Follicular Adenoma

Article Author:
Joshua Norris
Article Editor:
Ahmed AlEssa
Updated:
6/25/2020 1:05:24 PM
PubMed Link:
Follicular Adenoma

Introduction

Andreas Vesalius (1514 -1564) first formally described the thyroid in his anatomy manuscript, De humani corporis Fabrica Libri septem. Since then, we have come a long way in understanding the anatomy, physiology, and workings of this endocrine gland.[1] The thyroid gland is a midline structure in the neck. Derived from the primitive pharynx and neural crest cells, embryologically, the tissue mass divides, forming the isthmus and the two lateral lobes of the thyroid. Bu the age of 2, the gland is already half the adult size. Developmental anomalies could result in aberrant masses of ectopic thyroid tissue, cysts, and sinuses.[2] Apart from that, the thyroid gland is no stranger to neoplastic lesions. Follicular lesions of the thyroid include many subvariants from the benign follicular adenoma right up to malignant follicular carcinomas, follicular variants of other malignant thyroid lesions.[3] 

Follicular adenomas are one subset of benign neoplasms that can occur in the thyroid gland or ectopic thyroid tissue. They typically present as a solitary thyroid nodule or in association with nodular hyperplasia or thyroiditis. Thyroid nodules are palpable in 4 to 7 % of individuals, but the prevalence of nodules detected incidentally by ultrasound shows a higher prevalence of 19 to 67 percent. The majority of thyroid nodules are asymptomatic. Similar to worldwide incidence, 60 to 70% of the US population present with thyroid nodules. Most of these are benign, although 5% exhibit malignant features.[4] Although the distinguishing line between the adenoma itself and its malignant counterpart is tricky, this is for all practical purposes a benign neoplasm.[5]

Etiology

Although follicular adenomas are mostly sporadic, multiple other etiological factors identified. Other causes implicated in the development of a follicular adenoma include:

  • Iodine deficiency: This is a known risk factor seen in individuals consuming non-iodized sea salt regularly.
  • Genetic alterations: PTEN hamartoma tumor syndrome (PHTS) includes several syndromes like Cowden syndrome and BRRS. Multiple follicular adenomas may occur along with other clinical manifestations. PTHS is due to mutations causing inactivation of the PTEN tumor suppressor gene. Other genetic mutations in BRAFNRAS, RET, and KRAS can also cause unexplained follicular adenomas. Follicular adenomas are also part of various syndromes like Familial adenomatous polyposis(FAP), Carney Complex syndrome. Genetic rearrangement of the PAX8-PPAR gene causes loss of follicular growth inhibition, thus facilitating the development of follicular neoplasms.
  • Prior I-131 radiation exposure also increases the risk of malignant lesions of the thyroid.[6][7][8][9][10][11][12][13]

Epidemiology

Follicular adenomas usually present as a solitary thyroid nodule. They are benign neoplasms in nearly 2 to 4.3 % of the population.[14] A study done on 300 consecutive autopsies revealed a 3% incidence of follicular adenomas compared to a 2.7% incidence for follicular carcinoma.[15] Thyroid adenomas are typically more common in females.[16] Data in the US, more or less, reflect the same incidence for development.

Studies on individuals exposed to I-131 radiation post; the Chernobyl nuclear accident revealed an excess odds ratio per grey of 2.22 equal for both sexes, with the odds ratio increasing with higher I doses. (P < 0.01) Children aged less than two years found to have the highest risks.[9] This EOR/Gy was similar to studies done by the Belarusian (EOR/Gy = 2.15 ) and the Ukrainian cohorts, respectively.[10][11] This study indicates that when a specific etiology like radiation is involved, the incidence is different from that seen in the normal population.

