Do patients with familial nonmedullary thyroid cancer present with more aggressive disease? Implications for initial surgical treatment

doi:10.1016/j.surg.2018.05.075

Surgery

Volume 165, Issue 1, January 2019, Pages 50-57

https://doi.org/10.1016/j.surg.2018.05.075 Get rights and content

Abstract

Background

There are conflicting reports on whether familial nonmedullary thyroid cancer is more aggressive than sporadic nonmedullary thyroid cancer. Our aim was to determine if the clinical and pathologic characteristics of familial nonmedullary thyroid cancer are different than nonmedullary thyroid cancer.

Methods

We compared patients with familial nonmedullary thyroid cancer to a cohort of 53,571 nonmedullary thyroid cancer patients from the Surveillance, Epidemiology, and End Results database.

Results

A total of 78 patients with familial nonmedullary thyroid cancer from 31 kindreds presented at a younger age (P = .04) and had a greater rate of T1 disease (P = .019), lymph node metastasis (P = .002), and the classic variant of papillary thyroid cancer on histology (P < .001) compared with the Surveillance, Epidemiology, and End Results cohort. Patients with ≥3 affected family members presented at a younger age (P = .04), had a lesser female-to-male ratio (P = .04), and had a greater rate of lymph node metastasis (P = .009). Compared with the Surveillance, Epidemiology, and End Results cohort, we found a higher prevalence of lymph node metastasis in familial nonmedullary thyroid cancer index cases (P = .003) but not in those diagnosed by screening ultrasonography (P = .58).

Conclusion

Patients with familial nonmedullary thyroid cancer present at a younger age and have a greater rate of lymph node metastasis. The treatment for familial nonmedullary thyroid cancer should be more aggressive in patients who present clinically and in those who have ≥3 first-degree relatives affected.

Introduction

Thyroid cancer is the most common endocrine malignancy with more than 56,000 cases expected to occur in 2018. Thyroid cancers originating from follicular cells account for approximately 95% of all thyroid cancer cases, and the remaining cancers originate from parafollicular cells (medullary thyroid cancer).¹ Familial nonmedullary thyroid cancer (FNMTC) accounts for 3–9% of all thyroid cancer cases.2, 3 Most FNMTC cases are due to papillary thyroid cancer and its histologic variants, but follicular thyroid cancer, Hürthle cell carcinoma, and anaplastic thyroid cancer have also been reported, albeit rarely. FNMTC has an autosomal dominant pattern of inheritance with incomplete penetrance and may be syndromic or nonsyndromic. Nonsyndromic FNMTC accounts for most (>95%) cases of FNMTC.2, 3

Several investigators have suggested that FNMTC is associated with earlier age of onset, a greater rate of multifocal tumors, extrathyroidal extension, lymph node metastases, disease recurrence, and a decreased, disease-specific survival.4, 5, 6, 7, 8, 9, 10, 11 A recent meta-analysis, which included 12 studies with a total of 12,741 patients who were followed for 1.5–12.1 years, evaluated the aggressiveness of FNMTC in comparison to sporadic nonmedullary thyroid cancer (NMTC).¹² The analysis was based on retrospective studies, including 8 cohort studies and 4 case-control studies, of which 5 were conducted in Asia,4, 6^,13, 14, 15 4 in North America,2, 7^,16, 17 2 in Europe,18, 19 and 1 that was a combined US and Japanese cohort study.⁵ Based on data extracted from 6 eligible studies, FNMTC was found to have a greater rate of recurrence and a decreased disease-free survival compared with patients with sporadic NMTC.¹² They also found a younger age at diagnosis (2.4 years less on average for FNMTC patients as compared to sporadic NMTC) and a greater rate of multifocal tumors, bilateral disease, extrathyroidal extension, and lymph node metastases, but no difference in primary tumor size.¹² Taken together, these findings suggest that FNMTC is characterized by more aggressive behavior than sporadic disease, but none of these data were based on prospective studies, the study sample size was small in most studies, and in none of the kindred studied were disease status ascertained by screening to provide an accurate assessment of affected disease status.

In this study, we determined if the clinical and pathologic characteristics of patients with FNMTC were different than those with sporadic NMTC. We compared the clinical and pathologic characteristics of patients with FNMTC (papillary thyroid cancer and its subtypes) with at-risk kindred who underwent prospective screening to the cohort of 53,571 patients with papillary thyroid cancer and its subtypes from the Surveillance, Epidemiology, and End Results (SEER) database.

