Familial Nonmedullary Thyroid Carcinoma Patients Research Articles

Identification of P21 (CDKN1A) Activated Kinase 4 as a Susceptibility Gene for Familial Non-Medullary Thyroid Carcinoma.

Background: Familial non-medullary thyroid carcinoma (FNMTC) is a genetically predisposed disease with unclear genetic mechanisms. This makes research on susceptibility genes important for the diagnosis and treatment options. Methods: This study included a five-member family affected by papillary thyroid carcinoma. The candidate genes were identified through whole-exome sequencing and Sanger sequencing in family members, other FNMTC patients, and sporadic non-medullary thyroid carcinoma patients. The pathogenicity of the mutation was predicted using in silico tools. Cell phenotype experiments in vitro and models of lung distant metastasis in vivo were conducted to confirm the characteristics of the mutation. Transcriptome sequencing and mechanistic validation were employed to compare the disparities between PAK4 wild-type (WT) and PAK4 mutant (MUT) cell lines. Results: This mutation alters the protein structure, potentially increasing instability by affecting hydrophobicity, intra-molecular hydrogen bonding, and phosphorylation sites. It specifically promotes phosphorylated PAK4 nuclear translocation and expression in thyroid tissue and cell lines. Compared with the WT cells line, PAK4 I417T demonstrates enhanced proliferation, invasiveness, accelerated cell division, and inhibition of cell apoptosis in vitro. In addition, it exhibits a significant propensity for metastasis in vivo. It activates tumor necrosis factor signaling through increased phosphorylation of PAK4, JNK, NFκB, and c-Jun, unlike the WT that activates it via the PAK4-NFκ-MMP9 axis. In addition, PAK4 MUT protein interacts with matrix metalloproteinase (MMP)3 and regulates MMP3 promoter activity, which is not observed in the WT. Conclusions: Our study identified PAK4: c.T1250C: p.I417T as a potential susceptibility gene for FNMTC. The study concludes that the mutant form of PAK4 exhibits oncogenic function, suggesting its potential as a novel diagnostic molecular marker for FNMTC.

FAMILIAL NON-MEDULLARY THYROID CARCINOMA.

Familial non-medullary thyroid carcinoma (FNMTC) is defined as cancer developing in two or more first-degree relatives if predisposing factors, for example, radiation, are absent. The disease can be either syndromic, when it is a component of complex genetic syndromes, or non-syndromic (95% cases). The genetic basis of non-syndromic FNMTC is unknown; the clinical behavior of tumorsis unclear and, at times, contradictory. To analyze clinical manifestations of FNMTC and compare them with the data for sporadic papillary thyroid carcinomas in patients of the same age groups. We examined 22 patients (a "parents" group and a "children" group) suffering from the non-syndromic FNMTC. For comparison, two groups of sporadic papillary carcinomas patients of the same age were drawn up("adult" and "young"). We analyzed tumor size and frequency of the distributionby the categoryof TNM system, invasiveness, multifocality, metastases to lymph nodes, type and extent of surgical and radioiodine treatment, and prognosis according to the MACIS criterion. Whether sporadic or familial, the tumor size, metastatic potential, and invasive potential are higher in young people, asalready known. There was no significant difference between the "parents" and "adult" groups of patients in terms of tumor parameters. One exception was the higher frequency of multifocal tumors in the FNMTC patients. Meanwhile, compared to the "young" sporadic papillary carcinomas patients, the FNMTC "children" had a higher frequency of T2 tumors, metastasizing (N1a-N1ab), and multifocal tumors, but a lower frequency of carcinomas with intrathyroidal invasions.In the FNMTC "children" compared to FNMTC "parents" was a higher frequency of T2 tumors, metastasizing carcinomas, and tumors with capsular invasion. FNMTC carcinomas are more aggressive than sporadic ones, especially in patients who are first-degree relatives in a family with parents already diagnosed with the disease.

Risk of Second Malignant Neoplasm in Familial Non-Medullary Thyroid Cancer Patients.

