Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

Familial non-medullary thyroid cancer (FNMTC) constitutes 3–9% of all thyroid cancer (TC) cases and is divided into syndromic and non-syndromic FNMTC. In syndromic a FNMTC, patients are at risk of non-medullary thyroid cancer (minor component) and multiple other tumors with syndrome-specific clinical features (Familial adenomatous polyposis, Gardner syndrome, Cowden syndrome, Werner syndrome, Carney complex). The genes for syndromic FNMTC are known.

In non-syndromic FNMTC, thyroid cancer is the major feature of the disease, and the susceptibility gene has not yet been identified.

First, let’s define the diagnosis and management of FNMTC. Population studies have shown that the risk of TC increases nine-fold in patients who have a first-degree relative with TC. Traditionally, FNMTC is diagnosed when two or more first-degree relatives are affected [1]. The probability that a patient’s cancer is FNMTC is greater than 95% when ≥3 first-degree relatives are affected, compared to 31–38% when only two first-degree relatives are affected [2]. However, given the high incidence of TC in the general population, patients with only two first-degree relatives with non-medullary thyroid cancer (NMTC) could represent sporadic disease (a chance occurrence) and not an inherited predisposition [2].

In a prospective screening study at the National Cancer Institute [3], Dr. Klubo-Gwiezdzinska used thyroid ultrasound and physical examination in family members who had at least two first-degree relatives affected with TC and evaluated thyroid nodules according to the ATA guidelines. They found that 4.6% of people in families with two affected first-degree relatives had TC diagnosed on screening, while 22.7% of those from families with ≥3 affected first-degree relatives had a TC diagnosis. All cases diagnosed by screening had smaller tumor size, lower rate of central neck lymph node metastases, needed less extensive initial surgical intervention, and had a lower rate of radioiodine therapycompared to patients who presented with clinical disease. The youngest age of TC detection was 18 years old. They suggested screening with thyroid ultrasound in patients with ≥3 family members affected by FNMTC [3, 4]. However, recent ATA guidelines do not recommend screening and surveillance in non-syndromic FNMTC, citing a lack of evidence. To date, it is unknown whether earlier detection of less-advanced disease via this proposed screening and surveillance approach would result in a lower rate of TC recurrence and TC-related death or in overdiagnosis and overtreatment.

Second, is FNMTC more aggressive than sporadic disease? This is still debated. A meta-analysis of 12 studies with a total of 12,741 participants compared the extent of disease and outcomes in non-syndromic FNMTC versus sporadic NMTC and found that FNMTC was associated with a younger age at diagnosis and higher rate of multifocal and bilateral tumors, extrathyroidal invasion, lymph node metastasis, and recurrence rate [5]. In a recent prospective cohort study comparing 78 patients with FNMTC to 53,571 NMTC patients [6], FNMTC cases presented at a younger age, with a greater rate of lymph node metastasis. On the other hand, a retrospective study in which 67 patients with FNMTC and 375 controls with sporadic disease were followed for 10 years showed similar long-term disease-free survival rates [7]. Some of these discrepancies are due to study design shortcomings, such as variable inclusion criteria/definitions for FNMTC, data based on retrospective studies, and small sample size.

Third, which are the genes believed to cause non-syndromic FNMTC? By performing linkage analyses and whole-genome/-exome sequencing studies, several candidate genes have been found, including the serine/arginine repetitive matrix 2 gene (SRRM2) [8]; HABP2 germline variant, G534E [9]; and genes involved in the MAPK/ERK and PI3K/AKT pathways [10]. However, all these variants appear to be present in only a few patients, are most often not present within all family members affected by FNMTC, and are subsequently not validated across different populations. Unstudied alternative mechanisms, such as epigenetic mechanisms, might be involved in FNMTC and warrant further investigations.

These findings highlight a real black box and the need for future large prospective studies. Ensuing results might help establish improved management guidelines for providers and patients with multiple family members harboring TC and raise their awareness about FNMTC.