Pathophysiology

Iodine deficiency implicated in many studies for follicular lesions. Endemic goiter is a predisposing factor for follicular carcinoma with a higher rate of follicular carcinomas seen in low iodine areas.[6] Studies show that 4 to 13% of follicular adenomas exhibit rearrangement of the PAX8-PPAR. PAX8 helps follicular cell differentiation by encoding a nuclear protein product necessary for transcription of thyroid-specific factors. Martelli ML determined mutations in PAX8 that led to dysfunction and loss of optimal follicular growth inhibition.[7][8] A mutation causing inactivation of the PTEN tumor suppressor gene causes PTHS. Likewise, mutations in BRAFNRAS, RET, and KRAS can explain aberrant neoplasms, including the thyroid parenchyma.[12][13]

Functioning follicular adenomas arise as a result of a monoclonal increase of thyroid follicular cells with a predominance of activating mutations in the gene for the TSH receptor and less frequently in the adenylate cyclase-stimulating G alpha protein gene that results in increased thyroid hormone secretion independent of TSH. A monoclonal follicular cell expansion with activating mutations on the TSH receptor or in the adenylate cyclase-G protein mostly explains functioning follicular adenomas.[5] 20% of nonfunctioning follicular adenomas that have oncogene mutations can later progress to follicular carcinoma.[17]

Exposure to I-131 radiation has also caused an increased incidence of follicular adenomas, as documented by studies carried out in Chernobyl radiation affected areas. This supports the fact that radiation is also a likely etiology.[9][10][11]

Histopathology

A grossly follicular adenoma is solitary, encapsulated, having a size of 1-10cm. Light brown in color, solid and fleshy. It resembles multinodular goiter due to secondary changes in hemorrhage and cystic degeneration.

When viewed under the microscope, a thyroid lesion considered follicular when follicular growth patterns present in the entire or nearly entire lesion.[18] A follicular adenoma is a single lesion with the rest of the gland histologically normal. This solitary lesion is encapsulated and does not have any features suggestive of vascular or/and capsular invasion of the adjoining capsule and thyroid tissue. Follicular adenomas may show either a microfollicular or a macrofollicular growth pattern. Degenerative changes within the nodule rarely seen unless a prior FNA has been performed, which could result in degenerative changes.[19] The only way to determine whether a follicular neoplasm is a carcinoma is after histopathological examination.

The two key characteristics that make the follicular lesion malignant is the evidence of capsular invasion and angioinvasion. There is much debate about the extent to which tumor cells need to invade the capsule to determine it's malignant potential.[18] However, in a follicular adenoma, this is not the case. If the neoplasm only enters into the capsule without passing through the entirety of the capsule, then it is still an adenoma. When tumor cells invade a large vessel having an endothelial lining and attached to the wall, that is taken as a reliable sign of malignancy.[20] Many studies suggest a minimum of 10 tissue blocks with tumor capsule and thyroid tissue; this method has a better success rate in ruling out follicular carcinoma before definitely labeling the neoplasm as a follicular adenoma.[21]

History and Physical

Most patients with a follicular adenoma present with solitary thyroid nodule in the otherwise normal thyroid gland, however, it may occur in association with thyroiditis or nodular hyperplasia. Although most solitary nodules are asymptomatic and euthyroid, there is a <1% chance of hyperthyroidism. So while taking history and performing a physical of a patient with neck swelling, it is imperative to keep in mind the features of hyperthyroidism or hypothyroidism that could accompany the presentation. Thyroid medication history could help determine the etiology of many of these nodules.

