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Subspecialties Clinical care, Screening and monitoring, Microscopy and imaging, Histology

Benign or Malignant?

At a Glance

  • No clinical or imaging test allows the easy differentiation of benign from malignant thyroid follicular nodules
  • Even with the application of cytology, positive results for malignancy require additional, invasive testing to confirm
  • Some thyroid lesions that appear malignant at first glance may, in fact, be indolent and require little or no treatment
  • Pathologists must proceed conservatively with thyroid nodules in the absence of clear-cut invasive features

Thyroid nodules are of clinical significance because of the ever-present danger that they may represent cancer. In most cases, it is impossible to distinguish clinically benign from malignant thyroid follicular nodules; no clinical test or imaging modality can provide an answer for the clinician. That’s why tissue diagnosis has become the gold standard for the evaluation of thyroid nodules. The most commonly employed technique is fine needle aspiration (FNA) cytology. FNA is the least invasive technique, it’s easy to perform in the doctor’s office or in an outpatient setting, and it’s both quick and cheap. Unfortunately, it’s also only a screening procedure; in most instances, when it yields a suspicious or positive result for malignancy, it must be followed by biopsy or excision of the lesion.

Papillary pitfalls

The interpretation of thyroid follicular nodules can be tricky, and pathologists should be aware of several pitfalls. The most important one, of course, is separating benign from malignant lesions. Complete and thorough sampling is indispensable for accurate diagnosis – and it’s something that may be overlooked, or may not happen without pathologist oversight. Another potential pitfall lies in establishing reliable and reproducible criteria for defining vascular and capsular invasion; there is still significant variability in the perceptions of, and criteria applied by, different pathologists. Finally, the subjective element involved in deciding on the nuclear features of papillary carcinoma is a factor that we can no longer ignore, given that none of the accepted features we use today are limited to papillary cancers; the degree of change required to declare a tumor malignant can vary from pathologist to pathologist.

Misdiagnosis of malignant thyroid nodules as benign can lead to undertreatment, creating the potential for spread and dissemination of the disease. On the other hand, interpreting a benign lesion as malignant may result in unnecessary overtreatment – along with its attendant morbidity, cost and potential decrease in the patient’s quality of life.

Examples of follicular nodules showing infiltration of the capsule by tumor. In all three cases shown, the infiltration is not complete and does not break through the capsule into the surrounding tissues. In such cases, the pathologist must exercise caution not to overcall the lesion a “minimally invasive follicular carcinoma,” and should expend extra effort in making sure that there is no evidence of vascular invasion on extensive and complete sampling of the capsule.

A diagnostic how-to

To diagnose a follicular neoplasm, the standard criteria involve demonstration of capsular or vascular invasion. In papillary neoplasms, the main diagnostic criterion for the past 30 years has been the nuclear features of the tumor cells; however, more recent studies have reintroduced architecture and circumscription as indispensable criteria for the diagnosis of papillary thyroid carcinoma, particularly the follicular variant. A recent JAMA Oncology study (1) by an international collaboration of pathologists indicated that tumors with the cytologic features of this variant, if well-circumscribed or encapsulated (i.e., noninvasive), are associated with indolent behavior and should be designated as “noninvasive follicular neoplasms with papillary-like features” (2) to avoid overtreatment; lobectomy alone is generally curative in those patients.

Immunohistochemistry (IHC) plays a limited role in the diagnosis of follicular neoplasms of the thyroid. IHC can be used in equivocal cases to tilt the scales in favor of benign versus malignant, but should be used sparingly and not regarded as definitive proof either way.

Instead, we now use molecular testing to further stratify tumors by assaying for various genetic alterations commonly associated with thyroid cancers (such as BRAF, RAS, or PPAR). The presence of such alterations points toward a clonal process operating in a given tumor and supports the neoplastic versus hyperplastic nature of the lesion. But unfortunately, these methods are far from foolproof. Certain genetic alterations, such as BRAF  V600E, are a clear marker for papillary thyroid carcinomas, but they are not present in all cases – and that means their absence cannot be used as evidence for a benign process. Molecular testing holds great promise for the assessment of thyroid nodules and, as new studies are published and new technologies are implemented, I expect great progress over the next few years.

When a thyroid nodule is unequivocally benign or unequivocally malignant, diagnosis is straightforward and does not require ancillary tools – just the humble H&E-stained slides. The problem arises in borderline or equivocal cases in which the features are not clear-cut. Such cases can benefit from the restricted use of IHC and molecular testing – but, in a small percentage of cases, even these techniques won’t resolve the issue. My recommendation in the absence of clear-cut invasion, unequivocal infiltration of surrounding tissues, or evidence of vascular invasion, is to exhibit great caution in calling any lesion – particularly a follicular neoplasm – malignant. In such instances, I prefer to use the terminology proposed by the Chernobyl Group of Pathologists in 2000 – “follicular neoplasm of undetermined malignant potential” – with a note recommending close clinical follow-up to avoid unnecessary, aggressive treatment (3).

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  1. YE Nikiforov et al., “Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors”, JAMA Oncol, 2, 1023–1029 (2016). PMID: 27078145.
  2. M Schubert, “When Is a Cancer Not a Cancer?”, The Pathologist, 19, 15 (2016). Available at:
  3. ED Williams, “Guest editorial: two proposals regarding the terminology of thyroid tumors”, Int J Surg Pathol, 8, 181–183 (2000). PMID: 11493987.
About the Author
Saul Suster

Saul Suster is Professor and Chairman in the Department of Pathology and Laboratory Medicine at Medical College of Wisconsin, Milwaukee, USA.

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