IntroductionSurvival rates in patients with non-medullary thyroid carcinoma (NMTC) are high, increasing the possibility to develop a second malignant neoplasm (SMN). Many studies investigated the relationship between increased risk of SMN in NMTC patients treated with radioiodine, but few data are available about the impact of family history (FH) of thyroid cancer on SMN risk.PurposeTo assess the risk of SMN in a large cohort of sporadic and familial NMTC using the standardized incidence ratio (SIR).Patients and methodsWe studied 918 NMTC patients (73.9% female patients) followed for a median follow-up of 9 years. In 798/918 (86.9%) patients, NMTC was sporadic, while the remaining 120 (13.1%) were familial NMTC (FNMTC).ResultsWe identified 119/918 (13%) patients with SMN in association with NMTC. NMTCs had an increased risk of SMN when compared to the general population (SIR 2.1, 95% CI 1.7–2.5). The rate of SMN for all sites was significantly higher in familial compared to sporadic NMTC (20% versus 11.9%, p = 0.01), primarily driven by families with more than two affected members. The risk of SMN was remarkably higher for breast cancer, especially in familial cases (SIR 22.03, 95% CI 14.4–41.2) compared to sporadic cases (SIR:17, 95% CI 11.9–24.6).ConclusionsNMTC patients have a higher risk of SMN compared to the general population and this risk is much higher in patients with FNMTC. This observation raises the hypothesis that genetic risk factors for a first cancer may predispose to SMN, especially among individuals with familial clustering of the same or other tumors.

Comparison Between Clinicopathological Characteristics, BRAF V600E and TERT Promoter Mutation of Familial Non-Medullary Thyroid Carcinomas, and Sporadic Case.

BackgroundIt has been debated whether familial non-medullary thyroid carcinoma (FNMTC) is more aggressive and has a worse prognosis than sporadic non-medullary thyroid carcinoma (SNMTC). Our aim was to compare the invasiveness and prognosis of FNMTC and SNMTC by their biological behavior and molecular changes.Method and MaterialOur group mainly compared 106 patients with FNMTC whom have complete clinicopathological data during 2011–2019 in West China Hospital, Sichuan University, and 212 randomly selected cases with SNMTC were included to compare their biological behavior, recurrence and mortality, and molecular expression of BRAF V600E and TERT promoter. At the same time, FNMTC cases were divided into four subgroups, namely, two affected members group, three or more affected members, parent/offspring group, and sibling group, and they were compared with SNMTC separately to analyze the difference in their invasiveness and prognosis.ResultsWe found that the mean tumor size of FNMTC (0.96 ± 0.53cm) was smaller than that of SNMTC (1.15 ± 0.72 cm) (p = 0.020), while no significant difference in the incidence of other clinicopathological factors, including bilateral growth, capsular invasion, with thyroid nodular goiter or not, multifocality, lymph node metastasis, extrathyroidal extension, iodine 131 treatments, T stage, and American Joint Committee on Cancer (AJCC) stage, was observed between FNMTC and SNMTC (p > 0.05), between each FNMTC subgroup (p > 0.05), and between each FNMTC subgroup and SNMTC (p > 0.05). There was no significant difference in recurrence, mortality, and BRAF V600E and TERT promoter mutation between FNMTC and SNMTC, among which 50/60 (83.33%) of FNMTC patients had BRAF V600E mutation and 1/32 (3.13%) had TERT promoter mutation, while the mutation rates of SNMTC were 93/108 (86.11%) and 3/64 (4.69%) (p > 0.05).ConclusionThere was no significant difference in invasiveness and prognosis between FNMTC and SNMTC by biological behavior, patient survival, and molecular level comparison.

Is Familial Nonmedullary Thyroid Cancer A More Aggressive Type of Thyroid Cancer?