Section snippets

Methods and patients

The Institutional Review Boards of the National Cancer Institute and the National Institutes of Health approved this study, and patients gave written informed consent before evaluation and testing (NCT01109420).

Extent of disease in FNMTC cohort

Enrolled in our prospective cohort study were 31 kindreds with FNMTC. A total of 78 patients underwent operative management and were diagnosed with thyroid cancer on histologic examination. Details on demographics, clinical presentation, and pathologic findings are summarized in Table 1. The FNMTC patients had an average age of 43 ± 15 years at diagnosis with a peak incidence between the ages of 30 and 44 years (51%); 56 patients (72%) were women. Seventy-four patients (95%) underwent total

Discussion

In this study, we evaluated the clinical characteristics, operative approach, and pathology results of our FNMTC cohort compared to patients with NMTC in the SEER database, excluding cases of medullary thyroid cancer, anaplastic thyroid cancer, and poorly differentiated thyroid cancer. We found that patients from kindred with 3 or more affected members were younger at the presentation and had a greater rate of lymph node metastasis despite presenting with a lesser tumor stage.

Consistent with

Conflicts of interest

There are no conflicts of interest for all of the authors.

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Cited by (19)

Clinical characteristics and prognosis of familial nonmedullary thyroid carcinoma
2022, Endocrinologia, Diabetes y Nutricion
El carcinoma familiar de tiroides no medular (FNMTC, familial non-medulary thyroid carcinoma) se define por la presencia de 2 o más miembros familiares de primer grado con carcinoma diferenciado de tiroides (CDT). El objetivo de este estudio es analizar las características clínicas, anatomopatológicas y pronósticas del FNMTC respecto al carcinoma esporádico (CE).
Estudio retrospectivo de los casos de CDT registrados en nuestro centro hospitalario durante el periodo 1990-2018.
Se analizó a un total de 927 pacientes, de los cuales 61 son FNMTC, con un seguimiento medio de 9,7 ± 6,5 años. La prevalencia del FNMTC es del 6,6%, presentando un estadio TNM inicial más bajo (p = 0,003) debido a la mayor proporción de tumores inferiores a 2 cm (p = 0,003), además de ser más multifocales (p = 0,034) y del subtipo histológico papilar (p = 0,022), respecto al CE. No se detectaron diferencias significativas en la edad al diagnóstico (p = 0,347), género (p = 0,406), ni en otros marcadores de agresividad (bilateralidad, extensión extratiroidea, afectación ganglionar y metástasis). La tasa de persistencia/recurrencia (p = 0,656), supervivencia libre de enfermedad (p = 0,929) y mortalidad ocasionada por el propio tumor (p = 0,666) fueron comparables. En las familias con ≥ 3 familiares afectados, los tumores son más pequeños (p = 0,005), más multifocales (p = 0,040) y bilaterales (p = 0,002), además de haber una mayor proporción de hombres (p = 0,020). Los pacientes de la segunda generación presentaron al diagnóstico el FNMTC a una edad más precoz respecto a los de la primera (p = 0,001).
El FNMTC presenta en nuestro estudio, en comparación con el CE, una estadificación TNM más baja, mayor multifocalidad y representación del subtipo papilar, con similares datos de agresividad y sin diferencias en el pronóstico.
Familial non-medullary thyroid carcinoma (FNMTC) is defined by the presence of 2 or more first-degree family members with differentiated thyroid carcinoma (DTC). The aim of this study is to compare clinicopathological features and prognosis of FNMTC and sporadic carcinoma (SC).
Retrospective study of DTC included in the hospital database during the period 1990-2018.
A total of 927 patients were analyzed, 61 of them were FNMTC, with a mean follow-up of 9.7 ± 6.5 years. The prevalence of FNMTC was 6.6%, with a lower TNM staging presentation (P = .003) consequence of a higher proportion of tumors smaller than 2 centimeters (P=.003), combined with a greater multifocality (P=.034) and papillary histologic subtype (P=.022) compared to SC. No significant differences in age at diagnosis (P=.347), gender (P=.406), neither in other aggressiveness markers (bilaterality, extrathyroidal extension, lymph node involvement and metástasis) were detected. Rate of persistence/recurrence (P=.656), disease-free survival (P=.929) and mortality caused by the tumor itself (P=.666) were comparable. Families with ≥3 affected relatives, had smaller tumors (P=.005), more multifocality (P=.040) and bilaterality (P=.002), as well as a higher proportion of males (P=.020). Second generation patients present earlier FNMTC compared to those of the first generation (P=.001).
In our study FNMTC presents a lower TNM staging, higher multifocality and papillary variant, with similar aggressiveness and prognosis compared to SC.
Familial non medullary thyroid carcinoma: Beyond the syndromic forms
2021, Endocrinologia, Diabetes y Nutricion
El carcinoma diferenciado de tiroides familiar se define como la presencia de cáncer de tiroides no medular en dos o más familiares de primer grado, en ausencia de otros factores predisponentes. Representa hasta el 9% de los cánceres diferenciados de tiroides, y solo una minoría aparece en el seno de síndromes hereditarios bien conocidos que asocian el cáncer de tiroides, entre otras múltiples manifestaciones clínicas. Sin embargo, en más del 95% de los casos, el cáncer de tiroides aparece de manera aislada, y sus causas genéticas aún están por dilucidar. En esta revisión resumimos el estado actual del conocimiento de las bases genéticas de esta patología, así como sus características clínicas. La comprensión de los mecanismos genéticos implicados ayudaría a esclarecer las vías metabólicas involucradas, con la consiguiente potencial aplicación terapéutica. Además, permitiría ofrecer consejo genético y focalizar nuestros esfuerzos en los pacientes susceptibles de padecer la patología.
