Changes in the Histologic Diagnosis of Follicular Thyroid Carcinoma Over the Past 50 Years

Written by Kristin Della Volpe

Commentary by Nicole A. Cipriani, MD and Kennichi Kakudo, MD, PhD

Review of diagnostic slides from cases of follicular thyroid carcinoma diagnosed over the past 50 years resulted in reclassification of nearly three-fourths of cases, according to a study in the November issue of Thyroid. These diagnostic changes lead to a decrease in survival rates from follicular thyroid cancer from 83.5% to 33.7% at 20 years.

“This study emphasizes the importance of strict diagnostic criteria for thyroid tumors,” said lead author Nicole A. Cipriani, MD, Assistant Professor of Pathology and Medical Director of Gross Pathology at The University of Chicago Medicine & Biological Sciences. “The more we know about the histology and molecular biology of thyroid tumors, the better our diagnostic criteria and treatment become.”

“This has importance to both current patients as well as to research studies,” Dr. Cipriani said. “Accurate diagnosis of current patients helps guide targeted therapy. Accurate diagnosis in research studies requires histologic re-evaluation of historic cases in order to ensure the most current diagnosis and to properly stratify patients into prognostic groups.”

The study was designed to determine the long-term survival of follicular thyroid carcinoma (FTC) in patients treated at The University of Chicago. The authors reviewed 66 cases with a diagnosis FTC between 1965 and 2007, and reclassified them according to the current up-to-date diagnostic criteria as of 2015.

Nearly Three-Fourths of FTC Cases Were Reclassified
“We found that 29% of patients retained a diagnosis of FTC according to current guidelines,” Dr. Cipriani explained. “The remaining 71% of cases were rediagnosed according to current guidelines as either papillary thyroid carcinoma (36%; a tumor that is less aggressive than FTC and has a low mortality rate), follicular adenoma (27%; a benign tumor), or poorly differentiated carcinoma (8%, a tumor that is more aggressive than FTC and has a higher mortality rate).”

“After eliminating the non-FTC diagnoses, the cancer-specific survival of FTC patients was 77% and 33.7% at 10 and 20 years after diagnosis (meaning that if the patient died of reasons other than thyroid cancer, they were not considered as having cancer-specific death),” Dr. Cipriani continued. These percentages are lower than prereview FTC-specific survival rates, which were 83.5% and 75.1% at 10 and 20 years, respectively. No cancer-specific deaths occurred in the follicular adenoma or papillary thyroid carcinoma groups.

“In this [study], patients with follicular thyroid cancer that has invaded outside the thyroid (into the neck) or that has metastasized to a distant site showed decreased survival compared to those cases confined to the thyroid gland,” Dr. Cipriani noted.


Kennichi Kakudo, MD, PhD
Visiting Professor
Department of Pathology, Nara Hospital
Kindai University, Ikoma-city, Japan
Professor Emeritus
Wakayama Medical University, Japan

I am a pathologist in Japan (Eastern Society), in which there are some differences in practice compared with Western societies. From my previous observer variation studies on the diagnostic criteria of papillary thyroid carcinoma type nuclear features (PTC-N), I have identified some issues between the two types of practice that may be irreconcilable.1-3

There are fundamental differences between Eastern and Western cytopathology/pathology practices, deeply influenced by the differences in Eastern and Western thinking and use of logic. In Western pathology practice, it seems to me, avoiding possible litigation is an important issue for pathologists, thus leading to application of more lax criteria in their practice to avoid possible missed diagnoses of carcinoma. This parallels the increased incidence of thyroid malignancy reported in many studies from the United States4-9 and other geographic areas.10-13

The study by Cipriani et al presented how the application of more lax criteria for both PTC-N and capsular/vascular invasion have changed in the last half-century in Western practice.14 One of the most interesting findings in this study was that the proportions of FTC reclassified to PTC were higher in the 1960s and 1970s compared with the 2000s, suggesting that in the 2000s, application of PTC-N criteria was more relaxed and more cases with worrisome PTC-N were excluded from the follicular adenoma (FA)/FTC group and diagnosed as PTC. This tendency also was nicely pointed out by Renshaw and Gould in 2002.15

Another interesting observation in Cipriani et al’s study was that the proportion of cases reclassified to benign FAs increased over time, from <20% in the 1970s and 1980s to >30% in the 1990s and 2000s, as shown in Figure 1 of the study. This is likely due to application of more lax criteria for capsular/vascular invasion in the 1990s and 2000s than in the 1970s and 1980s. This is one of the reasons why no cancer death had been reported in those patients with minimally invasive FTC16,17 and patients with minimally invasive FTC live longer than control subjects.18

Over-diagnosis and overtreatment of indolent tumors with very low malignant potential is a significant issue, not only in Western society19 but also in Eastern society.20 This is fundamentally due to changing pathology practice using more lax criteria, which has resulted in an increased reported incidence of thyroid carcinomas and fluctuating ratio of histological subtypes over time, as pointed out in Cipriani et al’s study and a recent review by Ohori.21 The third important observation in this Cipriani et al’s study was that there was no cancer-specific death in the contaminant group of PTC and FA, which suggests reclassification (observer variation) of FTC occurred mostly in benign (indolent) borderline lesions.

It is essential to establish appropriate histological criteria to identify cancers that may develop recurrence or metastasis and result in cancer death at significant proportion (more than 50% at 10 years) if left untreated, as well as to exclude indolent (borderline) lesions, which can be treated with a simple excision and have only a negligible risk of progression if left untreated.19,22-24

Unfortunately, both types are treated equally and radically as malignant thyroid tumors in most of the Western clinical guidelines, which benefits only those patients with genuine cancers and causes more harm than benefit to the majority of patients with biologically benign borderline tumors.

I hope the introduction of borderline lesions in thyroid tumor classification by our group22,23 will open a new era where pathologists have 3 choices in their diagnoses: benign, borderline, and malignant.25 I believe, these choices will allow for a more accurate prognostic classification, and also significantly impact clinical management of patients. It opens a new era for endocrinologists and endocrine surgeons to have 3 treatment options to the patient with thyroid nodule: treat, not treat, and close follow-up (active surveillance), which should be different from the current clinical management of 2 choices (treat or not treat). This has already started in clinical managements of patients with papillary microcarcinoma, and an active surveillance (observation without immediate surgery) has become one of the treatment options in Japan.26-28

December 10, 2015


Cipriani NA, Nagar S, Kaplan SP, et al. Follicular thyroid carcinoma: how have histologic diagnoses changed in the last half-century and what are the prognostic implications? Thyroid. 2015;25(11):1209-1216.

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