Familial non-medullary thyroid cancer (FNMTC) is a distinct entity, increasingly diagnosed. By lacking an accurate genetic diagnostic test, its diagnosis is currently clinically based, with an ongoing debate over whether it has a more aggressive clinical behavior than sporadic non-medullary thyroid cancer (SNMTC). We seek to compare in this study, the clinicopathological variables, and the outcome of FNMTC versus SNMTC patients. We retrospectively searched a database of 465 patients that underwent thyroidectomy at Assaf Harofeh Medical Center (91.4% between 1990 and 2019) for demographics, risk factors, medical history, diagnostic workup, primary treatment, follow-up, and disease outcome data. We compared 47 FNMTC versus 321 SNMTC patients, and FNMTC patients with ≥2 (n = 34) versus ≥3 (n = 13) first-relative affected members. There were no significant differences in demographics, histopathology, TNM stage, treatment, and disease outcome between the FNMTC and SNMTC groups. The T2 and T4 tumor stage in the ≥3-member group were 25% and 8.3% compared to 0% and 0% in the two-member group (P = .02 and P = ns, respectively). Also, LN involvement was significantly higher in the ≥3-member group (61.6% vs. 24.2%, respectively; P = .036). FNMTC is not a more aggressive disease than SNMTC, but this may not apply for the ≥3-affected-relatives group. A large multicenter study including only families with three or more affected relatives is needed. Until then, a family history of NMTC should not be overlooked. 3/5 Laryngoscope, 131:E677-E681, 2021.

Next generation sequencing technology for susceptible gene screening in familial non-medullary thyroid carcinoma

Objective: To screen genes related to familial non-medullary thyroid carcinoma (FNMTC) using next-generation sequencing (NGS). Methods: A panel of NGS was designed and sequencing was performed for DNA samples extracted from peripheral blood leukocytes of FNMTC patients and sporadic non-medullary thyroid carcinoma (SNMTC) cases, respectively, and gene mutations were screened. In addition, the clinicopathological characteristics, including tumor size, extension of surgery, lymph node metastasis and extra-thyroidal extension, were compared between patients with or without mutations. Results: In 63 NMTC samples, 45 mutations were detected on 13 genes. 37 germline mutations were detected in 47 FNMTC patients, while 8 germline mutations were detected in 16 SNMTC patients. In 8 FNMTC family lineages, the same mutations were carried by FNMTC patients from the same pedigree. The number of carriers of mutations was 29 in the 47 FNMTC patients and 6 in the 16 SNMTC patients, with a non-significant difference (P= 0.092). Among the FNMTC patients, there were 22 patients with central lymph node metastasis in the 29 mutation-positive patients, significantly more than 7 in the 16 mutation-negative cases (P= 0.031). As for the parentage, there were 3 patients with central lymph node involvement among the 7 patients of parent generation, while all the 9 patients of offspring generation had central lymph node metastasis (P=0.019). Conclusions: This panel of NGS can be used to screen mutant susceptibility gene of FNMTC patients, and the findings may be helpful for early detection of FNMTC patients and predicting the disease risk to familial members of FNMTC patients.

Clinical Analysis of Familial Nonmedullary Thyroid Carcinoma.

To analyze the clinical characteristics of familial nonmedullary thyroid carcinoma (FNMTC), in order to provide evidence for early diagnosis and treatment. We retrospectively investigated the inpatients between September 2006 and September 2013 in the First Bethune Hospital of Jilin University, in which 78 patients with FNMTC from 31 families were analyzed by a comparison with 3445 control cases from the patients with sporadic nonmedullary thyroid carcinoma (SNMTC). There was no significant difference in gender, age, and tumor size between FNMTC and SNMTC patients. However, the characteristics of disease in multifoci, neck lymph node metastasis, invasion to the surrounding tissues, and coexistence with Hashimoto disease in two types of cancer patients show significant difference. They are: multifoci: 71.8% (56/78) in FNMTC versus 46.3% (1595/3445) in SNMTC; neck lymph node metastasis: 52.6% (41/78) in FNMTC versus 33.3% (1148/3445) in SNMTC; surrounding tissue invasion: 64.1% (50/78) in FNMTC versus 48.5% (1670/3445) in SNMTC; coexistence with Hashimoto disease: 30.8% (24/78) in FNMTC versus 20.0% (689/3445) in SNMTC. Lymph node metastasis, multifoci, invasion to the surrounding tissues, and combination with chronic lymphocytic thyroiditis are the main features of FNMTC, which suggests the extent of the operation for FNMTC patients should be amplified properly.

Targeted DNA Sequencing Detects Mutations Related to Susceptibility among Familial Non-medullary Thyroid Cancer.

