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June 2019

Thyroid Nodules

What are Thyroid Nodules?

A thyroid nodule is a radiologically distinct entity that appears different to the surrounding thyroid parenchyma usually on ultrasound scan. Nodules can be solid, cystic or a combination of these. Cystic portions are anechoic on ultrasound and they appear black with through transmission of ultrasound appearing bright at the far edge of the cyst whereas solid portions have varying degrees of echogenicity making them appear different shades of grey through to black.

What Causes Thyroid Nodules?

Firstly, thyroid nodules are very common appearing in 3-5% of the population as a palpable lump and in 20-70% of the population on neck ultrasound. They are more common in women and with increasing age. The vast majority of thyroid nodules are benign ( non cancerous) but up to 5% of thyroid nodules will be thyroid cancers. Benign nodules are more common in areas of iodine deficiency,  in patients with a background of autoimmune (Hashimoto’s) thyroiditis and also in those who have had radiation exposure to the thyroid gland. Thyroid nodules occur in families indicating that, at least in some cases, there is a genetic basis to their development. Studies have demonstrated up to 25% of benign nodules have mutually exclusive genetic mutations that are different to those found in papillary thyroid cancers. The mutations responsible for development of thyroid cancers include: BRAF, RET and NTRK-1  in PTC;   Pax8-PPARgamma and RAS group mutations in FTC; TP53 in ATC : and RET mutations in MTC. the RET mutations in PTC are seen most often in children that have been exposed to radiation.

Symptoms of Thyroid Nodules.

Small nodules are often asymptomatic but as they increase in size they can cause compressive symptoms and patients will complain of the sensation of pressure on the trachea (windpipe), the sensation of a lump associated with swallowing and even a gagging sensation. these symptoms are usually associated with nodules over 3 cm in size. As the nodules become even larger and particularly in the setting of multiple nodules as in a multi nodular goitre (MNG), patients may  experience further compression that can lead to shortness of breath, cough and wheeze. The voice can frequently be altered in this situation and patients can also have pain  if there is bleeding into thyroid nodules. Bleeding into nodules is not uncommon and patients present with the sudden onset of a thyroid lump and discomfort that settles over a few days as the nodule gets smaller. Occasionally thyroid nodules can be metabolically overactive and a patient will present with symptoms of hyperthyroidism or thyrotoxicosis including tremor, tachycardia, sweating, anxiety, heat intolerance and agitation. As lymphocytic thyroiditis is a precursor for thyroid nodularity patients with thyroid nodules may also have symptoms of hypothyroidism.

How are Thyroid Nodules Investigated?

The important primary investigations for a patient with a known or suspected thyroid nodule include and ultrasound scan and thyroid function tests.

Ultrasound Scan

Ultrasound is a highly accurate investigation for looking at the details of a nodule and for assessing its risk for being a cancer. There are several scoring systems that have been devised to identify the degree of risk and which nodules should be recommended for Fine Needle aspiration (FNA) biopsy, observation  or no follow up. The one in wide use in Auckland is The TIRADS system from the American College of Radiology (ACR). This system scores thyroid nodules based on shape, margin, echogenicity, density , and whether there are calcifications within the nodules. Scores range from TR1 (benign) through TR6 (biopsy proven malignancy) and then size is used to make recommendations regarding FNA. An online TIRADS Calculator makes this an easy system to utilise. A nodule with a TIRADS score of TR5 that is over 1cm in size should have a FNA similarly a nodule that Scores TR3 should only have FNA if it is >2.5cm and should be followed if it is >1.5cm.

A TIRADS TR5 nodule that is solid, hypoechoic, Taller than wide, Has an irregular margin and contains punctate echogenic foci (PEF) it is over 1 cm in size and biopsy is recommended.

A TIRADS TR5 nodule that is solid, hypoechoic, Taller than wide, Has an irregular margin and contains punctate echogenic foci (PEF) it is over 1 cm in size and biopsy is recommended.

TIRADS TR3 nodule that is isoechoic, spongiform, wider than tall shape, has an irregular margin and no calcifications. As it is 1.5 observation is recommended.

TIRADS TR3 nodule that is isoechoic, spongiform, wider than tall shape, has an irregular margin and no calcifications. As it is >1.5cm (in vertical dimension not shown)  observation is recommended.

Fine Needle Aspiration (FNA) Biopsy

FNA is an important second line investigation in the management of thyroid nodules. As mentioned above, the ultrasound study can allow risk stratification of thyroid nodules and identify which nodules should undergo biopsy. There are also a variety of risk assessment tools for FNA around the world and here in Auckland we use The Bethesda System developed by the NIH and adopted by the American Thyroid Association. Again, there are six categories with Bethesda 1 being non diagnostic and Bethesda 6 diagnostic of malignancy. See table 1

Table 1. The Bethesda System for thyroid cytopathology with associated risk of malignancy per category in 2009 and 2017.