References:
1. Malchoff, C.D. and D.M. Malchoff, Familial nonmedullary thyroid carcinoma. Cancer Control, 2006. 13(2): p. 106-10.
2. Charkes, N.D., On the prevalence of familial nonmedullary thyroid cancer in multiply affected kindreds. Thyroid, 2006. 16(2): p. 181-6.
3. Klubo-Gwiezdzinska, J., et al., Results of Screening in Familial Non-Medullary Thyroid Cancer. Thyroid, 2017. 27(8): p. 1017-1024.
4. Sadowski, S.M., et al., Prospective screening in familial nonmedullary thyroid cancer. Surgery, 2013. 154(6): p. 1194-8.
5. Wang, X., et al., Endocrine tumours: familial nonmedullary thyroid carcinoma is a more aggressive disease: a systematic review and meta-analysis. Eur J Endocrinol, 2015. 172(6): p. R253-62.
6. El Lakis, M., et al., Do patients with familial nonmedullary thyroid cancer present with more aggressive disease? Implications for initial surgical treatment. Surgery, 2019. 165(1): p. 50-57.
7. Robenshtok, E., et al., Clinical characteristics and outcome of familial nonmedullary thyroid cancer: a retrospective controlled study. Thyroid, 2011. 21(1): p. 43-8.
8. Tomsic, J., et al., A germline mutation in SRRM2, a splicing factor gene, is implicated in papillary thyroid carcinoma predisposition. Sci Rep, 2015. 5(10566).
9. Gara, S.K., et al., Germline HABP2 Mutation Causing Familial Nonmedullary Thyroid Cancer. N Engl J Med, 2015. 373(5):448-55.
10. Srivastava, A., et al., Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways. LID – 10.3390/biom9100605 [doi] LID – 605. Biomolecules 2019. 9(10): p. 605.

• General:           

  • Weight gain 
  • Fatigue
  • Cold intolerance and hypothermia
  • Hyponatremia

• Musculoskeletal:

  • Myalgia
  • Muscle cramps
  • Carpel tunnel syndrome
  • Elevation of creatine phosphokinase

• Skin:    

  • Dry and coarse skin
  • Pretibial myxedema (nonpitting edema) 
  • Dry and coarse hair
  • Hair loss

• Nervous System:

  • Depression
  • Decreased concentration
  • Dementia

• Head and Neck:

  • Hoarse voice     
  • Enlarged tongue   
  • Periorbital edema
  • Goiter

• Cardiovascular:

  • Bradycardia
  • Diastolic hypertension
  • Hypercholesterolemia
  • Pericardial effusion
  • Congestive heart failure

• Gastrointestinal:         

  • Constipation

• Reproductive:

  • Irregular menstrual periods / amenorrhea
  • Menorrhagia
  • Galactorrhea with elevated prolactin levels
  • Infertility
  • Increase risk of miscarriage

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👉In a recent study examining over 18,000 patients with hyperthyroidism, greater organ-absorbed doses of RAI may be associated with a modest increase in the risk of death from solid cancer.

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#ThyroidSurgeon

#ThyroidExpert

#Hyperthyroidism

#MountSinaiMedical Center

#HeadandNeckSurgeon

#Surgeon

#Teacher

#Miami

#Mexico

#Arrangoiz #CancerSurgeon #ThyroidSurgeon #ParathyroidSurgeon #HeadandNeckSurgeon #ThyroidExpert #SurgicalOncologist #EndocrineSurgery #MountSinaiMedicalCenter #Miami #ThyroidNodule #ToxicNodularGoiter #TNG #MultinodularGoiter #GravesDisease #Hyperthyroidism #Goiter

• Thyroiditis comprises a diverse group of disorders:
  • That are among the most common endocrine abnormalities encountered in medical endocrine clinical practice as well as by surgeons managing the thyroid
  • These disorders range from:
    • The extremely common chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis) to the extremely rare invasive fibrous thyroiditis (Riedel’s thyroiditis) 
  • Clinical presentations are also diverse:
    • Ranging from an incidental finding of a goiter to potentially life-threatening illness:
      • From hypothyroidism to thyrotoxicosis.
  • The term thyroiditis implies:
    • That the disorders are inflammatory processes involving the thyroid gland:
      • Although some of the lesions are not inflammatory and are included in the thyroiditis category largely for convenience.
  • A rational approach to such patients:
    • Including history, physical examination, laboratory evaluation, radionuclide or ultrasonographic imaging, and fine-needle aspiration biopsy:
      • Will allow the appropriate diagnosis to be made in the majority of cases.