Some studies have demonstrated that familial non-medullary thyroid cancer (FNMTC) has a more aggressive clinical behavior compared to sporadic NMTC (SNMTC). However, FNMTC is difficult to differentiate from SNMTC by the morphology and immunohistochemistry. Although genes responsible for FNMTC were unclear, screening for rare germline mutations on known important tumor suppressor genes might offer more insights on predicting susceptibility to FNMTC. Here, a customized panel was designed to capture all exons of 31 cancer susceptive genes possibly related to FNMTC. Using next-generation sequencing we performed deep sequencing to achieve 500× coverage of the targeted regions. At the end 45 variants were identified in 29 of 47 familial patients and 6 of 16 sporadic patients. Notably, several germline mutations were found matching between paired FNMTC patients from the same family, including APC L292F and A2778S, BRAF D22N, MSH6 G355S and A36V, MSH2 L719F, MEN1 G508D, BRCA1 SS955S, BRCA2 G2508S, and a GNAS inframe insertion. We demonstrated a novel approach to help diagnose and elucidate the genetic cause of the FNMTC patients, and assess whether their family members are exposed to a higher genetic risk. The findings would also provide insights on monitoring the potential second cancers for thyroid cancer patients.

Familial Non-Medullary Thyroid Cancer Represents an Independent Risk Factor for Increased Cancer Aggressiveness: A Retrospective Analysis of 74 Families

To assess whether familial non-medullary thyroid cancer (FNMTC) represents an independent risk factor for increased aggressiveness of the tumor, as concern as the clinical presentation and the long-term follow-up in respect of sporadic differentiated thyroid cancer (SDTC). Retrospective study; 1976-2014. Seventy-four FNMTC families (151 affected individuals): family relationship and number of affected family members were evaluated. Clinical and histopathological features and outcome were compared to that of 643 SDTC patients followed in the same period according to the same institutional protocols. Median follow-up was 57.7 months (range 12-136) in FNMTC and 59.7 (range 15-94.6) in SDTC patients. Three cases occurred in 3 families and 2 cases in the other 71. F:M was 3.7:1 in FNMTC and 4.3:1 in SDTC (NS). The family relationship was siblings in 62.2%. Mean age at diagnosis was lower in FNMTC than in SDTC (p < 0.005). Papillary/follicular histotype distribution was similar (86%). Papillary tumors were more frequently multifocal in FNMTC (p = 0.004) and with lymph-node metastases (p = 0.016). Disease-free survival (DFS) was shorter in FNMTC vs. SDTC (p < 0.0001) with 74.8 vs. 90.8% patients free of disease at the last control (p < 0.005). Three patients died in FNMTC group vs. 1 in SDTC (p = 0.02). Familial non-medullary thyroid cancer displays distinct characteristics as earlier age of onset and increased aggressiveness at diagnosis and a higher rate of persistent/recurrent disease and mortality with a shorter DFS in respect with SDTC. FNMTC patients, therefore, should be followed accurately. As the specific gene (or genes) responsible for susceptibility for FNMTC has not yet been identified, a low frequency periodic screening of relatives DTC patients may be useful to identify FNMTC patients at early stage of disease.

Endocrine tumours: familial nonmedullary thyroid carcinoma is a more aggressive disease: a systematic review and meta-analysis.

There is controversy as to whether familial nonmedullary thyroid carcinoma (FNMTC) is more aggressive than sporadic NMTC (SNMTC). The aim of the study was to evaluate the biological characteristics of patients with FNMTC by a meta-analysis. Four databases (PubMed, EMBASE, the Cochrane library databases, and the Web of Science) were searched to identify studies published before September, 2014. All original studies that compared clinical characteristics and prognosis of patients with FNMTC and SNMTC were included. The pooled effect sizes of interesting parameters were calculated by odds ratio (OR), standard mean difference (SMD), or hazard ratio (HR). Twelve studies with a total of 12 741 participants were included in this analysis. FNMTC patients had an increased rate of recurrence (OR=1.72, 95% CI: 1.34 to 2.20) and decreased disease-free survival (DFS) (HR=1.83, 95% CI: 1.34 to 2.52) in comparison with SNMTC patients. FNMTC possessed more aggressive biological behaviors, characterized by younger age at diagnosis (SMD=-0.91, 95% CI: -1.59 to -0.22), higher risk of multifocal (OR=1.50, 95% CI: 1.32 to 1.71), bilateral (OR=1.29, 95% CI: 1.00 to 1.66), extrathyroidal invasion (OR=1.20, 95% CI: 1.02 to 1.41), and lymph node metastasis (OR=1.18, 95% CI: 1.01 to 1.38). FNMTC is a more aggressive disease and possesses higher recurrence rate and lower DFS. More attention and careful consideration should be paid regarding the decision about treatment for patients with FNMTC.