Family history of autoimmune disease (Hashimoto disease, Grave disease) thyroid carcinoma or familial syndromes ( like Gardners) all are valid points to consider. Commonly patients present with and visually describe a slowly growing mass in the neck, pressure sensation over the neck. Pain seldom accompanies a thyroid nodule unless spontaneous hemorrhage or cystic degeneration has occurred within the nodule. Some patients may even complain of the cosmetic appearance of the mass. Pressure symptoms could cause dyspnea due to tracheal compression, increased coughing, voice hoarseness, and choking spells due to recurrent laryngeal nerve irritation and dysphagia secondary to esophagus compression.[5]

On physical examination, a diligent head to toe examination is imperative to assess if any signs are suggestive of a clinically non-euthyroid state. Patients with a follicular adenoma present with a thyroid nodule that's palpable on examination or identified on an imaging study. Nodules less than 1 cm are usually challenging to palpate unless located anteriorly on the gland. Careful consideration should be taken to assess the size, location, shape, borders, and consistency of the nodule. There may be more than one nodule that is palpated. However, even after neck palpation, nearly half of these nodules go undetected and can only be picked up on ultrasonography.[16]

Evaluation

Wong R describes four main parameters to assess a thyroid nodule, detailed patient history, and physical examination, a baseline serum TSH assay followed by an ultrasound. When indicated, aspiration by a fine-needle (FNA) can help in narrowing down to a diagnosis. They are reported according to the Bethesda Classification system.[19] Generally, follicular adenomas are benign but could have characteristics akin to follicular carcinoma. 5% of microfollicular adenomas, when subjected to histopathological examination, are reported as follicular cancers. Follicular carcinoma has a worse prognosis and hence should be carefully ruled out after thorough history, examination and investigations.[22] 

Preliminary laboratory assessment, including a baseline thyroid function test, helps determine the status of the gland (euthyroid, or hyper/hypothyroidism). Although FNA cytology remains the mainstay for assessing these nodules, it may not provide a diagnosis in up to 20% of cases.[7] The success rate of FNA is improved when the procedure is done under ultrasound guidance. Fine needle aspiration biopsy in patients with follicular adenoma is characterized by abundant follicular epithelial cells in sheets with crowding and overlapping of cells, microfollicle formation with scant or no colloid. Some patients have follicular cells with abnormal architecture with atypia that is more significant than usually seen with benign lesions but not sufficient enough to call it a neoplasm.

According to the Bethesda classification system, these patients are characterized as having "atypia of undetermined significance" or "follicular lesion of undetermined significance." A final diagnosis of follicular adenoma is made only after ruling out capsular and vessel invasion by standard HPE. Frozen section is not predictive and hence should not be used intraoperatively. Sonographic features of both follicular adenoma and follicular carcinoma are alike for the most part, except that a more extensive lesion size, hypoechogenicity, mixed or solid echotexture, absence of sonographic halo, micro/rim calcifications favor the malignant counterpart.[23][5][24] The lack of internal flow or predominantly peripheral flow is associated with a reduced probability of thyroid follicular malignancy.[25]

Radionuclide scanning is not routinely done in all cases unless the FNA reports indeterminate cytology or underlying thyrotoxicosis.[4] Simple follicular adenomas show poor uptake on radioiodine scintigraphy. In contrast, functioning follicular adenomas increase absorption and concentrate radioiodine within the nodule with the remainder of the gland showing a suppressed uptake.[5] If confusion remains, molecular assessment of indeterminate cytology can be helpful.[19]

CT scan and MRI have a limited role in the initial evaluation f solitary thyroid nodule.[26] Indications for these imaging techniques include suspected tracheal involvement, either by invasion or compression, extension into the mediastinum, or recurrent disease.

Treatment / Management

Usually, surgical management is preferred when it comes to follicular lesions.[5][4][22]

Medical Management

  • If the patient is not clinically euthyroid, medical therapy done to achieve a clinically euthyroid state.
  • Those with a low serum TSH level could signify a "toxic adenoma." In such lesions, additional, free T3, T4 assay must be done. As mentioned above, an iodine-123 thyroid scan may help determine the functionality of the nodule. These patients must be appropriately treated with medication.
  • The patient may undergo observation or levothyroxine suppression therapy as an initial treatment modality. Levothyroxine is administered for six months to determine if the nodule decreases in size. If the nodule falls in size with levothyroxine treatment, this medication is stopped with a follow-up examination of the nodule in three to six months. The growth of nodules during levothyroxine therapy is a strong indication for surgery. 
  • Almost all cases require surgical management.

