Nonmedullary thyroid cancer (NMTC) comprises thyroid cancers of follicular cell origin and accounts for more than 95% of all thyroid cancer cases (summary by Vriens et al., 2009). The remaining cancers originate from parafollicular cells (medullary thyroid cancer, ... Nonmedullary thyroid cancer (NMTC) comprises thyroid cancers of follicular cell origin and accounts for more than 95% of all thyroid cancer cases (summary by Vriens et al., 2009). The remaining cancers originate from parafollicular cells (medullary thyroid cancer, MTC; 155240). NMTC is classified into 4 groups: papillary, follicular (188470), Hurthle cell (607464), and anaplastic. Approximately 5% of NMTC is hereditary, occurring as a component of a familial cancer syndrome (e.g., familial adenomatous polyposis 175100, Carney complex 160980) or as a primary feature (familial NMTC or FNMTC). Papillary thyroid cancer (PTC) is the most common histologic subtype of FNMTC, accounting for approximately 85% of cases. PTC is characterized by distinctive nuclear alterations including pseudoinclusions, grooves, and chromatin clearing (summary by Bonora et al., 2010). PTCs smaller than 1 cm are referred to as papillary microcarcinomas. These tumors have been identified in up to 35% of individuals at autopsy, suggesting that they may be extremely common although rarely clinically relevant. PTC can also be multifocal but is typically slow-growing with a tendency to spread to lymph nodes and usually has an excellent prognosis.
Lote et al. (1980) identified 2 kindreds with 7 and 4 cases of papillary carcinoma in otherwise healthy, nonirradiated subjects. All grew up in 1 of 2 small fishing villages in northern Norway. The familial cases showed an ... Lote et al. (1980) identified 2 kindreds with 7 and 4 cases of papillary carcinoma in otherwise healthy, nonirradiated subjects. All grew up in 1 of 2 small fishing villages in northern Norway. The familial cases showed an earlier mean age at diagnosis (37.6 years) than did sporadic cases from the same region (52.8 years). Multiple endocrine adenomatosis, Gardner syndrome (175100), and arrhenoblastoma (see 138800) were excluded. Phade et al. (1981) described 3 affected sibs, of normal parents, with discovery of cancer at ages 12, 7, and 20 years. The authors found one other report of familial papillary carcinoma without polyposis coli, in a father and daughter, aged 40 and 12, respectively, at discovery (Lacour et al., 1973). The young age at occurrence and frequent bilateral involvement are characteristic of hereditary cancers. Stoffer et al. (1985, 1986) presented evidence for the existence of a familial form of papillary carcinoma of the thyroid, possibly inherited as an autosomal dominant. Four parents of patients with familial PACT had colon cancer and 5 other family members died of intraabdominal malignancy that was not further defined. Perkel et al. (1988) presented evidence suggesting a familial susceptibility factor in radiation-induced thyroid neoplasms. Grossman et al. (1995) identified 13 families with 30 individuals affected by familial nonmedullary thyroid cancer, which they abbreviated FNMTC. In 14 of these affected individuals whom they personally treated, 13 had multifocal tumors, and 6 of these were bilateral. The incidence of lymph node metastasis was 57%, as was the incidence of local invasion. Recurrences occurred in 7 patients during follow-up. The histologic diagnosis was papillary thyroid carcinoma in 13 of the 14 patients; in 1 patient it was Hurthle cell carcinoma. Takami et al. (1996) identified 34 families in Japan with 72 individuals affected by nonmedullary thyroid cancer: 17 men and 55 women. Pathologic diagnosis was papillary carcinoma in 64 patients, follicular carcinoma in 6, and anaplastic carcinoma in 2. From the findings in their study they concluded that familial nonmedullary thyroid cancer behaves more aggressively than sporadic nonmedullary thyroid cancer. Canzian et al. (1998) noted that families with multiple cases of nonmedullary thyroid cancer had been reported by Lote et al. (1980) and Burgess et al. (1997). FNMTC may represent 3 to 7% of all thyroid tumors. The tumors are usually multifocal, recur more frequently, and show an earlier age at onset than in sporadic cases. These characteristics are well exemplified by familial adenomatous polyposis-associated thyroid carcinoma, which, in addition, has been found to be a distinct morphologic entity, rather than the papillary carcinoma that it had previously been believed to be (Harach et al., 1994).