Clinical and biological features of familial nonmedullary thyroid carcinoma

To analyze the clinical and biological features of familial nonmedullary thyroid carcinoma (FNMTC). Clinical data of 66 FNMTC cases of 32 pedigrees was retrospectively analyzed, compared with that of 182 control cases taken randomly from the patients with sporadic papillary thyroid carcinoma (SPTC), who were diagnosed and treated in Tianjin Cancer Hospital between January 2008 and November 2012. The features of FNMTC of the first and second generations were objectively analyzed. Some data quoted from the literature were also used for the analysis. The median age at diagnosis of all the 66 FNMTC patients was 44 years, and 57 (86.4%) were females. Moreover, 71.2% (47 patients, 23 pedigrees) of the FNMTC patients exhibited a sibling relationship, and 28.8% (19 patients, 9 pedigrees) of the FNMTC patients exhibited a parent-offspring relationship, and 9 cases in the first generation and 10 cases in the second generation. There were significant differences between the FNMTC group and SPTC group in terms of tumor multicentricity, tumor bilaterality, lymph node metastasis, central lymph node metastasis, concomitant chronic thyroiditis and recurrence (P < 0.05). Compared with SPTC, sibling FNMTC presented a higher rate of central lymph node metastasis, while parent-offspring FNMTC showed frequent tumor bilaterality and a higher rate of recurrence (P < 0.05). Besides, patients in the second generation were diagnosed at an earlier age and had a higher male rate, the tumors were more frequently multifocal and bilateral, and had a higher rate of lymph node metastasis. FNMTC may be more aggressive than SPTC and patients in the second generation may exhibit the "anticipation" phenomenon. It's necessary to make sufficient detailed interrogation and long-term follow-up of the patients and their family for providing individual recommendations for clinical management.

Clinical features of familial non-medullary thyroid cancer patients

To analyze the clinical features of familial non-medullary thyroid cancers, and to discuss their management. Sixty thyroid cancer patients with familial non-medullary thyroid cancer (FNMTC) history during Sep. 2003 to Sep. 2012 were collected as study group, and another 60 sporadic thyroid cancer patients were randomly chosen as control. We compared the differences of their clinical features. All the patients were diagnosed as thyroid papillary carcinoma. The study group included 40 female and 20 male patients. There were 16 cases in stage T1, 37 in stage T3, and 7 in stage T4. The patients were 21-66-year old ( median age 42-years). The control group included 49 female and 11 male patients. The patients were 24- to 78-year old, and the median age was 45.5 years. 43.3% of the patients in the study group and 18.3% of the patients in the control group had bilateral carcinomas (P = 0.003). There were multifocal lesions in 53.3% of the patients in the study group and 35.0% of the control group, local invasion in 73.3% of the patients in the study group and 55.0% of the control group, and coexisting benign thyroid diseases in 81.7% of the patients of the study group and 50.0% of the control group (P < 0.05 for all). There were cervical lymph node metastases in 60.0% of the patients in the study group and 38.3% in the control group (P = 0.018). In the study group, 32 cases were of parent-offspring type and 28 cases of sibling type. Among the parent-offspring type patients, the median onset age of the first generation offsprings was 58 years, and that of the second generation offsprings was 32 years (P < 0.001). Familial nonmedullary thyroid cancer, especially in parent-offspring type patients, is more aggressive than sporadic nonmedullary thyroid cancer, and often involves bilateral lobes, has multifocality, and combines with benign thyroid diseases. We recommend a total thyroidectomy for treatment, and to screen all the family members >20 years old, with ultrasonography for early diagnosis and treatment.