Surgical Management

  • In the case of follicular neoplasms determined by FNA, the risk of malignancy is less than 1% in a hyperfunctioning nodule, with a higher 20% risk if the nodule is hypo functioning.
  • If the FNA result shows a follicular neoplasm, surgical management in the form of a thyroid lobectomy with isthmusectomy is the norm. If the ultrasound shows suspicious features, the surgeon should keep in mind the likelihood of malignancy.
  • After due consideration of additional risk factors like family history, the presence of other comorbidities, previous history of neck/head radiation, a decision of performing a total thyroidectomy may be taken.
  • Patients having a solitary toxic nodule, after determination of the functionality of the same, could undergo therapeutic iodine-131 therapy. Surgically, a unilateral thyroid lobectomy is adequate.
  • If the histopathological examination (HPE) examination confirms the Folllciular neoplasm as an adenoma, no further intervention is required.
  • Although beyond the purview of the topic, If the lesion fits HPE features of malignancy, then:
    •  A definitive total thyroidectomy is performed. Prophylactic neck node dissection is not recommended as <10% show nodal spread.
    •  The tumor must be staged according to the TNM staging system by the American Joint Committee on Cancer.
    • About six weeks of postoperative, some studies recommend treatment with I-131 to ablate residual thyroid tissue and reduce the risk of recurrence. 
    • Adequate postoperative surveillance must be done to rule out recurrence/ metastasis. Serum thyroglobulin levels, routine ultrasonography is recommended modalities for monitoring the outcome of the disease.
    • Metastatic lesions must be jointly dealt with the surgeon and the oncologist for better outcomes.

Main Advantages of Surgical Therapy

  • Relief from pressure-compressive symptoms like dyspnea, dysphagia, hoarseness, etc
  • Removal of the lesion helps alleviate the patient's anxiety
  • Resolves the issues of thyrotoxicosis in a toxic follicular adenoma
  • Avoids unnecessary radiation exposure to the healthy part of the thyroid

Differential Diagnosis

Follicular adenomas typically present as a solitary nodule; thus, all other likely causes of a solitary thyroid nodule should be considered.[5][4][18]

  • Follicular carcinoma
  • Other benign neoplasms
    • Hurtle cell adenoma
    • Non-invasive follicular tumor with papillary like nuclear features (NIFTP)
  • Other carcinomas
    • Papillary thyroid carcinoma
    • Medullary carcinoma
  • Thyroiditis: rarely can present as a nodule

Prognosis

Follicular adenomas are benign neoplasms. They are slow-growing and can progress to a size that may cause compressive symptoms such as dyspnea, dysphagia, hoarseness. After due evaluation of symptoms, the patient should ideally be reassured that these do not signify a malignant process but rather that the mass is causing compression on another structure.[5]

20% of nonfunctioning follicular adenomas have oncogene mutations that may progress to develop into a follicular carcinoma.[17] N-RAS and K-RAS have been implicated in this transformation.[27] If a follicular neoplasm is proven to be a carcinoma, then prompt oncological management is necessary. Patients with biopsy-confirmed follicular adenoma ideally do not need new therapy. Thyroxine supplementation is not recommended to suppress the gland unless hypothyroidism occurs after gland lobectomy.[28] The risk of malignancy is more in the Chernobyl post-radiation studies.[9][10][11]

