Journal of Head & Neck Physicians and Surgeons

: 2021  |  Volume : 9  |  Issue : 2  |  Page : 69--72

Differentiated thyroid cancer: Then and now. A personal perspective

Anita M Borges 
 Department of Histopathology, S L Raheja Hospital; Centre for Oncopathology, Mumbai, Maharashtra, India

Correspondence Address:
Dr. Anita M Borges
S L Raheja Hospital, Mahim, Mumbai - 400 001, Maharashtra

How to cite this article:
Borges AM. Differentiated thyroid cancer: Then and now. A personal perspective.J Head Neck Physicians Surg 2021;9:69-72

How to cite this URL:
Borges AM. Differentiated thyroid cancer: Then and now. A personal perspective. J Head Neck Physicians Surg [serial online] 2021 [cited 2022 Jan 20 ];9:69-72
Available from:

Full Text

I have spent over 40 years as a surgical pathologist in oncology. I have seen trends come and go, hype settle into reality, and continuous change happen in our conceptual understanding of cancer. I have chosen thyroid cancer to track this long journey because this field has always been in ferment. It would be impossible to write a review of all the changes in thyroid neoplasia that have occurred in my lifetime. I will therefore restrict myself to the evolution of the classification of differentiated thyroid cancer, its molecular pathology with special reference to encapsulated nodules, and the role of fine-needle aspiration cytology (FNAC) in its management.

 Evolution of the Classification of Differentiated Thyroid Cancer

I am old enough to remember a time when thyroid cancer was classified into four types: follicular, papillary, mixed follicular and papillary, and undifferentiated. Medullary carcinoma was unrecognized until it was described by Hazard, Hawk, and Crile in 1959.[1] Thereafter came the classification of thyroid neoplasms into those derived from follicular epithelium and those derived from C cells.

 Papillary Thyroid Carcinoma Nuclei as the Defining Feature of Papillary Thyroid Carcinoma

The next major change in the classification came with the realization that mixed papillary and follicular thyroid carcinomas were essentially papillary carcinomas with follicular growth patterns. They all shared characteristic nuclear features, including the famed “Orphan Annie” nucleus [Figure 1]. These nuclei became the defining diagnostic feature of papillary thyroid carcinoma (PTC). It was soon noticed that there were tumors that were entirely follicular but exhibited the nuclear features of PTC. These were classified as follicular variants of PTC (FVPTC). Rosai[2] in a critique wrote “… a thyroid tumor can have a papillary, follicular, solid, trabecular, or cribriform pattern of growth; it can be composed of large, small, oncocytic, clear, round, spindle, or columnar cells; it can be encapsulated, minimally invasive, or widely invasive; in sum, it can have any of those features and more, but as long as it has PTC-type nuclei it is thought to be a PTC or one of its innumerable variants.” Much of this is still the state of the art. However, with an understanding of molecular pathology in a clinical context, the PTC nuclei no longer hold the same overarching diagnostic significance as they did before.{Figure 1}

 Poorly Differentiated Thyroid Carcinoma

An entity that had been defined variously over the years was added to the classification in the first decade of the 21st century after a group of pathologists met in Turin and published consensus criteria for its recognition. The term was meant to represent the diagnostic reality of tumors that “lie both morphologically and behaviorally between well-differentiated and undifferentiated (anaplastic) carcinomas.”[3] However, like a wit once said, “a consensus is what everyone agrees to say collectively what no one believes individually.” Although the Turin criteria have made their way into the WHO 2017 classification, they are not universally accepted.[4] The last word on this category of thyroid carcinomas has not been written.

 Molecular Pathology of Differentiated Thyroid Carcinoma

This has been one of the most fascinating areas of thyroid pathology that has occurred in my lifetime. This is not merely an academic or conceptual issue. The results have practical implications that were not foreseen when the molecular pathology was elucidated.

Although the morphology of conventional PTC varies little with respect to the nuclear features, the molecular underpinnings vary considerably. In children, especially in those exposed to radiation, PTC shows RET gene rearrangements with an ever-increasing list of partner genes. In fact, the finding of a RET/PTC rearrangement should alert one to radiation exposure. These tumors rarely show resistance to radioiodine therapy and are seldom encountered in adults. BRAF mutations on the other hand, especially the BRAF V600E mutation, have been detected in upward of 40% of conventional adult PTC, the highest incidence (approximately 90%) being in the tall cell variant.[5] The association with PTC is so strong that it is used as a preoperative test to evaluate indeterminate and suspicious nodules on FNAC.[6] The jury is still out on whether the presence of a BRAF mutation is an independent factor of poor outcome in PTC. It is believed to confer relative resistance to radioiodine uptake.