GENETIC OF THYROID CANCER FAMILIAL NON MEDULLARY THYROID CANCER

Differentiated non-medullary thyroid cancer (NMTC) is mostly sporadic, but the recurrence of familial form of the disease has been reported. Short or dysfunctional telomeres have been associated with familial benign diseases and familial breast cancer. We aimed to study the telomere-telomerase complex in familial NMTC (FNMTC). The genetic analysis included the measurement in the peripheral blood of relative telomere length (RTL), telomerase reverse transcriptase (hTERT) gene amplification, hTERT mRNA expression, telomerase protein activity and search of hTERT or TERC (telomerase RNA component) gene mutations. We, also, studied telomeric fusions and associations as well as other chromosomal fragility features by conventional and molecular cytogenetic analyses, in phytohemagglutinin stimulated T-lymphocytes from familial patients, unaffected family members, sporadic PTC patients and healthy subjects. We found that, telomere lenght was significantly shorter in the blood of familial patients compared to sporadic PTCs, healthy subjects, nodular goiter and unaffected siblings. hTERT gene amplification was significantly higher in FNMTC patients compared to the other groups and, in particular, it was significantly greater in offspring with respect to parents. hTERT mRNA expression as well as telomerase activity were significantly higher in FNMTC patients compared to sporadic In addition, we demonstrated that familial patients have a significant increase in spontaneous telomeric associations and telomeric fusions compared to healthy subjects and sporadic cases. Q-FISH analysis demonstrated that familial cases display a significant decrease in the telomeric PNA-FISH signal intensity in metaphase chromsome. Our study demonstrates that patients with FNMTC display an imbalance of the telomeretelomerase complex in the peripheral blood.

GENETIC OF THYROID CANCER FAMILIAL NON MEDULLARY THYROID CANCER

Differentiated non-medullary thyroid cancer (NMTC) is mostly sporadic, but the recurrence of familial form of the disease has been reported. Short or dysfunctional telomeres have been associated with familial benign diseases and familial breast cancer. We aimed to study the telomere-telomerase complex in familial NMTC (FNMTC). The genetic analysis included the measurement in the peripheral blood of relative telomere length (RTL), telomerase reverse transcriptase (hTERT) gene amplification, hTERT mRNA expression, telomerase protein activity and search of hTERT or TERC (telomerase RNA component) gene mutations. We, also, studied telomeric fusions and associations as well as other chromosomal fragility features by conventional and molecular cytogenetic analyses, in phytohemagglutinin stimulated T-lymphocytes from familial patients, unaffected family members, sporadic PTC patients and healthy subjects. We found that, telomere lenght was significantly shorter in the blood of familial patients compared to sporadic PTCs, healthy subjects, nodular goiter and unaffected siblings. hTERT gene amplification was significantly higher in FNMTC patients compared to the other groups and, in particular, it was significantly greater in offspring with respect to parents. hTERT mRNA expression as well as telomerase activity were significantly higher in FNMTC patients compared to sporadic In addition, we demonstrated that familial patients have a significant increase in spontaneous telomeric associations and telomeric fusions compared to healthy subjects and sporadic cases. Q-FISH analysis demonstrated that familial cases display a significant decrease in the telomeric PNA-FISH signal intensity in metaphase chromsome. Our study demonstrates that patients with FNMTC display an imbalance of the telomeretelomerase complex in the peripheral blood.

The Long-Term Outcomes of the Second Generation of Familial Nonmedullary Thyroid Carcinoma Are More Aggressive than Sporadic Cases

