1- What is a thyroid nodule?
Thyroid nodules are an almost para-physiological condition, therefore extremely common especially in people over 50 years old. The nodules in question are generally very small and benign. The benign nodules, which have no clinical significance, are much more common than malignant ones. In the past, when the diagnostic techniques were not so good as today, only nodules of a certain size were diagnosed: first because they caused a compressive symptomatology towards the esophagus, trachea or larynx; secondly for aesthetic reasons.
Anamnesis is fundamental in the patient who has thyroid nodules. Family history is initially investigated to identify any predispositions to thyroid tumors and then move on to the history of the lump of the patient (if new onset, already present etc …). The physical examination assesses the consistency and relationships of the lump with the neighboring structures; nodules of elastic consistency, smooth and painless tend to be benign. Blood tests allows you to determine if thyroid nodular pathology is associated with dystiroidism (alteration of thyroid function). The first test concerns TSH (thyrotropin) which, if altered, allows to carry out tests aimed at detecting the free fractions of thyroid hormones (freeT3 and freeT4). If you have a lump and blood tests with high TSH, low fT3 and fT4 we are in a case of hypothyroidism. This condition is most frequently caused by one autoimmune condition. If, on the other hand, a single lump is present, with TSH low or zeroed, fT3 slightly high and fT4 very high compared to the normal threshold, you are in a condition of hyperthyroidism that may be caused by the lump in the form of a hyperfunctioning autonomous adenoma (toxic or Plummer adenoma) or by Graves’ disease. Ultrasound is the gold standard for diagnosis in thyroid disease. This allows to detect and analyze microcalcifications, vascularization, peripheral halo, infiltrative forms and margins. These are not pathognomonic features, but if taken together they can strongly direct towards diagnosis of neoplasm.
Thyroid scintigraphy uses Technetium59 as a tracer, and is used to differentiate hot nodules from cold nodules. Scintigraphy was much more used in the past, when the ultrasound had not yet been perfected and therefore not able to identify the nodular characteristics. Today scintigraphy is used mainly to identify hyperfunctioning nodules that cause lower TSH. Following these tests, if the clinical doubt arises that the lump may conceal a tumor, we proceed with an ultrasound-guided fine needle aspiration under ultrasound guidance followed by a cytological examination. If before they could only sting clinically visible nodules, today it is possible to prick nodules of a few millimeters thanks to the ultrasound guide. Cytological examination reveals the nature of the lump: cystic, adenomatous, neoplastic, indeterminate. In undetermined lesions normal thyrocytes (follicular cells) are identified, however these can be part of a follicular carcinoma. A carcinoma or a follicular adenoma is not distinguished through cytology (the structure of the thyrocyte remains normal) but through a histological examination (preceded by a biopsy) which allows to identify the infiltration of the capsule and the vessels and thus make a diagnosis of carcinoma follicular.
Cytological examination following needle aspiration can give different results:
– Tir1: non-diagnostic. This result may also be due to operator errors. About 20% of cytological samples is inadequate and to repeat a needle aspiration it is necessary to wait 2-3 months for the hematoma caused by the previous reabsorbs;
– Tir2: it is found simply colloid therefore it is an indication of a benign nodule;
– Tir3: follicular/indeterminate proliferations. Based on the number of cells and the presence of colloids, the pathologist tries to discern between: Tir3A or low risk malignancy nodules that need only follow up; and Tir3B or nodules with high malignancy risk that require surgical treatment;
– Tir4: suspected malignant nodule. Patients are referred to the surgeon.
– Tir5: malignant nodule. Patients are referred to the surgeon.
2- Malignant Thyroid Nodules
Malignant thyroid nodules can be classified as:
– Differentiated: originating from a tumor degeneration of thyroid cells (thyrocytes responsible for follicular thyroid cancer and papillary thyroid cancer; parafollicular cells responsible for medullary thyroid carcinomas);
– Undifferentiated: Anaplastic thyroid cancer, resulting from the dedifferentiation of a differentiated tumor of the thyroid. Unlike differentiated tumors, anaplastic carcinomas lose the ability to collect iodine (and therefore intuitively they cannot be treated with radiotherapy with radioactive iodine).
– Non-Epithelial cells (rare): Linfoma; Sarcoma; Metastasis (frequently from kidney, lung and mammary gland)
PAPILLARY THYROID CANCER
About 75-80% of thyroid malignancy is Papillary thyroid cancer (PTC). It can be diagnosed on cytology obtained by fine needle aspiration, where It has characteristic nuclear and cytoplasmic changes.
Malignant thyroid nodules can be classified as: Papillary thyroid cancer has a peak of incidence in the third and fourth decade of life. Ofter it presents itself as multifocal, with very low tendency to give blood metastasis (to lungs, liver, bones and central nervous system), which however increases in untreated patients or elderly. PTC has a local invasiveness through the glandular and lymphatic capsule, therefore it presents very early metastasis to lymph nodes. Fortunately, it is good to remembered that it has an extremely slow growth, and even if there is any lymph node metastasis, the prognosis is very good when well treated. Surgery and radioiodine are very effective treatments: 95% of patients survive after 10 years from diagnosis. One type of papillary carcinoma does not capture iodine and is poorly differentiated: Insular Thyroid Cancer. It is recognizable by histological examination, and it does not follow the classic course of PTC. The prognosis is usually poor.
FOLLICULAR THYROID CANCER
About 10-15% of thyroid malignancies are Follicular Thyroid Cancers. Differently from follicular thyroid adenoma, the follicular thyroid carcinoma invades the follicular capsule and the vessels, with very low tendency to give lymph node metastases but high tendency to give hematogenous metastases towards lung, bone and Central Nervous System. They have a worse prognosis than PTC.
