At least three genes account for familial papillary thyroid carcinoma: TCO and MNG1 excluded as susceptibility loci from a large Tasmanian family.

Recent studies have mapped two susceptibility loci which appear to account for familial multinodular goitre (MNG1) and a variant of familial papillary thyroid cancer (PTC), with associated multinodular goitre (TCO). A Tasmanian family (Tas1) has been identified with an autosomal dominant form of PTC. This study has examined the MNG1 and TCO loci to determine if they are similarly predisposing the Tas1 family to PTC. Linkage analysis using identical microsatellite markers described in the two previous studies was used to determine the significance of these loci in the Tasmanian family. The resultant LOD scores were sufficiently negative using multipoint parametric analysis to exclude these two loci from involvement in the Tasmanian family. In addition, six candidate genes, RET, TRK, MET, TSHR, APC and PTEN were also excluded as susceptibility genes in Tas1 by using microsatellites that are positioned in or in close proximity to these genes. These results suggest that there are at least three susceptibility genes that predispose families to familial PTC.     

Familial non-medullary thyroid carcinoma (FNMTC): analysis of fPTC/PRN, NMTC1, MNG1 and TCO susceptibility loci and identification of somatic BRAF and RAS mutations

Linkage analysis has identified four familial non-medullary thyroid carcinoma (FNMTC) susceptibility loci: fPTC/PRN (1p13.2-1q22), NMTC1 (2q21), MNG1 (14q32) and TCO (19p13.2). To date, there is no evidence for the involvement of genes from the RAS/RAF signalling pathway in FNMTC. The aim of our study was to evaluate the role of the four susceptibility loci, and RAS/RAF signalling pathway genes, in FNMTC. In total, 8 FNMTC families, and 27 thyroid lesions from family members (22 papillary thyroid carcinomas (PTCs): 11 classic, 10 of the follicular variant and 1 of the mixed variant; 4 follicular thyroid adenomas (FTAs) and 1 nodular goitre (NG)), were evaluated for the involvement of the four susceptibility regions, using linkage and loss of heterozygosity (LOH) analyses. BRAF and H-, N- and K-RAS mutations were also screened in the 27 lesions and patients. Linkage analysis in seven informative families showed no evidence for the involvement of any of the four candidate regions, supporting a genetic heterogeneity for FNMTC. Twenty tumours (74%), of which 18 were PTCs, showed no LOH at the four susceptibility loci. The remaining seven tumours (four PTCs, two FTAs and one NG) showed variable patterns of LOH. Fourteen tumours (52%) had somatic mutations: BRAF-V600E mutation was observed in 9 out of the 22 PTCs (41%); and H-RAS and N-RAS mutations were detected in 5 out of the 22 PTCs (23%). Our data suggest that the four candidate regions are not frequently involved in FNMTC and that the somatic activation of BRAF and RAS plays a role in FNMTC tumourigenesis.     

Genetic heterogeneity in familial nonmedullary thyroid carcinoma: exclusion of linkage to RET, MNG1, and TCO in 56 families. NMTC Consortium.

Epidemiological studies show a very high relative risk for first degree relatives of probands with thyroid cancer. The familial form of nonmedullary thyroid carcinoma (NMTC) gives a more severe phenotype and appears earlier than its sporadic counterpart. Moreover, benign thyroid pathologies are often observed in NMTC kindreds. Little is known about the genetic risk factors of the disease. To study them, an international consortium has been organized at the International Agency for Research on Cancer over the past 2 yr to collect biological samples from NMTC families. The only genes known to be directly involved in susceptibility to NMTC are MNG1 on chromosome 14q32 and TCO on chromosome 19q13.2, previously localized by us and others. In addition to those two genes, the genes for Cowden's syndrome and familial adenomatous polyposis are associated with thyroid cancer, but not as an indicative phenotype. Another important gene in thyroid carcinogenesis is RET, which is mutated in the majority of cases of hereditary medullary thyroid cancer and rearranged in an important fraction of sporadic cases of NMTC. Here we report the result of a linkage analysis performed on the 56 more informative kindreds we have collected through the international consortium. Linkage analysis using both parametric and nonparametric methods excluded MNG1, TCO, and RET as major genes of susceptibility to NMTC and demonstrated that this trait is characterized by genetic heterogeneity.     