Familial nonmedullary thyroid carcinoma (FNMTC) is frequently detected, but the prevalence or the aggressiveness of FNMTC is still unclear. We aimed to investigate the prevalence, clinical characteristics, and prognosis of FNMTC. This study included 3056 nonmedullary thyroid carcinoma (NMTC) patients who were pathologically confirmed to exhibit differentiated thyroid carcinoma from January 1962 through March 2010. The duration of follow-up was 6.2±6.2 years. The prevalence of FNMTC was 9.6%; 37.9% of the FNMTC patients exhibited a parent-offspring relationship, and 62.1% exhibited a sibling relationship. FNMTC was smaller in tumor size (1.2±0.9 vs. 1.4±1.1 cm) and more multifocal (33.6% vs. 27.0%) than sporadic cases. FNMTC presented higher recurrence rates (29.5% vs. 19.8%) and shorter recurrence-free survival than sporadic NMTC (p=0.046). When we compared sporadic NMTC with parent-offspring or sibling FNMTC separately, parent-offspring FNMTC was more multifocal (39.3% vs. 27.0%), while sibling FNMTC was more prevalent in female patients (89.6% vs. 82.5%) and presented smaller tumors (1.2±0.8 vs. 1.4±1.1 cm) than sporadic NMTC. The recurrence rate was higher than that of sporadic NMTC in parent-offspring FNMTC (35.6% vs. 19.8%) but not in sibling FNMTC. Among the 123 parent-offspring FNMTC cases, the second generation exhibited an earlier age at the diagnosis (38±11 vs. 57±11 years), more extrathyroidal invasion (57.8% vs. 29.4%), a higher recurrence rate (50.0% vs. 19.0%), and shorter recurrence-free survival (p=0.015) than the first generation. FNMTC was found to have a very high prevalence in our population. Parent-offspring FNMTC demonstrated higher recurrence than sporadic NMTC; specifically, the second generation of parent-offspring FNMTC cases exhibited more aggressive clinical characteristics than the first generation.

Patients with familial non-medullary thyroid cancer have an outcome similar to that of patients with sporadic papillary thyroid tumors

The purpose of this study was to determine whether familial non-medullary thyroid cancer (FNMTC) is more aggressive than sporadic thyroid cancer. We compared the clinical behavior and outcome of 16 subjects with FNMTC from 7 unrelated kindred with those observed in 160 subjects with sporadic PTC (SPTC) from our database. The only different baseline characteristics observed between both groups were: bilateral malignancy, 38% vs. 24%, respectively (p = 0.03), and lymph node metastasis, 56.2% vs. 39%, respectively (p = 0.01). Considering the outcome, in the FNMTC, 9 (56.2%) patients were rendered free of disease, one patient died from thyroid cancer (6%), and 6/16 (37.5%) had persistent disease. In the SPTC Group, 87 (54%) patients were considered free of disease, 11 (7%) died due to PTC, and 62 (38%) had persistent disease (p = ns). Despite the higher incidence of lymph node metastasis in FNMTC patients this situation seemed not to alter the compared outcome.

Familial non-medullary thyroid carcinoma displays the features of clinical anticipation suggestive of a distinct biological entity

Non-medullary thyroid carcinoma (NMTC) is mostly sporadic, but familial clustering is described. We aimed to compare the features of patients with sporadic and familial NMTC (FNMTC) patients and to assess whether FNMTC patients with parent-child relationship exhibit the 'anticipation' phenomenon (earlier age at disease onset and increased severity in successive generations). Among 300 NMTCs followed in the Section of Endocrinology (University of Siena, Italy), 34 (11.3%) patients, all with the papillary histotype, (16 kindred), met the criteria of FNMTC. Twenty-seven of them (79.4%) exhibited a parent-child relationship and seven (20.6%) a sibling relationship. These patients were compared with 235 patients with sporadic papillary thyroid cancer (PTCs). To analyze the features of FNMTC of the first and second generations, we cumulated the series of Siena with 32 additional FNMTC patients (15 kindred) from the Department of Endocrinology-Endocrine Oncology, Thessaloniki, Greece. Significant difference between sporadic PTC and FNMTC patients included more frequent tumor multifocality (P=0.001) and worse final outcome in FNMTC patients (P=0.001). Among 47 FNMTC with parent-child relationship, we found an earlier age at disease presentation (P<0.0001), diagnosis (P<0.0001), and disease onset (P=0.04) in the second generation when compared with the first generation. Patients in the second generation were more frequently males (P=0.02); their tumors were more frequently multifocal (P=0.003) and bilateral (P=0.01), had higher rate of lymph node metastases at surgery (P=0.02) and worse outcome (P=0.04) when compared with the first generation. In conclusion, FNMTC displays the features of clinical 'anticipation' with the second generation acquiring the disease at an earlier age and having more advanced disease at presentation.