Follicular-patterned lesions typically show RAS mutations or PPARƳ rearrangements. Point mutations are encountered in any of the RAS genes, NRAS, KRAS, or HRAS, with the highest mutations being found in NRAS codon 61.[5] RAS mutations are not found in conventional PTC or the infiltrative variant of FVPTC. Acquaviva et al.[5] have drawn attention to the interesting fact that in well-differentiated thyroid carcinoma, there appears to be a morphological and molecular continuum from an invasive, BRAF mutated, conventional papillary thyroid carcinoma, through an invasive follicular patterned thyroid carcinoma with PTC nuclei with a lower incidence of BRAF mutations, to an encapsulated follicular lesion with PTC like nuclei where RAS mutations appear and BRAF mutations are almost nonexistent. Finally, at the other end of the spectrum lies RAS-mutated conventional follicular carcinoma without PTC nuclei that may be encapsulated or invasive.

PDTC has TERT[5] mutations or other aberrations associated with progression, including p53, with the latter being most prevalent in anaplastic thyroid carcinoma.

The promise of BRAF targeted therapy in radioiodine-resistant differentiated thyroid carcinoma has not been realized to the extent that it has been in other tumors, e.g., melanoma. However, recent results with inhibiting MEK1 and MEK2 by selumetinib have shown promise for reversal of radioiodine resistance.[7]

 Encapsulated Follicular-Patterned Lesions

These have been and still remain the cause of anxiety among most pathologists. Despite reams of literature on the subject, diagnostic dilemmas remain. There is still considerable ambiguity about what constitutes capsular invasion. Illustrations in textbooks and papers by experts do not really help to clarify the issue.

Encapsulated follicular-patterned lesions with PTC nuclei

Such lesions were the main bone of contention for many years. Examples with very florid PTC nuclei were called encapsulated FVPTC (EFVPTC). Those with doubtful or few PTC nuclei caused sleepless nights to countless pathologists because of the consequences of the decision to call or not to call a lesion a carcinoma. Reports on the wide inter-observation variation between experts did not help.[8] As a result, many pathologists took the path of “it is better to be safe than sorry.” As the incidence of PTC grew and countless thyroidectomies were performed for a nonlethal lesion, a nomenclature revision consensus was arrived at in 2016. Encapsulated FVPTC (EFPTC) has now entered the lexicon as noninvasive follicular tumor with papillary thyroid nuclei (NIFTP).[9]

Noninvasive follicular tumor with papillary thyroid nuclei

This is the erstwhile EFVPTC. While it is obvious that the word carcinoma has been removed from the label, ambiguity still remains in the use of the word “tumor.” If this neoplasm is by definition noninvasive and encapsulated, why not call it an adenoma? Especially, as every one of the 109 patients included in the publication who were treated with a lobectomy without radioiodine ablation were alive and without disease at final follow-up for a median of 13 years (range: 10–26 years).[9] The reasons remain speculative. My own feeling is that the abrupt revision of a malignant diagnosis to a benign one could have had wide-ranging consequences. Perhaps, NIFTP will be revised by consensus to follicular adenoma with papillary-like nuclei. This will make moot the issue of identifying PTC nuclei in a noninvasive encapsulated lesion.

Invasive encapsulated follicular tumor with papillary-like thyroid nuclei

Whereas, the nomenclature of the noninvasive tumor with PTC nuclei has been resolved, the current WHO classification of thyroid[10] cancer refers to its invasive counterpart as invasive encapsulated FVPTC. This is a contradiction in terms. If papillae are absent and the tumors resemble NIFTP in all respects except for demonstrable capsular or vascular invasion, why are they not called minimally invasive FTP? We hope for another consensus meeting! Until then, we will continue to live in a schizophrenic world of taxonomy.