#Arrangoiz

#Teacher

#Surgeon

#Cirujano

#ThyroidExpert

#ThyroidSurgeon

#CirujanodeTiroides

#ExpertoenTiroides

#ExpertoenParatiroides

#Paratiroides

#Hiperparatiroidismo

#CancerdeTiroides

#ThyroidCancer

#PapillaryThyroidCancer

#SurgicalOncologist

#CirujanoOncologo

#CancerSurgeon

#CirujanodeCancer

#HeadandNeckSurgeon

#CirugiaEndocrina

#EndocrineSurgery

#MountSinaiMedicalCenter

• Thyrotoxicosis:
  • Is the common feature of both:
    • Toxic nodular goiter (TNG) and Graves’ disease
  • It may be clinical or subclinical:
    • Subclinical hyperthyroidism:
      • Presents few, if any, mild symptoms ;
        • In the presence of a suppressed TSH with normal free thyroid hormones (T3 and T4)
  • Early in Graves’ disease:
    • Hyperthyroidism may be from:
      • Preferential T3 secretion:
        • So-called T3 toxicosis
• History and Physical Examination:
  • The clinical presentation ranges from:
    • No symptoms and a suppressed sensitive serum TSH level to overt or obvious clinical hyperthyroidism:
      • The latter includes symptoms associated with:
        • Increased adrenergic tone and resting energy expenditure and other hormonal effects
        • Features related to increased adrenergic tone include:
          • Nervousness
          • Tremor
          • Increased frequency of defecation
          • Palpitations
          • Diaphoresis
          • Irritability
          • Insomnia
          • Headaches
          • Lid retraction and lid lag
          • Muscle weakness
          • Tachycardia
          • Hyperreflexia, and widened pulse pressure
        • Those related to increased energy expenditure include:
          • Heat intolerance
          • Unintentional weight loss without anorexia
          • Warm, moist skin
      • In elderly subjects, the presentation may be subtle, with:
        • Atrial fibrillation
        • Weight loss
        • Weakness
        • Depression
    • Goiter may be detected in patients with either TNG or Graves’ disease:
      • Nodular irregularity is characteristic of TNG:
        • Whereas Graves’ disease is more typically:
          • Diffuse, soft, and rubbery and may have an overlying thyroid region bruit
  • Patients with Graves’ disease often have a:
    • Goiter:
      • Diffuse, soft, and rubbery:
        • May have an overlying thyroid region bruit
    • May present with hyperthyroidism alone, or
    • May have one or more extra-thyroidal manifestations
  • Clinically apparent eye disease may occur in up to a third of patients with Graves’ disease:
    • But orbital CT may detect changes in a majority of patients
    • Signs of eye disease include:
      • Proptosis or exophthalmos
      • Lid lag and retraction
      • Impaired extraocular muscle function
    • Eye symptoms and signs generally begin about six months before or after the diagnosis of Graves’ disease:
      • It is generally uncommon for eye involvement to develop after the thyroid disease has been successfully treated:
        • There is great variability, however, and in some patients with eye involvement, hyperthyroidism may never develop
      • The severity of eye involvement is not related to the severity of hyperthyroidism
      • Early signs of eye involvement may be:
        • Red or inflamed eyes
      • Ultimately, proptosis may develop from the inflammation of retro-orbital tissues
      • Diminished or double vision is a rare problem:
        • That usually occurs later
      • It is not well known why, but problems with the eyes occur much more often in people with Graves’ disease who smoke cigarettes than in those who do not smoke
  • Other features of Graves’ disease include:
    • Onycholysis, acropachy, and pretibial myxedema
    • Pretibial myxedema:
      • Is a rare, reddish lumpy thickening of the skin of the shins
      • This skin condition is usually painless and is not serious
      • Like the eye disorders of Graves’ disease, the skin manifestation does not necessarily begin precisely when hyperthyroidism starts
      • Its severity is not related to the level of thyroid hormones
      • It is not known why this problem is usually limited to the lower leg or why so few people have it
  • Occasionally symptoms related to the mass effect of a large goiter may occur:
    • Very large goiter may extend retrosternally or substernally, resulting in symptoms and signs of tracheoesophageal pressure:
      • These may include:
        • Dysphagia
        • Cough
        • Choking sensation
        • Stridor:
          • Particularly if severe tracheal narrowing exists
        • The development of facial plethora, cyanosis, and distention of neck veins:
          • With raising both arms simultaneouslymay result from deep goiter compression of the structures located within the bony confines of the thoracic inlet (Pemberton sign)

#Arrangoiz #CancerSurgeon #ThyroidSurgeon #ParathyroidSurgeon #HeadandNeckSurgeon #ThyroidExpert #SurgicalOncologist #EndocrineSurgery #MountSinaiMedicalCenter #Miami #ThyroidNodule #ToxicNodularGoiter #TNG #MultinodularGoiter #GravesDisease #Hyperthyroidism #Goiter

Did you know? 🤔
The major horn of the hyoid bone is a useful repair in lateral neck surgeries.
Its highlight allows us to specify the location:

• towards the upper: of the hypoglossal nerve next to the ranine veins and of the lingual artery (in the triangle of Beclard).
• downwards: from the nerve and the superior laryngeal vessels (in the Portmann quadrilateral).