Table 1. The Bethesda System for thyroid cytopathology with associated risk of malignancy per category in 2009 and 2017.

There is a risk of malignancy associated with each category as shown in table 1 and this has changed over time with increased data and changes in diagnostic categories. I find in my own practice that FNA performed under ultrasound guidance gives a much higher yield of diagnostic aspirates and I perform nearly all FNA biopsies under ultrasound guidance.

Thyroid Function Tests

Thyroid function tests are necessary when investigating thyroid nodules. It is important to know whether a nodule is overactive because if so, it would be extremely unlikely to be malignant and also thyroid surgery is an appropriate way of managing a toxic nodule. It is important also to know whether a patient is hypothyroid as the risk of malignancy is higher in patients with a background of lymphocytic (hashimotos) thyroiditis.

Go to Treatment of thyroid Nodules and Cancer

Types of thyroid cancer

There are several different types of thyroid cancers and they are broadly broken into categories based on the cells that they originate from and their behaviour. Most thyroid cancers are low grade, differentiated thyroid cancers that originate from thyroid follicle cells, generally behave in an indolent fashion and have very high rates of survival. At the other end of the spectrum are anaplastic thyroid cancers that are among the most aggressive human cancers, have a rapidly progressive disease course and have  rates of disease specific death approaching 100%. In between these are a group of poorly differentiated cancers that also originate from thyroid follicular cells, occur in older patients and do worse than differentiated thyroid cancers. Finally, there is medullary thyroid cancer, a neuroendocrine tumour of parafollicular c cell origin that just happens to occur in the thyroid gland but is not of thyroid cell origin. We now understand quite a lot about the molecular pathways involved in the development of thyroid cancers and this has helped to classify variants of these tumours and also helped to identify therapeutic strategies in cancers that are beyond surgical treatment. The mainstay of treatment of thyroid cancer however, remains  surgery and the vast majority of thyroid cancers are cured with this and sometimes the use of I131.

Differentiated Thyroid Cancer

Papillary Thyroid Cancer

Papillary thyroid cancer (PTC) is the most common thyroid malignancy making up 75-80% of all thyroid cancers. It occurs in woman 4 x more frequently than men and is predominantly a tumour of adulthood in the child bearing age group but it does occur in children. 67% present with a thyroid nodule, 13 % present with a nodule and lymph nodes and 20% present with lymph nodes alone. Lymph nodes can be small and can undergo cystic change and be mistaken for branchial cleft cysts. Occult micropapillary cancers occur in 6% of the population and are present at autopsy. There are a number of variants of PTC some of which have behaviour similar to or better than classic variant PTC like Follicular Variant , Encapsulated Variant, Cribriform-morular variant and Diffuse Sclerosing variant. Some have worse behaviour and generally occur in older patients such as Tall Cell Variant, Columnar Cell Variant, Hobnail Cell Variant and Solid and Trabecular Variant PTC.

Follicular Thyroid Cancer

Follicular thyroid cancer (FTC) is the next most common making up 6-10% of all thyroid cancers. 75% occur in women and age incidence peaks at 40-60 years. Iodine deficiency and radiation exposure are risk factors. Most present with a thyroid nodule and lymph node involvement is uncommon but up to 69% develop distant metastases to lung and bone . There are 3 main types of FTC: Minimally Invasive FTC with a very good long term prognosis, Encaspulated Angioinvasive FTC which does worse and Widely Invasive FTC with a high distant metastatic rate and 50% longterm mortality.

Hurthle Cell Thyroid Cancer

A follicular tumour with >75% oncocytic cells. The oncocytic (Hurthle) cells are due to being packed with abnormal mitochondria. These tumours are most common in older men ( mean age 57yrs). Hurthle cell cancers are more aggressive than follicular cancers with more extrathyroid extension, more metastases to lymph nodes and higher rates of mortality ( up to 80%)

Poorly Differentiated Thyroid Cancer

This is a malignancy of Follicular cell origin that makes up 0.3-7% of all thyroid cancers. It occurs in older patients and presents as a large solid thyroid mass. There is a high rate of nodal and haematogenous metastases and a 3 yr survival rate of around 35%. It has behaviour that sits between differentiated thyroid cancer and anaplastic cancer and can originate de novo or from a differentiated thyroid cancer or goitre and can under go a series of mutations to de-differentiate. There are insular, solid and trabecular variants and these cell pattern types can be mixed. Tumours must also demonstrate tumour necrosis, a high mitotic rate and or convoluted nuclei.

