What is poorly differentiated thyroid cancer?

When clinicians describe a cancer in terms of its differentiation, we mean how much the cancer cell still resembles its cell of origin. In thyroid cancer therefore we are looking to see if the cancer cell still exhibits the characteristics of a thyroid cell. Well-differentiated cancer cells look more like normal thyroid cells and tend to grow and spread more slowly than poorly differentiated or undifferentiated cancer cells.

Differentiation is a spectrum with the most common papillary and follicular thyroid cancers remaining well differentiated and the rare, aggressive anaplastic thyroid cancer, being undifferentiated. Poorly differentiated cancers sit somewhere between these two extremes.

How common is it?

Poorly differentiated thyroid cancer (PDTC) is rare and makes up about 3-5% of all thyroid cancers. It is recognised that there is a need for more research in this area. There is not currently a standard treatment approach specifically for PDTC but it is understood that this subset of thyroid cancer requires further clinical trials to improve outcomes and to identify more targeted therapeutic approaches.

What causes PDTC?

Thyroid cancer develops when the DNA in thyroid cells changes (mutates) and the cells grow without control to form a tumour. The specific reasons that trigger this change is often not clear. There is no evidence to suggest that this type of thyroid cancer is inherited so it cannot be passed on to family members.

Our understanding of the biology of thyroid cancer is improving, particularly with molecular profiling which provides us with information about the genetic changes (mutations, fusions) which have caused the development of a tumour. This knowledge is enabling us to begin to build up patterns of tumour characteristics and signatures that may be associated with disease behaviour and prognosis. Despite the World Health Organisation defining PDTC based on pathological characteristics, the point at which a differentiated thyroid cancer becomes a PDTC is not black and white, and this is an area of continued observation and learning.

How is PDTC treated?

The treatment of PDTC is initially surgery, usually a total thyroidectomy.  Sometimes there will be a two-phase procedure with a hemithyroidectomy followed by a completion thyroidectomy if the diagnosis wasn’t certain on biopsy. Radioiodine (RAI) is usually recommended because until this is given we cannot fully predict which tumours will respond or not. RAI can be very effective in controlling disease so it is important to consider this post thyroidectomy.

In cases where RAI is not helpful, or is only helpful in the short term, which is unfortunately more likely in PDTC, the cancer is termed ‘iodine refractory’ (and sometimes called 'iodine-resistant' or ‘non-iodine-avid’). At this point drug treatment with kinase inhibitors such as Lenvatinib or sorafenib are considered. These drugs will not cure the cancer but slow down the progression and may reduce the size or amount of disease. These are drugs that are taken orally and managed as an outpatient. They have side effects such as high blood pressure, diarrhoea, rashes, weight loss and fatigue. Clinical trials are in progress to look at drugs that might be useful in the second line, i.e. once the cancer has escaped the control of either Lenvatinib or sorafenib.

The levothyroxine dose is also part of the treatment aimed at controlling the thyroid cancer growth. The dose prescribed will be slightly higher than that required purely to replace what is lost when your thyroid is removed. The slightly high doses of levothyroxine cause the Thyroid Stimulating Hormone (or TSH, which is produced by the pituitary gland in the brain) to be suppressed. The aim of TSH suppression is to keep it at less than 0.1 mU/l so that there is no stimulation of the growth of the thyroid cancer cells.

Genetic testing

If and when thyroid cancer becomes iodine refractory it is recommended that the tumour tissue is examined for genetic abnormalities. This is called molecular profiling. In rare cases a particular genetic change can be identified and there may be a drug that targets this change, so it is sensible to test all tumours in this way. In most cases it will be possible to do this testing on the specimen from your original surgery which will have been preserved in case further analysis is required

What research is there in this field?

PDTC is now a focus for research. Trials are looking into the use of immunotherapy with or without kinase inhibitors but this is not yet a proven, licensed or funded treatment option. We await further data. Another approach is to try to re-differentiate the tumour, therefore enabling it to take up radioiodine again. This is also an area of research and only available through clinical trials. Unfortunately, there are no clinical trials currently open in the UK for PDTC but it is always worth asking your oncologist as trials may become available in the future.

References/further reading

Judy's story - poorly differentiated thyroid cancer

Targeted treatment for advanced thyroid cancer FAQs 

BTF Joe Plater Research Award 2021