Complications

    • Pressure symptoms are not usually complications but are a known effect once the nodule reaches a size where it can compress on adjacent structures.[5]
      • A dull dragging sensation owing to the mass and size of the lesion is almost always the complaint of the patient
      • Dyspnea, due to compression of the trachea
      • Dysphagia, due to oesophageal compression
      • Hoarseness of voice if the lesions press on the recurrent laryngeal nerve
    • Pain over the nodule: This is more concerning to the patient. It could mean that spontaneous hemorrhage or cystic degeneration has occurred within the nodule
    • A toxic nodule could, in the worst-case scenario, precipitate thyroid storm requiring additional patient care.[5]
    • Surgical complications:[29]
      • Bleeding
      • Infection
      • Scarring: hypertrophic or keloid formation
      • Thyroid crises
      • Temporary hypocalcemia or permanent if the parathyroids entirely removed
      • Recurrent laryngeal nerve transection could lead to a loss of voice and, in worse cases, even respiratory failure necessitating invasive ventilation

Postoperative and Rehabilitation Care

When surgical intervention is done due to compressive symptoms, the following points should be taken care of in the postoperative period:

  • Routine wound care
  • Watch out for complications listed above
  • Assess for parathyroid insufficiency and treat accordingly
  • Continuity clinic until biopsy-proven benign follicular neoplasm

Consultations

The management of follicular adenoma is a multidisciplinary approach, that's why liaison between the following departments is essential for a good outcome:

  • General or endocrine surgery
  • Endocrinology
  • Radiology
  • Nuclear Medicine
  • Histopathology

Deterrence and Patient Education

  • Patients who identify a growing mass over the neck should get evaluated by a licensed provider.
  • Although many thyroid neoplasms exist, follicular neoplasms are relatively common.
  • FNA cytology cannot rule out if the follicular neoplasm is malignant as tissue architecture for invasion can only be identified in a tissue biopsy specimen.
  • Complications occurring in a follicular neoplasm should not be identified as a cause for malignant transformation. A proven benign follicular tumor rarely, if not ever, transforms into a malignant lesion.

Pearls and Other Issues

    • Follicular adenomas are common and usually present as solitary thyroid nodules.
    • Fine needle aspiration cytology cannot differentiate between a follicular adenoma or carcinoma. A definitive diagnosis is by a tissue biopsy specimen.
    • A lobectomy and isthmusectomy are adequate for such lesions. Rarely, if other comorbidities are present, a total thyroidectomy may be necessary.
    • An interdisciplinary team approach between the surgeon, the pathologist, the radiologist must perform to optimize patient outcomes.

Enhancing Healthcare Team Outcomes

Thyroid nodules remain a challenge when it comes to diagnosis, evaluation, and clinical management. Usually, these neck swellings develop gradually as a solitary thyroid nodule, more often at the edge of the thyroid gland. These involve the isthmus or may be present over the lobes. Neck examination helps determine the location of these nodules that often are palpated or visualized over the neck. Follicular adenomas are usually the most common neoplasms that present as a solitary thyroid nodule. Adequate history and factors like age, gender, diet history( especially that of inadequate iodine supplementation), medical history, comorbidities, and radiation exposure must be considered. 

While often these cases usually present to the endocrine or general surgeon, to ensure best patient outcomes, an interdisciplinary team approach must be performed. The careful gaze of a pathologist helps determine whether the neoplasm is benign or malignant. The expertise of a radiologist helps identify sonographic features of the nodule/s or if any suspicious features coexist. This enables the primary care provider to understand the disease process better and formulate a definitive plan for management.[23][5][23]

Before surgery, routine clearances should be obtained depending on the comorbidities of the patient. Collaboration, teamwork, and careful decision making are paramount for a good outcome. Nurses assess the patient regularly and could identify surgical complications when they occur. Complications like bleeding, surgical site infection, thyroid crises, hypocalcemia may occur postoperatively. Scarring causing the patient distress, be it a hypertrophic scar or keloid formation, could be referred to as a plastic surgeon for further cosmetic management.[5][29]

In an ideal scenario, the patient should be followed up until the biopsy returns with a report confirming a benign follicular adenoma. If a malignancy is determined, aggressive management is required. The oncologist, the oncologic surgeon, must be involved at this stage to better the prognosis of the patient. Integrated interprofessional care provided to the patient, combined with an evidence-based approach, helps achieve the best results.


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