Prevalence, Pathogenesis, and Natural History of Multinodular / Substernal Goiter

• Multinodular goiter affects:
  • 4% of the U.S. population and up to 10% of the British population
• New thyroid nodular disease occurs in:
  • 0.1% to 1.5% of the general population per year
• Globally, iodine deficiency contributes to the majority of cases of multinodular goiter:
  • It is estimated to affect 1.5 billion people:
    • Or nearly 30% of the world’s population in 1990
• Further, it is estimated that approximately:
  • 655 million people in 118 countries are affected by endemic goiter:
    • Endemic goiter regions are defined as:
      • Iodine-deficient regions in which at least 5% to 10% of the population is affected by goiter
    • In certain iodine-deficient regions, higher goiter rates occur:
      • In 1994, in Bangladesh, approximately 47% of the population was affected by endemic goiter
  • The majority of the natural iodine supply exists as iodide in the world’s oceans:
    • It is therefore mainly non-coastal mountainous and lowland regions:
      • Where iodine is leached from the soil by flooding, heavy rainfall, and deforestation that are at risk for endemic goiter
• Sporadic forms of multinodular goiter do occur in iodine-replete regions with lesser prevalence:
  • Prevalence estimates of sporadic goiters vary between authors:
    • Ranging from less than 4% (clinical evaluation series) and between 16% and 67% (ultrasound series)
• Based on tuberculosis screening radiography in Australia and in the United States, substernal goiter has been estimated:
  • To be present in 0.02% of general population and 0.05% of females older than 40
  • The incidence of substernal goiter was found to significantly increase with age:
    • With 60% of substernal goiters occurring in patients older than age 60
  • Rates of substernal goiter in the past several decades appear to be decreasing, perhaps related to:
    • The introduction of iodized salt, thyroid hormone suppressive therapy, radioiodine use in selective cases, and perhaps more sensitive detection and earlier intervention
  • Substernal goiter, as a percentage of patients undergoing thyroidectomy, ranges depending on the series:
    • From less than 1% to greater than 20%, with most suggesting a rate of approximately 10%
  • Substernal goiters represent approximately:
    • 5% of all mediastinal tumors
• Pathogenesis
  • The pathogenesis of goiter formation has classically relied on the notion that iodine deficiency promotes persistent elevated thyroid-stimulating hormone (TSH) levels:
    • Inducing diffuse thyroid enlargement through thyrocyte proliferation
    • Nodules form in the enlarged thyroid as the patient ages, eventually giving rise to multinodular goiter
  • Since the early 2000s, this classic model has been challenged by the view that the thyroid gland has an intrinsic propensity to form nodules over time:
    • In this new model, low iodine levels and elevated TSH are considered additional factors, exacerbating the innate process of nodule formation
  • The shift in conceptualization of goiter pathogenesis has stemmed from new cellular models, first proposed by Studer and Derwahl:
    • These authors have argued that the development of multinodular goiter, at least in the later stages, is independent of TSH levels
    • Nodules arise because thyroid follicles are embryologically derived from polyclonal progenitors and have thus a heterogeneous sensitivity to TSH signaling
    • Thyroid follicles have similarly a differential growth response to continuous exposure to goitrogens:
      • Explaining the multinodular pattern of goiters
    • In addition, thyrocytes may undergo somatic mutations and acquire a distinct growth capacity:
      • The contribution of somatic mutations in multinodular goitrogenesis remains, however, controversial
    • This is in contrast with rare growth-promoting germline mutations of the TSH receptor gene:
      • Which are believed to be pivotal in congenital diffuse goiter with hyperthyroidism
    • Importantly, activating mutations in the TSH receptor gene have not been associated with an increased risk of malignancy
• Natural History
  • The natural history of untreated, sporadic, nontoxic goiter is not completely understood:
    • But slow growth appears to be the general predictable pattern:
      • Berghout et al. suggested a steady volume increase of up to 10% to 20% per year
  • Pregnancy, iodine deficiency, consumption of goitrogens, and alteration in suppressive or anti-thyroid medical regimens can result in goiter progression
  • Hemorrhage into a preexisting nodule:
    • Can also result in the development of acute, regional, and airway symptoms
  • In patients presenting with diffuse goiter:
    • There is a general tendency toward nodule formation and progressive autonomy:
      • With hyperthyroidism ultimately developing in up to 10% of patients 
• Most substernal goiters arise in the setting of preexisting cervical goiter:
  • It is of note, however, that some patients with substernal goiter have no significant cervical goiter component
  • Substernal goiters virtually always have a connection to the cervical orthotopic gland
  • Lahey, in his experience of approximately 24,000 goiter surgeries, believed that all substernal goiters arise from the cervical gland and maintain their cervical blood supply:
    • Even in cases of extreme substernal goiter extending to the diaphragm, the mediastinal component has been found to contain connections to the cervical gland and a blood supply from the inferior thyroid artery
    • Connection to the cervical gland may be robust or attenuated, but it virtually always exists
  • The work of Torre, based on an impressive series of 237 substernal goiters:
    • Suggests that substernal goiters arise 10 years after cervical goiter presentation:
      • Suggesting that substernal goiter evolves from preexisting cervical goiter in most cases
  • The inferior extension of cervical goiter and formation of substernal goiters is poorly understood:
    • The inferior descent relates in part to the pattern of nodular disease within the cervical gland
    • Inferior progression results from a limitation of the strap muscles anteriorly, trachea medially, and vertebral column posteriorly:
      • As Lahey and Swinton have described, the neck is “a space with no bottom”
    • The repetitive forces of deglutition, respiratory dynamics, negative intrathoracic pressure, and gravitational forces in the setting of permissive mediastinal and neck base fascial planes:
      • Facilitate the downward extension of cervical goiter
    • Typically, anterior mediastinal extension (substernal goiter type I):
      • Occurs from the ipsilateral lobe’s inferior expansion
    • Descent associated with significant retrotracheal posterior mediastinal extension may arise from more posterior elements of the thyroid gland such as posterior tubercles of Zuckerkandel

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