Follicular Adenoma

Etiology

Although follicular adenomas are mostly sporadic, multiple other etiological factors have been identified[6][7][8]. 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 BRAF, NRAS, 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.[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]; small nodules, measuring less than 15 mm in diameter, have a prevalence of 5 to 10% (based on autopsy studies)[16]. The data vary between different geographic areas, Finland having the highest reported incidence of occult microcarcinomas [17]. Thyroid adenomas are typically more common in females.[18] Data in the US, more or less, reflect the same incidence for development.

During the past 30 years, the incidence of thyroid cancer has raised from 4.3 cases per 100,000 in 1980 to 12.9 cases per 100,000 in 2008 [19], and there is a strong debate in whether the increase in incidence should be considered an artifact of improved detection[20]. The availability of ultrasound imaging, the technological improvement in medical equipment, the increased awareness in the general practice and among patients, the screening campaigns in higher-risk population[21][22] are all factors that contributed to an increase in incidence rates. 

The incidence rates for thyroid nodules are also increasing in the pediatric population; increased detection is surely a great component but can only explain a part of the cases [19][20]. Birth cohort analyses showed the correlation with environmental exposures (such as diagnostic radiography, cosmic radiation[23], and other exposures[24][25]). Studies on individuals exposed to I-131 radiation after Chernobyl's nuclear accident revealed an excess odds ratio per Grey of 2.22 equal for both sexes, with the odds ratio increasing with higher doses. Children aged less than two years were found to have the highest risks[9]. Population studies[10][11] indicate that when a specific etiology (i.e. radiation) is involved, the incidence differs from the normal population. The peak in incidence seen in the last 30 years cannot be fully explained by the increased detection, suggesting that there might be a true increase, but the specific causing agent has not been identified yet.

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 BRAF, NRAS, 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.[26]

Histopathology

Follicular adenoma is grossly described as a solitary, encapsulated nodule; the size can be extremely variable, ranging from a few millimeters to 10-15 cm. The color vary from tan to light brown with solid and fleshy appearance. It can resemble multinodular goiter due to secondary changes in hemorrhage and cystic degeneration.

Histological examination of the nodule reveals a follicular architecture present in the entire or nearly entire lesion[27]. The nodule can be described as either microfollicular or macrofollicular growth pattern, and the thyrocytes have a normal cytological appearance. Follicular adenoma is usually a solitary encapsulated lesion and does not have any features suggestive of vascular or/and invasion of the adjoining capsule or to the neighboring thyroid tissue. Degenerative changes within the nodule may be seen in cases of prior FNA (fine needle aspiration performed for cytological diagnosis), which could result in degenerative changes.[28] 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.[27] 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.[29] 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.[30]

Toxicokinetics

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

History and Physical

Most patients with a follicular adenoma present with solitary thyroid nodule in an 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.[18]

Evaluation

Thyroid nodules are evaluated according to the American Thyroid Association Guidelines[31][32]. The four main parameters to assess in a thyroid nodule evaluation are detailed patient history, physical examination, baseline serum TSH assay followed by an ultrasound. The ultrasound examination provides important informations regarding size and feature of the nodule so it determines the following steps of evaluation. In general, follicular adenomas are benign but could have characteristics akin to follicular carcinoma; also an important differential diagnosis is with the non-invasive follicular thyroid neoplasm with papillary-like nuclear features or NIFT[33][34]. 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.[35]  Nodules with a size >1 cm should be completely evaluated since they have the potential to be, or evolve to, cancer. Occasionally nodules <1 cm require evaluation is symptomatic or associated with lymphadenopathy. Preliminary laboratory assessment, including a baseline thyroid function test, helps determine the status of the gland (euthyroid, or hyper/hypothyroidism). When indicated, aspiration by a fine-needle (FNA) to obtain a cytological sample can aid in narrowing down to a diagnosis. 

Sonographic features of both follicular adenoma and follicular carcinoma are similar and careful examination can help distinguish the two entities. An extensive lesion size, hypoechogenicity, mixed or solid echotexture, absence of sonographic halo, micro/rim calcifications favor the malignant counterpart.[36][5][37] The lack of internal flow, or a predominantly peripheral flow are associated with a reduced probability of thyroid follicular malignancy.[38] A neck US should be performed during the thyroid evaluation. It is a time-efficient manner to evaluate all patients with a thyroid nodule, nodular goiter, or in cases of a thyroid nodule incidentally detected in other ways. The presence of a solid hypoechoic component in nodules with irregular margins, microcalcifications, taller than wide, rim calcifications are strongly suspicious and should be evaluated with FNA if the size is at least 1 cm. Nodules that are isoechoic or hyperechoic solid or partially cystic without the suspicious feature of irregular margins, microcalcifications, taller than wide, rim calcifications, should be evaluated with FNA only if bigger than 1,5 cm. Purely cystic nodules are considered not at risk and do not need evaluation with cytology.

In thyroid nodules >1 cm (in any diameter) it is recommended to measure serum thyrotropin (TSH) during the initial evaluation. If the TSH is low a I thyroid scan should be performed, if TSH is normal or elevated the radionuclide scan is not recommended. Radionuclide scanning can be evaluated together with US findings, FNA reports and clinical information.[4] Simple follicular adenomas show less uptake on radioiodine scintigraphy comparing with functioning follicular adenomas, which increase absorption and concentrate radioiodine within the nodule; the internal control is the neighboring tissue of the gland showing a suppressed uptake.[5]

Serum Tg levels should not be measured in the initial workup of a thyroid nodule because has a low specificity rate in the general evaluation but should be monitored in selected cases (i.e. after total thyroidectomy). Laboratory screening for calcitonin is neither recommended nor inappropriate: serum calcitonin can be evaluated for screening purposes because it may detect incidentally C-cell hyperplasia or medullary thyroid cancer at an earlier stage, improving overall survival.

CT scan and MRI have a limited role in the initial evaluation f solitary thyroid nodule.[39] Indications for these imaging techniques include suspected tracheal involvement, either by invasion or compression, extension into the mediastinum, or recurrent disease.

FNA is performed to provide a cytological examination of the nodule, and it remains the mainstay for assessing these lesions, although it may not provide a diagnosis in all cases.[7] The success rate of FNA is improved when the procedure is done under ultrasound guidance. The cytopathological findings are reported using one of the three major international nomenclatures: the British Thyroid Association and Royal College of Pathologists (Thy), the Italian Consensus (TIR) and the Bethesda System for Reporting Thyroid Cytopathology[40][28]. Thyroid nodule fine-needle aspiration (FNA) washout may be examined for calcitonin in the preoperative evaluation in patients with elevated serum calcitonin (20–100 pg/mL). In patients with follicular adenoma the cytological sample has abundant follicular epithelial cells organized in sheets with crowding and overlapping of cells, microfollicle formation with scant or absent 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". Molecular assessment of indeterminate cytology can be helpful[28]. A final diagnosis of follicular adenoma is made only after ruling out capsular and vessel invasion by standard nodulectomy or thyroidectomy with subsequent histological examination. Frozen section should not be requested in clinically benign nodules but is a common practice in cases of suspect papillary thyroid carcinoma hence its evaluation intraoperatively can guide in performing lymphadenectomy.

Treatment / Management

Usually, surgical management is preferred when it comes to follicular lesions.[5][4][35]

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][27]

• 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.[26] N-RAS and K-RAS have been implicated in this transformation.[41] 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.[42] 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:[43]

• 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