Familial non-medullary thyroid cancer is defined as the presence of non-medullary thyroid cancer in two or more first-degree relatives, in the absence of other predisposing factors. It represents up to 9% of differentiated thyroid cancers, and only a minority appears in well-known hereditary syndromes that associate thyroid cancer among many other clinical manifestations. However, in more than 95% of cases, thyroid cancer appears isolated, and its genetic causes have yet to be elucidated. We review here the current knowledge of the genetic basis of this pathology, as well as its clinical characteristics. Understanding the genetic mechanisms implied would help to comprehend the metabolic pathways involved, with the consequent potential therapeutic application. In addition, it would allow genetic counseling and to focus our efforts on patients at risk of developing this disorder.
Genetic testing in endocrine surgery: Opportunities for precision surgery
2020, Surgery (United States)
Citation Excerpt :
Familial nonmedullary thyroid cancer (FNMTC) accounts for 3% to 9% of all thyroid cancer cases and is defined as syndromic (thyroid cancer occurs with other tumors) or nonsyndromic (thyroid cancer is the predominant cancer). Nonsyndromic FNMTC is more common (90% of FNMCT cases), and most studies suggest it is associated with more aggressive disease compared with sporadic thyroid cancer.7 Patients with nonsyndromic FNMTC present at an earlier age and have a higher rate of persistent and/or recurrent disease, with increased mortality and relatively shorter disease-free survival.7
Recent innovations in molecular and genetic diagnostic techniques have led to rapid advances in genomic medicine and their application to the clinic. The identification and classification of various genetic associations, syndromes, and susceptibility genes in endocrine surgical disorders are increasingly relevant to patient care. Hereditary endocrine disorders represent a significant proportion of disease encountered by endocrine surgeons. Hence, genetic testing has emerged as an important adjunct for the diagnosis and management of patients with endocrine surgical disorders. This article summarizes commonly encountered inherited endocrine disorders and their tumor susceptibility genes, with a focus on the clinical utility of genetic testing and its impact on the surgical management of endocrine disorders.
MicroRNA-574-5p directly targets FOXN3 to mediate thyroid cancer progression via Wnt/β-catenin signaling pathway
2020, Pathology Research and Practice
Citation Excerpt :
Thyroid cancer is a common tumor in endocrine system, and its treatment mainly includes surgery, assisting iodine 131 radiotherapy and endocrine inhibition therapy [25]. The incidence of thyroid cancer has consistently increased and poses a serious threat to human’s healthcare [26]. Studies have confirmed that high level of estrogen, exposure to radiation, and excessive iodine intake are risk factors for thyroid cancer [27,28].
Thyroid cancer is the most common endocrine tumor. A large number of thyroid cancer-related miRNAs have been studied and identified. However, the detailed roles of miR-574-5p in thyroid cancer remain poorly understood. This work mainly aimed to investigate the role of miR-574-5p/FOXN3 axis and its mechanism in the thyroid cancer progression.
MiR-574-5p, FOXN3, Wnt/β-catenin pathway, and apoptosis-related markers were measured by quantitative real-time PCR (qRT-PCR) and western blotting analysis, respectively. Luciferase reporter assay was employed to validate the direct targeting of FOXN3 by miR-574-5p. MTT, flow cytometry, wound healing and transwell experiments were applied to analyze the functions of FOXN3 and miR-574-5p in thyroid cancer cells.
Knockdown of miR-574-5p up-regulated FOXN3 expression and miR-574-5p directly targeted FOXN3 in thyroid cancer cells. Biological function experiments showed that knockdown of miR-574-5p inhibited proliferation, migration, invasion and promoted apoptosis of thyroid cancer cells. The activation of Wnt/β-catenin pathway was suppressed by MiR-574-5p silencing. FOXN3 silencing reversed the effects of miR-574-5p inhibitor on FOXN3 level and Wnt/β-catenin singling pathway, also reversed the effects on cell migration, proliferation, invasion and apoptosis.
The miR-574-5p/FOXN3 axis is a novel molecular mechanism that promotes thyroid cancer progression, suggesting their potential for clinical therapy of thyroid cancer.
Screening for differentiated thyroid cancer in selected populations
2020, The Lancet Diabetes and Endocrinology
Citation Excerpt :
Some reports, including a meta-analysis of 12 studies, have noted more aggressive behaviour of familial non-medullary thyroid cancer compared with their sporadic counterparts,85,94–98 while others found no difference.99–103 In particular, most studies found familial non-medullary thyroid cancer to be more frequently multifocal,94,95,97,98,100 and some studies found more frequent extrathyroidal extension95,104 and lymph node metastases.85,95,104 More frequent recurrence was also reported by some authors,85,94,95,97,98 but not by others.100–103
The main purpose of cancer screening programmes should not be to detect all cancers, but to discover potentially fatal or clinically relevant cancers. The US Preventive Services Task Force recommends against screening for thyroid cancer in the general, asymptomatic adult population, as such screening would result in harms that outweigh any potential benefits. This recommendation does not apply to patients with symptoms or to individuals at increased risk of thyroid cancer because of a history of exposure to ionising radiation (in childhood, as radioactive fallout, or in medical treatment as low-dose radiotherapy for benign conditions or high-dose radiation for malignancy), inherited genetic syndromes associated with thyroid cancer (eg, familial adenomatous polyposis), or one or more first-degree relatives with a history of thyroid cancer. We discuss the evidence for and against screening individuals who are at high risk, and consider the different screening tools available.
Reply: Do patients with familial nonmedullary thyroid cancer present with more aggressive disease? Implications for initial surgical treatment
2019, Surgery (United States)