Sugg et al. (1998) examined the expression of RET/PTC-1, -2, and -3 in human thyroid microcarcinomas and clinically evident PTC to determine its role in early-stage versus developed PTC and to examine the diversity of RET/PTC in multifocal ... Sugg et al. (1998) examined the expression of RET/PTC-1, -2, and -3 in human thyroid microcarcinomas and clinically evident PTC to determine its role in early-stage versus developed PTC and to examine the diversity of RET/PTC in multifocal disease. Thirty-nine occult papillary thyroid microcarcinomas from 21 patients were analyzed. Of the 30 tumors (77%) positive for RET/PTC rearrangements, 12 were positive for RET/PTC1, 3 for RET/PTC2, 6 for RET/PTC3, and 9 for multiple RET/PTC oncogenes. In clinically evident tumors, 47% had RET/PTC rearrangements. Immunohistochemistry demonstrated close correlation with RT-PCR-derived findings. The authors concluded that RET/PTC expression is highly prevalent in microcarcinomas and occurs more frequently than in clinically evident PTC (P less than 0.005). Multifocal disease, identified in 17 of the 21 patients, exhibited identical RET/PTC rearrangements within multiple tumors in only 2 patients; the other 15 patients had diverse rearrangements in individual tumors. The authors inferred that RET/PTC oncogene rearrangements may play a role in early-stage papillary thyroid carcinogenesis, but seem to be less important in determining progression to clinically evident disease. In multifocal disease, the diversity of RET/PTC profiles, in the majority of cases, suggested to Sugg et al. (1998) that individual tumors arise independently in a background of genetic or environmental susceptibility. By RT-PCR, Learoyd et al. (1998) analyzed the 3 main RET/PTC rearrangements and RET tyrosine kinase domain sequence expression in a prospective study of 50 adult PTCs. The genetic findings were correlated with the MACIS clinical prognostic score and with individual clinical parameters. Three of the patients had been exposed to radiation in childhood or adolescence. Four of the PTCs contained RET/PTC1, confirmed by sequencing, and none contained RET/PTC2 or RET/PTC3. The prevalence of RET rearrangements was 8% overall, but in the subgroup of 3 radiation-exposed patients it was 66.6%. Interestingly, RET tyrosine kinase domain mRNA was detectable in 70% of PTCs using RET exon 12/13 primers, and was detectable in 24% of PTCs using RET exon 15/17 primers. RT-PCR for calcitonin and RET extracellular domain, however, was negative. There was no association between the presence or absence of RET/PTC in any patient's tumor and clinical parameters. Learoyd et al. (1998) concluded that RET/PTC1 is the predominant rearrangement in PTCs from adults with a history of external irradiation in childhood. Finn et al. (2003) assessed the prevalence of the common RET chimeric transcripts RET/PTC1 and RET/PTC3 in a group of sporadic PTCs and correlated them with tumor morphology. Thyroid follicular cells were laser capture microdissected from sections of 28 archival PTCs. Total RNA was extracted and analyzed for expression of glyceraldehyde 3-phosphate dehydrogenase (138400), RET/PTC1, and RET/PTC3 using TaqMan PCR. Ret/PTC rearrangements were detected in 60% of PTCs. Specifically, transcripts of RET/PTC1 and RET/PTC3 were detected in 43% and 18% of PTCs, respectively. Ret/PTC3 was detected in only follicular variant subtype (60%) and was not detected in classic PTC. One case of tall cell variant demonstrated chimeric expression of both RET/PTC1 and RET/PTC3 transcripts within the same tumor. A sharp increase in the incidence of pediatric PTC was documented after the Chernobyl power plant explosion. An increased prevalence of rearrangements of the RET protooncogene (RET/PTC rearrangements) had been reported in Belarussian post-Chernobyl papillary carcinomas arising between 1990 and 1995. Thomas et al. (1999) analyzed 67 post-Chernobyl pediatric PTCs arising in 1995 to 1997 for RET/PTC activation; 28 were from Ukraine and 39 were from Belarus. The study, conducted by a combined immunohistochemistry and RT-PCR approach, demonstrated a high frequency (60.7% of the Ukrainian and 51.3% of the Belarussian cases) of RET/PTC activation. A strong correlation was observed between the solid-follicular subtype of PTC and the RET/PTC3 isoform: 19 of 24 (79%) RET/PTC-positive solid-follicular carcinomas harbored a RET/PTC3 rearrangement, whereas only 