A comprehensive analysis of MNG1, TCO1, fPTC, PTEN, TSHR, and TRKA in familial nonmedullary thyroid cancer: confirmation of linkage to TCO1

About 5% of nonmedullary thyroid cancer is familial. These familial nonmedullary thyroid cancer cases are characterized by an earlier age of onset, more aggressive phenotype, and in some families a high propensity to benign thyroid disease. Little is known about the genes conferring predisposition to nonmedullary thyroid cancer. Three loci have been identified through genetic linkage: MNG1 on 14q32, TCO1 on 19p13.2, and fPTC on 1p21. In addition to these putative genes, a number of loci represent candidate familial nonmedullary thyroid cancer predisposition genes by virtue of their involvement in sporadic disease (TRKA), their role in benign disease (TSHR), and because they underlie syndromes with a risk of nonmedullary thyroid cancer (PTEN). To evaluate the roles of MNG1, TCO1, fPTC, PTEN, TSHR, and TRKA in familial nonmedullary thyroid cancer, we have carried out a comprehensive mutation and linkage analysis of these genes in 22 families. One family was linked to chromosome 19q13.2, confirming that TCO1 underlies a subset of familial nonmedullary thyroid cancer. None of the families was linked to MNG1 or fPTC, and there was no evidence to support the roles of PTEN, TSHR, or TRKA. Familial nonmedullary thyroid cancer is an emerging clinical phenotype that is genetically heterogeneous, and none of the currently identified genes accounts for the majority of families.     

CD10 expression is useful in the diagnosis of follicular carcinoma and follicular variant of papillary thyroid carcinoma.

CD10/neutral endopeptidase 24.11(NEP) is a membrane-bound zinc metalloproteinase the expression of which represents a useful tool in the classification and diagnosis of malignant leukemia and lymphoma. Recently, CD10 has been found to be expressed in nonhematopoietic tissues and various types of neoplasms. In this study, we examined CD10 immunostaining in paraffin sections of 70 distinct lesions to investigate whether CD10 is a useful diagnostic marker for thyroid neoplasms. CD10 was not detected in normal thyroid tissue, benign lesions (15 follicular lesions and 15 adenomatous goiters), and pure papillary carcinomas except for follicular variants. In contrast, CD10 was expressed in 8 of 10 (80%) follicular carcinomas and 7 of 9 (77%) follicular variant of papillary thyroid carcinomas. This appears to be the first report on the expression of this member of a newly identified gene family in thyroid tumors. In conclusion, immunohistochemistry of CD10 in paraffin sections is valuable in the classification of thyroid follicular lesions into benign and malignant groups and in the diagnosis of follicular variant of papillary thyroid carcinoma.     

Cribriform variant papillary thyroid cancer: a characteristic of familial adenomatous polyposis.

Inherited cancer syndromes may predispose to more than one type of cancer, and these characteristically develop at an earlier age than their sporadic counterparts. The occurrence in a single individual of multiple, early onset primary cancers may indicate an inherited cancer susceptibility. Familial adenomatous polyposis (FAP), an autosomal, dominantly inherited susceptibility to colorectal adenomas and cancer also predisposes to childhood medulloblastomas and to a specific rare histologic type (cribriform variant) of papillary thyroid cancer. We describe a patient who developed a childhood medulloblastoma of the cerebellum, and subsequently a cribriform papillary thyroid cancer. These cancers predated the diagnosis of FAP in this patient, who was later found to have several relatives with FAP. The adenomatous polyposis coli (APC) mutation delineated in this family was in the region associated with those causing an increased risk of thyroid cancer. We submit that the diagnosis of the cribriform variant of papillary thyroid cancer in a young individual, especially after a previous cancer diagnosis, should alert the physician to the possibility of a diagnosis of FAP.     

A clear cell variant of follicular carcinoma presenting as an autonomously functioning thyroid nodule.

We report a case of an autonomously functioning thyroid nodule (AFTN) that proved to be almost exclusively a clear cell variant of follicular carcinoma. AFTNs are generally felt to be benign lesions with exceptions forming the basis of case reports. Likewise, clear cell tumors of the thyroid are rare. To our knowledge, this combination of two unusual thyroid conditions has not been previously reported. The initial scans of this patient were so characteristic for a degenerating AFTN that attention was first directed toward a very large contralateral lobe. While it is debatable whether all AFTNs should be biopsied, on the basis of this and other cases, it is recommended that AFTNs that contain a central photopenic area on scan be biopsied to be sure that cystic degeneration, a commonly seen phenomenon in larger AFTNs, is indeed present rather than a malignancy.     

An overview of the management of papillary and follicular thyroid carcinoma.