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Do patients with familial nonmedullary thyroid cancer present with more aggressive disease? Implications for initial surgical treatment

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Methods and patients

Extent of disease in FNMTC cohort

Discussion

Conflicts of interest

Surgery

Cancer statistics, 2017

CA Cancer J Clin

Prevalence, clinicopathologic features, and somatic genetic mutation profile in familial versus sporadic nonmedullary thyroid cancer

Thyroid

Clinical features and genetic predisposition to hereditary nonmedullary thyroid cancer

Thyroid

The long-term outcomes of the second generation of familial nonmedullary thyroid carcinoma are more aggressive than sporadic cases

Thyroid

Is familial non-medullary thyroid carcinoma more aggressive than sporadic thyroid cancer? A multicenter series

Surgery

Familial nonmedullary thyroid carcinoma characterized by multifocality and a high recurrence rate in a large study population

World journal of surgery

In patients with thyroid cancer of follicular cell origin, a family history of nonmedullary thyroid cancer in one first-degree relative is associated with more aggressive disease

Thyroid

Clinicopathologic characteristics of familial versus sporadic papillary thyroid carcinoma

Acta Otorhinolaryngol Ital

Family history of malignant and benign thyroid diseases and risk of thyroid cancer: a population-based case-control study in New Caledonia

Cancer Causes Control