Follicular thyroid cancer is not multifocal, and it has a relatively slow growth. Treatments involve surgery and radioiodine: 75% of patients survive after 20 years from diagnosis.
These carcinomas include Hurtle cell cancer, which is a slightly more aggressive variant.
MEDULLARY THYROID CANCER
About 5% of thyroid malignancies are Medullary Thyroid Cancers: it occurs sporadically in 75% of cases, or in family forms (15% of cases) where it tends to be multifocal. This type of thyroid cancer does not originate from thyrocytes (cells that from thyroid follicle) but from parafollicular cells (or C cells), whose job is to produce calcitonin, an hormone involved in Calcium homeostasis. They are involved in two characteristic endocrine tumor genetic syndromes: multiple endocrine neoplasia 2 or MEN2. In this syndrome, medullary thyroid cancer coexists with pheochromocytoma: that’s why as a doctor diagnoses Medullary cancer he has also to look for pheochromocytoma before suggest surgical removal of the thyroid (when possible). It has a very high tendency to early lymph node diffusion and for this reason it has surgical indication of lymphadenectomy (lymph nodes surgical removal) even if there is no evidence of pathological lymph nodes. One of the peculiar markers of these tumor types is the increase in calcitonin levels which strongly addresses the diagnosis. However confirmation by cytological examination is mandatory. Survival is 75% at 10 years and therapy this time does not involve radioiodine, since C cells do not pick up iodine.
ANAPLASTIC THYROID CANCER
Anaplastic thyroid carcinoma is characterized by a very high subversion of cell morphology. It is very rare, but more frequent in elderly patients (because in older patients cancer has the time to dedifferentiate from a differentiated form, often from a follicular cancer). It has a very high tendency to infiltrate adjacent structures such as trachea, esophagus, vessels blood, skin. It is a very aggressive tumors that are often detected when inoperable or when it has already given distant metastases. Palliative therapies such as feeding tubes (in case of esophageal infiltration), tracheal prostheses to keep the lumen patent and any chemotherapy, radiotherapy and surgery to reduce mass are usually used in these patients. It is very invasive locally, lymphatically and hematogenously and has an average survival time from the diagnosis of 6 months.
3- Thyroid: Anatomy and Embyology
The thyroid is an endocrine gland located in the anterior median median of the neck. It consists of two lateral lobes united by a bridge, called isthmus. The thyroid is applied on the ventral surface of the larynx and the first two tracheal rings. It is partially covered by the sternocleidomastoid, sternothyroid and homoioid muscles, belonging to the subioid muscle group and from the middle cervical fascia that wraps them. For the characteristic oblique direction of the aforesaid muscles, the gland is no covered by along the midline. Here, just two cervical fascia, medium and superficial, separate thyroid from the skin.
Laterally, however, the gland is also covered by the two sternocleidomastoid muscles and more superficially from the bundles of the platysma muscle (you cannot see the platisma in the image above). The drawing below shows the path of the thyroid gland during embryogenesis. Thyroid originates from the thyroglossal duct. It is possible that during migration some tissue residues in the path, then it can give rise to cysts of the thyroglossal duct which can manifest as congenital benign lesions without pathological consequences, if not of aesthetic impact.
These cysts can be removed by the surgeon. On physical examination, in presence of a normal thyroid volume and in absence of nodular thyroid alteration, thyroid is not palpable. Thyroid palpation is executed from behind of the patient or alternatively with the patient in a supine position.
THYROID MICROSCOPIC ANATOMY
The thyroid gland is composed of a single-layer epithelial tissue that makes up the follicule, the structure basic anatomy of the thyroid. In the image below you can see how thyrocytes are disposed in a single layer around a central cavity called colloid so called because of the fact itself which contains colloid, a gelatinous substance which is more than 99% composed of thyroglobulin, the molecular precursor of thyroid hormones consisting of tyrosine molecules.
In addition to follicular cells or thyrocytes, the parenchyma is made up of another cell population: C cells or parafollicular. These cells have an endocrine function independent of the follicular thyroid function. Their product is an hormone called calcitonin, which participates in the regulation of phospho-calcium metabolism (which will be covered in other thyroid pills). The elevation of this hormone rarely has a physiological meaning. mostly it is pathological, being an indicator of malignant neoplasm of the thyroid gland, especially of medullary thyroid cancer. Calcitonin presents a diagnostic sensitivity is very high. When elevated calcitonin is present associated with a nodule or presumed neoplasm of the thyroid gland, it is almost certain that that neoplasm is a medullary thyroid cancer.
4- Thyroid cysts
Thyroid cystic lesions are a frequent finding in Thyroid Ultrasound (US) clinical practice, representing up to 30% of all thyroid nodules studied by US. In almost all cases, it is a completely benign finding.
Pure thyroid cyst are less frequent, explaining about 1% of thyroid nodule, while hemorrhage and necrotic changes are seen in the most art of thyroid cysts. Normally, these lesions are completely asymptomatic: however, they can produce cosmetic or compressive discomfort. Fine-Needle aspiration (FNA) of the fluid content can transiently relief symptoms, but in up to 80% of cases, thyroid cysts recur after FNA. In the last 25 years, PEI has been successfully used to treat thyroid cysts, whit a reduction of cosmetic and symptomatic problem in about 70% and 80% of patients, depending of the study series. PEI is currently considered the first-line and resolutive treatment for cystics lesions causing local discomfort and/or cosmetic concerns in patients.