Follicular tumor of uncertain malignant potential (FT-UMP) and well differentiated tumor of uncertain malignant potential

The problem of identifying capsular and vascular invasion has not got easier. This is an area fraught with contradictory opinions. The criteria of full-thickness invasion of the capsule and an endothelium-lined embolus, respectively, are not always easy to apply. Follicular tumor of uncertain malignant potential is the preferred term when questionable invasion is present in a follicular-patterned tumor without PTC nuclei, whereas well-differentiated tumor of uncertain malignant potential is the recommended term when there is both questionable invasion and questionable PTC nuclei.[10] The fact remains that all these encapsulated lesions, barring those with unequivocal angioinvasion, are indolent lesions which do not need aggressive treatment [Figure 2].{Figure 2}

 Fine-Needle Aspiration Cytology in the Management of Thyroid Nodules

FNAC has become an indispensable investigation in the management of thyroid nodules. The Bethesda System for Reporting Thyroid Cytology (TBSRTC) has been adopted all over the world because it is said to be both diagnostic and prescriptive.[11] However, the utility of the system has not been extensively validated in parts of the globe where the prevalence of follicular versus papillary tumors varies with respect to the West. In parts of the world where follicular lesions outnumber papillary carcinoma, the positive predictive value (PPV) of TBSRTC would be low. In a meta-analysis published from India, this is reflected in a high (34%, range; 23–45) risk of malignancy in category III of TBSRTC which includes atypia of undetermined significance (AUS)/follicular lesion of uncertain significance (FLUS).[12] Molecular diagnosis of aspirates from indeterminate lesions (AUS/FLUS) is offered in some centers in the West where commercially available tests are available at prices that range from approximately 500 $ to 6000 $ depending on whether a single gene (BRAF) or a limited gene signature is being evaluated.[13] The negative predictive value (NPV) is above 90% for all the tests. However, the question must be answered as to whether introducing an expensive test with a high NPV is justified in a country where the cost of a lobectomy is relatively low. The utility of any screening system, therefore, is only as good as its PPV, NPV, and the cost of the test.


Thyroid cancer is the most frequent endocrine cancer and its incidence is increasing. Change is the only constant in the story of thyroid cancer. The more we know the more we change our diagnostic and management practices. Management on the whole has become more conservative and risk adapted. Pathologists have contributed to this shift by incorporating information from morphology, molecular pathology, and clinical factors into their reports. The last word on differentiated thyroid cancer has not been written. It will surprise us yet.


This material has never been published and is not currently under evaluation in any other peer-reviewed publication.

Ethical approval

Not applicable as this is an editorial article with no patients involved.

Informed consent

Not applicable as this is an editorial article with no patients involved.


1Hazard JB, Hawk WA, Crile G Jr. Medullary (solid) carcinoma of the thyroid; a clinicopathologic entity. J Clin Endocrinol Metab 1959;19:152-61.
2Rosai J. Papillary thyroid carcinoma: A root-and-branch rethink. Am J Clin Pathol 2008;130:683-6.
3Volante M, Collini P, Nikiforov YE, Sakamoto A, Kakudo K, Katoh R, et al. Poorly differentiated thyroid carcinoma: The Turin proposal for the use of uniform diagnostic criteria and an algorithmic diagnostic approach. Am J Surg Pathol 2007;31:1256-64.
4Ibrahimpasic T, Ghossein R, Shah JP, Ganly I. Poorly differentiated carcinoma of the thyroid gland: Current status and future prospects. Thyroid 2019;29:311-21.
5Acquaviva G, Visani M, Repaci A, Rhoden KJ, de Biase D, Pession A, et al. Molecular pathology of thyroid tumours of follicular cells: A review of genetic alterations and their clinicopathological relevance. Histopathology 2018;72:6-31.
6Alexander EK, Kennedy GC, Baloch ZW, Cibas ES, Chudova D, Diggans J, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N Engl J Med 2012;367:705-15.
7Ho AL, Grewal RK, Leboeuf R, Sherman EJ, Pfister DG, Deandreis D, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 2013;368:623-32.
8Elsheikh TM, Asa SL, Chan JK, DeLellis RA, Heffess CS, LiVolsi VA, et al. Interobserver and intraobserver variation among experts in the diagnosis of thyroid follicular lesions with borderline nuclear features of papillary carcinoma. Am J Clin Pathol 2008;130:736-44.
9Nikiforov YE, Seethala RR, Tallini G, Baloch ZW, Basolo F, Thompson LD, et al. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: A paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol 2016;2:1023-9.
10Lloyd R, Osamura RY, Kloppel G, Rosai J, editors. WHO Classification of Tumours of the Endocrine Organs. Lyons: IARC Press; 2017.
11Cibas ES, Ali SZ. The 2017 Bethesda system for reporting thyroid cytopathology. Thyroid 2017;27:1341-6.
12Agarwal S, Jain D. Thyroid cytology in India: Contemporary review and meta-analysis. J Pathol Transl Med 2017;51:533-47.
13Nishino M, Nikiforova M. Update on molecular testing for cytologically indeterminate thyroid nodules. Arch Pathol Lab Med 2018;142:446-57.