📚References:
1- Major horn (horn) of the hyoid bone.
2- Hypoglossal nerve.
3- Lingual artery: 3a -in the area of the triangle of Beclard, behind the hyoglossus muscle. 3b- in the area of the Pirogoff triangle, behind the mylohyoid and hyoglossus muscle.
4- Anterior belly of the digastric muscle.
5- Superior laryngeal nerve.
6- Mylohyoid muscle (in submental triangle).
7- Posterior belly of the digastric muscle.
8- Minor horn (horn) of the hyoid bone.
9- Body of the hyoid bone.
10- Cranial insertion of the omohyoid muscle.
11- Thyrohyoid muscle.
12- Sternocleidohyoid muscle.
13- Lateral thyroid ligament.
14- Portmann quadrilateral.
15- Upper horn of the thyroid cartilage.
16- Trunk of the superior thyroid artery and superior laryngeal artery.
17- Primitive carotid artery.
18- Internal jugular vein.
19- Projection of the imaginary “safety” line in the Sistrunk operation.
20- Stylohyoid muscle.
21- Fascial sling of the intermediate tendon of the digastric muscle.

• Hyperthyroidism in the United States:
  • Occurs in 0.05% to 1.3% of the general population:
    • With the majority of cases consisting of subclinical disease
  • The prevalence of hyperthyroidism:
    • Is approximately 5 to 10 times less than that of hypothyroidism
    • White and Hispanic populations in the United States:
      • Have a slightly higher prevalence of hyperthyroidism than black populations
• TNG:
  • Is the most frequent cause of thyrotoxicosis:
    • In the elderly
  • It accounts for about 5% to 15% of patients with endogenous hyperthyroidism:
    • But the proportion is:
      • Higher in iodine-deficient geographic regions
  • Changes in the iodine content of salt and in the iodine supplementation of water have been linked to changes in the incidence of TNG:
    • In Switzerland in 1980 and in Spain in 1994:
      • The iodine content of salt was increased, and this was associated with a transient increased incidence of thyrotoxicosis followed by decreased incidence:
        • Mainly the result of reduced TNG incidence
• Graves Disease:
  • Being the most common cause of thyrotoxicosis in all age groups
  • Graves’ disease accounts for 70% to 80% of endogenous hyperthyroidism
  • The incidence of Graves’ disease is five times higher in females than in males:
    • Occurring generally during women’s reproductive years:
      • Although it may occur at any age

#Arrangoiz #CancerSurgeon #ThyroidSurgeon #ParathyroidSurgeon #HeadandNeckSurgeon #ThyroidExpert #SurgicalOncologist #EndocrineSurgery #MountSinaiMedical Center #Miami #ThyroidNodule #ToxicNodularGoiter #TNG #MultinodularGoiter #GravesDisease #Hyperthyroidism #Goiter

• In the absence of extra-thyroidal symptoms or diffuse goiter, measurement of thyrotropin-receptor antibodies is performed and has a sensitivity and specificity of over 99%

#Arrangoiz #ThyroidSurgeon #ThyroidExpert #CancerSurgeon #HeadandNeckSurgeon #Hyperthyroidism #GravesDisease #EndocrineSurgery #Miami #Mexico #MountSinaiMedicalCenter

• Hyperthyroidism refers to thyrotoxicosis:
  • Caused by the overproduction of the thyroid hormones:
    • Thyroxine (T4) and triiodothyronine (T3)
• The most common type of thyrotoxicosis encountered in the United States and worldwide:
  • Is Graves’ disease
• Toxic nodular goiter (TNG):
  • Is the second most common type of thyrotoxicosis
• Goiter:
  • Is enlargement of the thyroid gland:
    • That is commonly encountered in clinical endocrine practice
  • It may be classified as:
    • Diffuse or
    • Nodular
      • May be either:
        • Non-toxic or
        • Toxic
  • Nodular goiter may include:
    • Multiple nodules:
      • Multi-nodular goiter (MNG)or
    • A single nodule
  • Regardless of different possible mechanisms of development:
    • Diffuse thyroid enlargement eventually evolves into a nodular stage
• A TNG is a thyroid gland that contains:
  • Autonomously functioning thyroid nodule(s):
    • With resulting hyperthyroidism
  • Also called Plummer’s disease:
    • TNG was first described by Henry Plummer at Mayo Clinic in 1913
  • TNG is the second most common cause of hyperthyroidism in the Western world, after Graves disease:
    • In elderly individuals and in geographic areas of endemic iodine deficiency:
      • TNG is the most common cause of hyperthyroidism
• Graves’ disease:
  • Is the most common type of thyrotoxicosis encountered in the industrialized world
  • Graves’, disease owes its name to an:
    •  Irish doctor, Robert James Graves’ who described the first case of goiter with exophthalmos in 1835
  • Patients with Graves’ disease usually have:
    • Diffuse, nontender, symmetric enlargement of the thyroid gland

#Arrangoiz #ThyroidExpert #ThyroidSurgeon #CancerSurgeon #EndocrineSurgery #Miami #MountSinaiMedicalCenter #Hyperthyroidism #Goiter #ThyroidNodules #HeadandNeckSurgeon #MulitnodularGoiter #MNG #PlummerDisease #ToxicNodularGoiter #TNG #Mexico