An Evidence‐based Approach to Familial Nonmedullary Thyroid Cancer: Screening, Clinical Management, and Follow‐up

Approximately 5% of nonmedullary thyroid cancers are of familial origin. When two or more family members are diagnosed with nonmedullary thyroid cancer in the absence of other known associated syndromes it is termed familial nonmedullary thyroid cancer (FNMTC). The genetic inheritance of FNMTC remains unknown, but it is believed to be an autosomal dominant mode of inheritance with incomplete penetrance and variable expressivity. FNMTC has been shown to be more aggressive and to have a worse prognosis than sporadic nonmedullary thyroid cancer. For example, studies have demonstrated that individuals with FNMTC have an increased risk of multifocal disease, local invasion, and lymph node metastases. These aggressive features appear to contribute to the higher recurrence rate and decreased disease-free survival seen in FNMTC patients compared to those with sporadic differentiated thyroid cancer. This article is an overview of the literature available in the English language discussing FNMTC. Critical questions regarding the screening, management, and follow-up of these patients are addressed with answers proposed based on the available literature. The quality of the evidence is ranked according to Sackett's criteria. Overall, the literature quality is somewhat limited, based on the low prevalence of FNMTC, the difficulty in identifying familial cases, the variable study designs, and limited long-term follow-up. To date, the optimal clinical approach is yet to be established, but improved awareness and screening will permit earlier detection, more timely intervention, and hopefully improved outcomes for patients and their families.

Familial Non‐Medullary Thyroid Cancer: A Matched‐Case Control Study

Familial non-medullary thyroid cancer (FNMTC) is a newly recognized disease entity and can be distinguished from the more common sporadic non-medullary thyroid cancer. The purpose of this study was to determine some of the potential distinguishing features of FNMTC. Retrospective association study and matched-case control study. Five hundred forty-three cases of well-differentiated follicular origin thyroid cancers were identified and collected in a database. Among this population, 24 cases of FNMTC were identified. A case of FNMTC was defined as a patient with the following two criteria: a well-differentiated follicular origin thyroid cancer and at least one first-degree relative with a well-differentiated epithelial origin thyroid cancer. The unmatched sporadic and FNMTC groups were compared using t test, Phi test, Cramer V test, and Pearson and Spearman correlation tests. Twenty-four FNMTC cases were matched to 24 sporadic cases based on age, gender, stage of disease at presentation, and tumor size. Clinicopathologic features, management, and outcome were analyzed statistically using a matched-proportional z test. Disease-free survival and disease-specific survival were analyzed using log-rank test and the Kaplan-Meier function. A P-value less than .05 was considered statistically significant. : There was no significant difference in ionizing radiation exposure, disease multifocality, surgical management, or recurrence between the sporadic and FNMTC patients. Although FNMTC patients tend to have improved disease-free survival and disease-specific survival, the difference was not significant at the 5% level. Although FNMTC is characterized by strong family history, these patients do not tend to have worse prognosis.

Detection of Asymptomatic Differentiated Thyroid Carcinoma by Neck Ultrasonographic Screening for Familial Nonmedullary Thyroid Carcinoma

Mass screening for the purpose of detecting thyroid cancer at its earliest stage may not be recommended at the present time, but screening focused on certain risk groups is advocated. Familial nonmedullary thyroid carcinoma (FNMTC) is a distinct clinical entity with a high incidence of multifocality and association with multiple benign nodules. FNMTC patients have shorter disease-free survival than do sporadic disease patients because of frequent locoregional recurrence. Screening by neck ultrasonography was performed for symptom-free family members of patients with FNMTC. A total of 149 subjects representing 53 FNMTC families were examined in this study. The average age of the patients was 41.0+/-19.0 years (range 3-76 years) with a female/male ratio of 104:45. At least one thyroid nodule was found in 77 (51.7%) of the 149 patients. Surgery was performed in 18 patients, and thyroid cancer was discovered in 15 of them (10.1%; 14 women, 1 man; 32-61 years of age). Papillary thyroid cancer (PTC) was found in 14 and follicular thyroid cancer combined with PTC in 1. The tumors averaged 9.1+/-5.4 mm (3-21 mm) in greatest diameter. Intraglandular metastases were found in 7 (47%) of the 15 patients with thyroid cancer. Lymph node metastases were found in 6 (43%). Ultrasonographic screening for FNMTC family members may enable the discovery of asymptomatic thyroid cancer. Because of the high incidence of intraglandular and lymph node metastases, we recommend screening with ultrasonography for early detection in family members of patients with FNMTC.