“Indeterminate” Thyroid Nodules

Fine needle aspiration biopsy (FNA) is the best method we have to evaluate thyroid nodules. Unfortunately, it is not perfect . In rare instances, it may suggest cancer when the nodule is benign ( false +) or it may show benign findings when cancer is actually present (false -). Overall the accuracy of FNA is usually greater than 98%.

On occasion the results from an FNA are “indeterminate” . This means that the pathologist has adequate materials to evaluate the nodule but can not draw a conclusion as to whether or not it is benign or malignant. These biopsies are usually category 3 or 4 . Remember, a “non-diagnostic” biopsy ( category 1) does not have enough material to evaluate the nodule at all.

Indeterminate biopsies are commonly reported as “ follicular neoplasms” or “Hurthle cell neoplasm”  or “atypical cellularity” or other ill-defined, but not clearly benign, wordage. The possibility for malignancy is real. The actual risk for cancer depend on a variety of associated clinical features including patient demographics such as sex and age. The size of the nodule and its appearance on ultrasound is important as well. Other risk factors, such as family history of thyroid cancer or a personal history of head and neck radiation may influence the risk an indeterminate nodule poses to the patient.

As an example, a 60 year old man with a 4 cm solid thyroid nodule whose FNA shows a follicular neoplasm, has a greater the 40% risk of malignancy. On the other hand, a 35 year old female with a 1.5 cm solid nodule found after a recent pregnancy, with an indeterminate biopsy, may have less than a 10 % risk of malignancy. Each patient and clinical situation is different and the approach to an indeterminate biopsy varies patient to patient.

Approach to an “Indeterminate” Biopsy

Historically, a patient with an indeterminate biopsy is recommended to have a diagnostic thyroid lobectomy because, commonly, malignancy can’t be diagnosed ( or excluded) without a detailed pathologic examination of the entire nodule. This is possible only by removing the thyroid lobe that contains the mass.

As an initial approach, a careful analysis of the patient’s entire clinical picture is undertaken. The pathology report is shown to at least 2 pathologists within the department to confirm the “indeterminate” opinion. Commonly, we can come to a conclusion about how best to proceed at that point. If uncertainty still exist then we have the option of repeat FNA and/or a second pathologic opinion at an outside facility. Unfortunately, while this approach sounds good in theory, sometimes we get conflicting information that doesn’t make decision making any easier.

To help with the analysis, recent research has suggested that DNA analysis of the tumor cells may help differentiate an indeterminate nodule into likely benign or malignant.  This helps us remove only those that are very likely malignant and avoid operations on people with lower risk nodules. One of the first commercially available tests for this is the Afirma test from a company called Veracyte. This test involves sending the FNA to the company facility where a second pathologic opinion is rendered and a genetic expression classifier analysis is performed where the expression of approximately 142 genes is assessed. An overall estimate of the risk for malignancy of a given “indeterminate” biopsy is developed. This can then be used to help decide if surgery is necessary or the extent of surgery. Another genetic test is the Asuragen test for a variety of genetic mutations. This may also assist in determining the risk of malignancy.

There is some expense with these tests  but most insurances allow it. Our results so far have been good but not always perfectly predictive. While the test can be helpful it is not always definitive. Some recent independant reports of its predictive power are not as favorable as initial studies. Additionally, there is the possibility that “follicular neoplasms” may be premalignant and should be removed anyway. This theory has not been scientifically proven.

In the final analysis, dealing with indeterminate biopsies involves considering a variety of clinical, personal and technical factors to make the best medical decision for the patient.