Long-term survival rate for papillary and follicular carcinoma is more than 90%, but this varies considerably among subsets of patients. About 30% of patients, however, develop tumor recurrence, depending on the initial therapy. Two-thirds of the recurrences occur within the first decade after therapy, but the others may appear years later. We found that among patients with recurrent cancer, 30% could not be fully eradicated and another 15% died of disease. Tumor recurred outside the neck in 21% of our patients, most commonly in the lungs (63%), which resulted in death in about half the patients. Mortality rates are lower when recurrences are detected early by radioiodine scans rather than by clinical signs. We believe that the best treatment for most patients with differentiated thyroid carcinoma is near-total thyroidectomy followed by 131I ablation of the thyroid remnant, which in our experience reduces the recurrence rate, improves survival and facilitates follow-up. A long delay in initiating this therapy has an adverse and independent effect on prognosis, more than doubling the 30-year cancer mortality rate. If only partial lobectomy has been performed, it is best to consider completion thyroidectomy for lesions 1 cm or larger because of the high rate of residual carcinoma in the contralateral lobe. Completion thyroidectomy and 131I whole-body scanning allows for the diagnosis and treatment of unrecognized carcinoma and when performed early, results in significantly fewer lymph node and hematogenous recurrences and enhances survival. A large and growing number of studies demonstrates decreased recurrence of papillary carcinoma and decreased disease-specific mortality attributable to 131I therapy. On the basis of our observations and other studies, we believe that an aggressive approach to initial management and follow-up may render nearly 90% of the patients permanently free of disease. Periodic follow-up should be done with whole-body scanning and serum thyroglobulin (Tg) measurements, performed either during thyroid hormone withdrawal or by recombinant human thyrotropin (TSH)-stimulated scanning and Tg measurement. A scheme for follow-up management is presented.     

Synchronous occurrence of a follicular, papillary and medullary thyroid carcinoma in a recurrent goiter

The simultaneous occurrence of different types of thyroid carcinoma in a single patient is an unusual event. We report the case of a 52-year-old man with the history of two previous thyroid operations for benign goiters, who developed a recurrent goiter. The patient was referred to our department for thyroidectomy. In the pathohistological examination the specimen showed a 5 cm follicular carcinoma and a 0.3 cm papillary microcarcinoma in the right lobe as well as a 1.5 cm medullary carcinoma in the left lobe. All tumors were clearly separated from each other, representing the pure entity of each type. Postoperatively, RET germline mutation was ruled out by sequence analysis of peripheral blood leucocytes. Postoperative I-131-radioiodine scan showed multiple lung and liver metastases, while calcitonin was negative. There is no known common cause of these three different tumor types and they developed most independently from each other. The personal history of our patient was interesting in two aspects: (1) he suffered a period of severe staphylococcal sepsis with temporal immunosuppression and (2) he worked for long years as a coremaker in a foundry. This work represented possible long term exposure to inhalative carcinogenous toxins like hydrazine, which caused thyroid parafollicular cell adenomas in an animal model.     

Diffuse sclerosing variant of papillary carcinoma of the thyroid: imaging and cytologic findings.

Diffuse sclerosing variant of papillary thyroid carcinoma (DSPC) is a rare variant of papillary thyroid carcinoma, for which the imaging and cytologic features have not been reported. The aim of this study is to gain better insight into the characteristic imaging and cytologic features of DSPC and to suggest treatment guidelines. We retrospectively analyzed the ultrasonographic and computed tomographic (CT) features in eight patients diagnosed with pathologically proven DSPC between 1996 and 2006. Of these eight patients, five patients underwent preoperative ultrasonography (US)-guided fine-needle aspiration (FNA). All the patients were women, who presented at a relatively young age (mean age: 31.9 years) with large tumors (mean diameter: 5.9 cm) and cervical lymph node metastases. The US features (7/8) of DSPC were heterogeneous echotexture (7/7), solid composition (7/7), ill-defined margins (4/7), scattered microcalcifications having snowstorm appearance (7/7), and various echogenicities. CT findings (6/8) revealed numerous microcalcifications and multiple enlarged nodes in all the patients. Cytological examination showed lymphocytes intermingled with nests of tumor cells, psammoma bodies, and squamous differentiation with typical nuclear features of papillary carcinoma in all. Through the combination of typical imaging findings and careful cytological examination, DSPC can be diagnosed preoperatively, allowing for the aggressive surgical treatment required in treating this disease.     

Factors related to the survival of papillary and follicular thyroid carcinoma patients with distant metastases.