Medullary Thyroid Cancer

A neuroendocrine tumor derived from C cells  of the ultimobranchial body of the neural crest, which secrete calcitonin. Makes up  1 – 2% of thyroid carcinomas. 70% are  sporadic (nonhereditary) and 30% familial (hereditary). The sporadic tumours are solitary and peak in ages 40 – 60. The hereditary type occurs in  younger patients (mean age 35) and are usually bilateral and  multicentric with C cell hyperplasia. Familial MTC is due to MEN 2A or 2B syndromes, familial medullary thyroid carcinoma (FMTC) syndrome, von Hippel-Lindau disease or neurofibromatosis. This is caused by gain of function germline mutations in the RET gene. Presents as a hard thyroid mass and up to 75% have nodal metastases. Serum calcitonin correlates with tumour burden and those with systemic metastases may have diarrhoea and flushing. 5 year survival is 65-90% and prognosis is worse with higher stage, nodal metastases, male, MEN2B, 918RET mutation, high mitotic activity and vascular invasion.

 

Anaplastic Thyroid Cancer

Anaplastic thyroid cancer (ATC) is among the most aggressive and deadly human cancers. It makes up 2-5% of thyroid cancers but is responsible for 40% of thyroid cancer deaths. This tumour presents as a rapidly progressive large neck mass with invasion of central compartment structures associated symptoms of hoarseness, dyspnoea and dysphagia. There are usually involved lymph nodes and 30-40% present with distant metastases. 50% have a prior multi nodular goitre and 20% have a prior differentiated thyroid cancer. 20% have a concurrent differentiated thyroid cancer and dedifferentiation occurs in this tumour with a high rate of TP53 mutation. 1 year survival is in the 10-20% range.

 

Thyroid cancer warning signs.

1. Thyroid nodule:

The most common presentation of thyroid cancer is a nodule in the thyroid gland. Cancerous nodules tend to be harder, more fixed, larger  and more irregular than non cancerous nodules.

thyroid ultrasound showing right thyroid cancer

thyroid ultrasound showing right thyroid cancer

Thyroid cancer is also highly likely in a patient who has a thyroid nodule and has:

2. Lymph nodes:

Thyroid cancer lymph nodes are frequently cystic and can often appear lower in the neck than metastases from other head and neck primary sites. The nodes are usually large, round and have loss of the normal architecture. The appearance on ultrasound often mimics the appearance of the primary thyroid cancer and punctate echogenic foci (PEF) appearing as small bright flecks can often be seen.

metastatic left level 2 neck lymph node

metastatic left level 2 neck lymph node

3. Hoarse Voice:

Less commonly thyroid cancer can invade surrounding structures and the most common structure is the recurrent laryngeal nerve that supplies muscles of the voice box. This can lead to a breathy and hoarse voice.

4. Haemoptysis (coughing up blood):

The trachea (windpipe) is next most commonly involved and invasion of this can lead to bleeding

5. Stridor (noisy breathing) and shortness of breath:

Also caused by tracheal invasion

6. Dysphagia (difficulty swallowing):

Invasion of the oesophagus can lead to increasing difficulty swallowing. This is relatively uncommon and usually the muscle of the oesophagus is involved and not the mucosal lining

7. Family history of thyroid cancer:

A patient with a strong family history of thyroid cancer and a nodule has a higher risk of thyroid cancer. Particularly in medullary thyroid cancer. This is far less of an issue in papillary thyroid cancer unless there are 3 first degree relatives in a family with the diagnosis

8. History of radiation to neck:

A patient with a thyroid nodule and a history of previous therapeutic or environmental radiation exposure particularly in childhood is at much higher risk of having thyroid cancer. Populations who live in iodine deficient areas and around volcanoes are also at much higher risk of thyroid cancers.

9. Ultrasound risk features:

A thyroid nodule that is solid, hypoechoic ( darker on ultrasound), an irregular margin, taller than wide in shape and has multiple punctate echogenic foci is high risk for being a thyroid cancer. These features are used in scoring systems that are used as risk assessment tools for thyroid nodules to determine which should be biopsied or observed and which can be ignored. One such system in common use in Auckland is the TIRADS system.

Thyroid nodule in left upper pole: Hypoechoic, solid, taller than wide and irregular margin with punctate echogenic foci. TIRADS TR5

Thyroid nodule in left upper pole: Hypoechoic, solid, taller than wide and irregular margin with punctate echogenic foci. TIRADS TR5

10. Diarrhoea: 

Patients with a thyroid nodule and persistent diarrhoea may have medullary thyroid cancer with an elevated calcitonin level that leads to the diarrhoea. These patient will also usually have an elevated CEA level which is a non specific marker for cancer.

 

Any patients with these features should be referred early for assessment with Examination, laryngeal endoscopy, ultrasound and FNA biopsy all available in one stop in Dr Chaplin’s practice at Mauranui Clinic

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