumor. The absence of implantation of normal or hyperplastic thyroid, despite the high frequency of partial thyroidectomy in Graves' disease, has pathobiological implications. These findings also support the generally held view that lobectomy rather than nodulectomy is the operation of choice for a solitary nodule.

Thyroid cancer and thyroiditis in Salta, Argentina: a 40-yr study in relation to iodine prophylaxis.

The natural history of thyroid cancer and thyroiditis in relation to iodine prophylaxis in the region of Salta, Argentina, where goiter is common was investigated over a time span of 40 yr. For analysis of thyroid cancer, the specimens were divided into two periods. The first 15 yr (59 cases), including 5 yr before prophylaxis, was compared with the second 25 yr (182 cases), a period well after salt iodination. Papillary carcinomas formed the largest group of tumors in both periods, with a significant increase in their proportion in the second period (44 vs 60%, chi(2): p < 0.05), while the percentage of follicular and undifferentiated carcinomas decreased and medullary carcinoma remained about the same. The ratio of papillary to follicular carcinoma rose from 1.7:1 in the first period to 3.1:1 in the second. Four thyroid lymphomas of non-Hodgkin's B-cell type occurred in the second period in females over age 50. A severe lymphoid thyroiditis was present in the two cases with assessable background thyroid tissue. The frequency of moderate to severe lymphoid infiltrate in females rose from 2 of 12 (16.6%) in the preprophylaxis period to 34 of 114 (28.0%) in the last 25 yr after prophylaxis. After salt prophylaxis, thyroiditis was more frequent in patients with papillary carcinoma (36.2%) than in those with nonpapillary tumors (14.7%) (chi(2), p < 0.02). These observations indicate that a high dietary intake of iodine may be associated with a high frequency of papillary carcinoma and thyroiditis, and that thyroiditis is more commonly associated with papillary carcinoma than with other thyroid tumors. The occurrence of non-Hodgkin's lymphomas only in the postprophylaxis period may be linked to an increase in thyroiditis.

Pathology of the autonomously functioning (hot) thyroid nodule.

We describe the pathologic findings of 73 clinically and scintigraphically confirmed hot nodules. In general, hot nodules from an unselected group primarily treated by surgery were smaller and the sex ratio was closer to equality compared with the ample female predominance in the referral, pre-, and post-prophylaxis groups. Malignancy was observed in six cases (8.2%) (5 follicular, 1 papillary). Of the 67 benign tumors, 48 (71.6%) were adenomas which showed the cytoarchitectural features of hot nodules described previously, and 19 (28.3%) were less well-differentiated adenomas that included a few oxyphil tumors. Intracolloid oxalate crystals from background thyroid tissue were present in 59 assessable cases (83%) overall, the majority showed more than occasional crystals that had a tendency to increase in number with decreasing morphologic activity of the thyroid epithelium. Thyroglobulin protein and mRNA stainings tended to be more pronounced in cell cytoplasm of the tumors than in background thyroid. This study shows that hot nodules may show a wide morphologic spectrum of follicular neoplasms and can be occasionally malignant. It is inferred from the morphologic and other findings that it is likely that some, if not all, of the primary follicular cancers associated with hyperfunction arise by clonal progression from benign hot nodules. This progression is rare, probably because most hot nodules present with the symptoms of hyperfunction and receive early treatment.

Thyroid multifocal granulomatous folliculitis (palpation thyroiditis): An immunocytochemical study.

We analyzed lymphoid cell populations from thyroid multifocal granulomatous folliculitis (palpation thyroiditis) with a panel of antibodies in order to assess the nature of the immunologic process underlying this otherwise clinically insignificant condition as compared with other specific types of thyroiditis. In general, T lymphocytes predominated over B lymphocytes as shown by the extent of the staining with UCHL-1 (CD45RO or CD3 and L26 (CD20) antibodies, respectively. The ratio of kappa-to-lambda-containing plasma cells was 1.4 to 1. Histiocytes, macrophages, and multinucleate giant cells were all found to stain consistently strongly with KPI (CD68) and, when intraluminal, not infrequently also for thyroglobulin, probaby due to colloid phagocytosis. The differing patterns of light chain restriction observed in multifocal granulomatous folliculitis as compared with Riedel's thyroiditis and Graves disease thyroiditis, for instance, may reflect differences in the nature of the underlying immune response.

Fatal sporadic medullary carcinoma of the thyroid.

Thirteen cases of fatal sporadic medullary carcinoma of the thyroid (MCT) that killed the patient within 1 year after diagnosis were compared with 12 nonfatal MCTs with excellent prognosis. Males predominated in fatal cases whereas the reverse was true in MCTs with good prognosis. The two groups of tumors showed generally similar cytoarchitectural features. Outstanding features of fatal MCTs, as compared with nonfatal ones, included more cellular atypia, less frequent amyloid stroma and calcification, higher mitotic rate, tumor necrosis, and a generally lower proportion of neoplastic cells stained for calcitonin. We believe that the morphological features based on routine histological studies, together with immunohistochemistry, should be reported by the pathologist since they could be useful for the management and follow-up of patients with MCT.