5 had a RET/PTC1 rearrangement. The authors concluded that these results support the concept that RET/PTC activation played a central role in the pathogenesis of PTCs in both Ukraine and Belarus after the Chernobyl accident. Fenton et al. (2000) examined spontaneous PTC from 33 patients (23 females and 10 males) with a median age of 18 years (range, 6-21 years) and a median follow-up of 3.5 years (range, 0-13.4 years). RET/PTC mutations were identified in 15 tumors (45%), including 8 PTC1 (53%), 2 PTC2 (13%), 2 PTC3 (13%), and 3 (20%) combined PTC mutations (PTC1 and PTC2). This distribution is significantly different from that reported for children with radiation-induced PTC. There was no correlation between the presence or type of RET/PTC mutation and patient age, tumor size, focality, extent of disease at diagnosis, or recurrence. The authors concluded that RET/PTC mutations are (1) common in sporadic childhood PTC, (2) predominantly PTC1, (3) frequently multiple, and (4) of different distribution than that reported for children with radiation-induced PTC. Elisei et al. (2001) evaluated the pattern of RET/PTC activation in thyroid tumors from different groups of patients (exposed or not exposed to radiation, children or adults, with benign or malignant tumors). They studied 154 patients, 65 with benign nodules and 89 with papillary thyroid cancer. In the last group, 25 were Belarus children exposed to the post-Chernobyl radioactive fallout, 17 were Italian adults exposed to external radiotherapy for benign diseases, and 47 were Italian subjects (25 children and 22 adults) with no history of radiation exposure. Among patients with benign thyroid nodules, 21 were Belarus subjects (18 children and 3 adults) exposed to the post-Chernobyl radioactive fallout, 8 were Italian adults exposed to external radiation on the head and neck, and 36 were Italian adults with naturally occurring benign nodules. The overall frequency of RET/PTC rearrangements in papillary thyroid cancer was 55%. The highest frequency was found in post-Chernobyl children and was significantly higher (P = 0.02) than that found in Italian children not exposed to radiation, but not significantly higher than that found in adults exposed to external radiation. No difference of RET/PTC rearrangements was found between samples from irradiated (external x-ray) or nonirradiated adult patients, as well as between children and adults with naturally occurring thyroid cancer. RET/PTC rearrangements were also found in 52.4% of post-Chernobyl benign nodules, in 37.5% of benign nodules exposed to external radiation and in 13.9% of naturally occurring nodules (P = 0.005, between benign post-Chernobyl nodules and naturally occurring nodules). The relative frequency of RET/PTC1 and RET/PTC3 in rearranged benign tumors showed no major difference. The authors concluded that the presence of RET/PTC rearrangements in thyroid tumors is not restricted to the malignant phenotype, is not higher in radiation-induced tumors compared with those naturally occurring, is not different after exposure to radioiodine or external radiation, and is not dependent on young age. Mechler et al. (2001) reported 6 cases of familial PTC associated with lymphocytic thyroiditis in 2 unrelated families. PTC was diagnosed on classic nuclear and architectural criteria, and was bilateral in 5 cases. Architecture was equally distributed between typical PTC and its follicular variant. Lymphocytic thyroiditis was present in variable degrees, including, in 4 cases, oncocytic metaplasia. By use of RT-PCR, Mechler et al. (2001) demonstrated RET/PTC rearrangement in the carcinomatous areas of patients of both families: PTC1 in family 1, PTC3 in family 2, and a RET/PTC rearrangement in nonmalignant thyroid tissue with lymphocytic thyroiditis in family 2. The findings suggested that the molecular event at the origin of the PTCs was particular to each of the studied families, and confirmed that RET protooncogene activating rearrangement is an early event in the thyroid tumorigenic process and that it may occur in association with lymphocytic thyroiditis. Zhu et al. (2006) analyzed 65 papillary carcinomas for RET1/PTC1 and RET/PTC3 using 5 different detection methods. The results suggested that broad variability in the reported prevalence of RET1/PTC arrangement is at least in part a result of the use of different detection methods and tumor genetic heterogeneity.