There is limited clinical information comparing presentations and results of treatment of papillary and follicular thyroid carcinoma patients with distant metastases. We retrospectively analyzed data of 1,257 thyroid cancer patients who received their treatment and follow-up at Chang Gung Memorial Hospital. We found 992 patients with papillary carcinoma and 205 patients with follicular thyroid carcinoma. Of these, 68 patients with papillary thyroid carcinoma (6.9%) had distant metastases at the time of diagnosis or during the follow-up period. Of the follicular thyroid carcinoma patients, 69 (33.7%) had distant metastases. Of the 68 patients with papillary carcinoma, only 33 were categorized as stage IV at the time of diagnosis. Nine of the patients were categorized as clinical stage I carcinoma, 10 as stage II, and 16 as stage III. Sixteen patients (23.5%) died during the study period, all but 2 of thyroid cancer. Twelve of the 68 patients were disease-free after treatment. Of the 69 patients with follicular thyroid carcinoma, 58 were categorized as stage IV at the time of diagnosis. Six of the patients were categorized as clinical stage I carcinoma, 2 as stage II, and 3 as stage III at the time of diagnosis; all of these patients deteriorated to stage IV during the follow-up period. Of the 42 patients with follicular thyroid carcinoma involving bone, 24 presented with bone metastases during the initial diagnosis. After treatment, 25 of 69 patients with follicular carcinoma died of follicular carcinoma. Only 3 patients were disease-free after the treatment. In patients with follicular carcinoma, only tumor size was an important prognostic factor. In this study, 8 patients categorized as clinical stages I to III at the time of operation had thyroglobulin (Tg) levels less than 5 ng/mL and developed distant metastases during the follow-up period. In conclusion, at diagnosis a large group of Asian patients with metastatic well-differentiated thyroid cancer was more likely to have follicular than papillary histology, and that, as expected, metastases from follicular cancer were present earlier and more frequently, were more likely to involve bone, were more likely to be associated with mortality, and were linked to tumor size but not gender. Also unlike some other reports, treatment producing a low Tg did not always produce a good outcome. More aggressive surgical procedures may be able to improve outcomes.     

Cribriform-morular variant of papillary thyroid carcinoma: characteristic histologic feature of adenomatous polyposis. A case report

We report the case of a 24-year-old woman with familial adenomatous polyposis and diagnosed with cribriform-morular variant of papillary thyroid carcinoma. Neck ultrasound and computed tomography identified multiple nodules in the thyroid gland and neck lymph nodes. The cytological analysis was compatible with the diagnosis of papillary cancer of the thyroid. Total thyroidectomy with lymph node dissection was performed. The histological analysis established the diagnosis of cribriform-morular variant of papillary thyroid carcinoma. Despite preoperative findings suggesting an aggressive form of thyroid cancer with lymph node involvement, the final diagnosis was a variant of papillary thyroid carcinoma often associated with familial adenomatous polyposis and known to have a good prognosis.     

Relationship between tumor burden and serum thyroglobulin level in patients with papillary and follicular thyroid carcinoma.

Serum thyroglobulin (Tg) is a reliable marker for detecting recurrent and persistent disease during the follow-up of patients with papillary and follicular thyroid carcinoma. The goal of this study was to assess the relationship between the serum Tg level measured after thyroid hormone withdrawal and the tumor mass in thyroid cancer patients who underwent surgery with the use of an intraoperative probe for lymph node metastases with (131)I uptake. Patients were classified into one of three groups according to the Tg level: undetectable (n = 18); 1-10 ng/mL (n = 21); and greater than 10 ng/mL (n = 33). The main clinical characteristics and the extent of the disease at the time of initial treatment were similar in these three groups. Lymph node metastases were found in 13 of the 18 patients with undetectable Tg level. Eight patients had persistent foci of uptake after surgery that were located behind the sterno-clavicular joint in six patients. The number of metastatic lymph nodes and their total surface (in mm(2)) or their total volume (in mm(3)) were significantly linked with serum Tg/thyrotropin [TSH] level (p = 0.002 and p < 0.0001, respectively). For a given metastatic surface or volume, the serum Tg/TSH value was no longer linked with the number of metastatic lymph nodes (p = 0.32), suggesting that the total surface or total volume is the characteristic that best summarizes the influence of the disease on the serum Tg/TSH level. In conclusion, patients with higher serum Tg levels tend to have more extensive disease and should undergo more aggressive treatment modalities. Nevertheless, undetectable serum Tg should not be considered as a reliable criteria to exclude a minimal tumor burden in patients who have already been treated with (131)I.     

Carcinoma of the thyroid with a mixed medullary, papillary, follicular, and undifferentiated pattern

While papillary and follicular thyroid carcinomas are frequently mixed, this is a case of a medullary, papillary, follicular, and undifferentiated carcinoma of the same gland. In addition, all four tumor types were metastatic to regional lymph nodes. The patient described herein did not demonstrate features of the multiple endocrine neoplasia type 2 syndrome. Immunoperoxidase staining for calcitonin and thyroglobulin was positive in the follicular and medullary areas of tumor. Because the embryologic origin of the thyroidal follicular cells is from the endoderm and the origin of the parafollicular cells of the medullary carcinoma is from the ectodermal neural crest, this case seems noteworthy for demonstrating mixed metastatic tumor of composite embryologic origin. Alternatively, this case may represent an extension of what has recently been termed differentiated thyroid carcinoma, intermediate type by Ljungberg and co-workers.