Kimura et al. (2003) identified a val600-to-glu (V600E; 164757.0001) mutation in the BRAF gene in 28 (35.8%) of 78 cases of PTC; it was not found in any of the other types of differentiated follicular neoplasms arising from ... Kimura et al. (2003) identified a val600-to-glu (V600E; 164757.0001) mutation in the BRAF gene in 28 (35.8%) of 78 cases of PTC; it was not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). RET/PTC mutations and RAS (see 190020) mutations were each identified in 16.4% of PTCs, but there was no overlap in the 3 mutations. Kimura et al. (2003) concluded that thyroid cell transformation to papillary cancer takes place through constitutive activation of effectors along the RET/PTC-RAS-BRAF signaling pathway. Namba et al. (2003) determined the frequency of BRAF mutations in thyroid cancer and their correlation with clinicopathologic parameters. The V600E mutation was found in 4 of 6 cell lines and 51 (24.6%) of 207 thyroid tumors. Examination of 126 patients with papillary thyroid cancer showed that BRAF mutation correlated significantly with distant metastasis (P = 0.033) and clinical stage (P = 0.049). The authors concluded that activating mutation of the BRAF gene could be a potentially useful marker of prognosis of patients with advanced thyroid cancers. Xing et al. (2004) detected the V600E mutation in the BRAF gene in thyroid cytologic specimens from fine-needle aspiration biopsy (FNAB). Prospective analysis showed that 50% of the nodules that proved to be PTCs on surgical histopathology were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were no false-positive findings.
The world's highest incidence of thyroid cancer has been reported among females in New Caledonia, a French overseas territory in the Pacific located between Australia and Fiji. Chua et al. (2000) investigated the prevalence and distribution of RET/PTC ... The world's highest incidence of thyroid cancer has been reported among females in New Caledonia, a French overseas territory in the Pacific located between Australia and Fiji. Chua et al. (2000) investigated the prevalence and distribution of RET/PTC 1, 2, and 3 in papillary thyroid carcinoma from the New Caledonian population and compared the pattern with that of an Australian population. Fresh-frozen and paraffin-embedded papillary carcinomas from 27 New Caledonian and 20 Australian patients were examined for RET rearrangements by RT-PCR with primers flanking the chimeric region, followed by hybridization with radioactive probes. RET/PTC was present in 70% of the New Caledonian and in 85% of the Australian samples. Multiple rearrangements were detected and confirmed by sequencing in 19 cases, 4 of which had 3 types of rearrangements in the same tumor. The authors concluded that this study demonstrates a high prevalence of RET/PTC in New Caledonian and Australian papillary carcinoma. The findings of multiple RET/PTC in the same tumor suggested that some thyroid neoplasms may indeed by polyclonal. Hrafnkelsson et al. (2001) studied the incidence of thyroid cancer in the relatives of Icelandic individuals in whom a diagnosis of nonmedullary thyroid cancer was made in the period 1955 to 1994. They identified 712 cases. The relative risk for thyroid cancer in all relatives was 3.83 for male relatives and 2.08 for female. The risk was highest in the male relatives of male probands (6.52) and lowest in the female relatives of female probands (2.02). For first-degree relatives the risk ratios were 4.10 for male relatives and 1.93 for female relatives. Abubaker et al. (2008) studied the relationship of genetic alterations in the PIK3CA gene with various clinicopathologic characteristics of PTC in a Middle Eastern population. PIK3CA amplification was seen in 265 (53.1%) of 499 PTC cases analyzed, and PIK3CA gene mutations in 4 (1.9%) of 207 PTC. N2-RAS mutations were found in 16 (6%) of 265 PTC, and BRAF mutations in 153 (51.7%) of 296 PTC. NRAS mutations were associated with an early stage and lower incidence of extrathyroidal extension, whereas BRAF mutations were associated with metastasis and poor disease-free survival in PTCs. Abubaker et al. (2008) noted that the frequency of PIK3CA amplification was higher than that observed in Western and Asian populations, and remained higher after the amplification cutoff was raised to 10 or more.