Clear Cell Variant of a Follicular Thyroid Tumor With Uncertain Malignant Potential: A Case Report

Introduction

Follicular thyroid tumors constitute a challenge to the pathologists, as the distinction between benign follicular thyroid adenomas (FTAs) and malignant follicular thyroid carcinomas (FTCs) lie not in the cytological description but instead in the histological interpretation of the tumor cells in relation to the capsule and blood vessels. ¹ The difficulties in establishing a correct diagnosis are exemplified by the terminology “follicular tumor of uncertain malignant potential” (FT-UMP). For this entity, the histological findings required for an FTC diagnosis (capsular or vascular invasion) are lacking, but the tumor does exhibit unclear relations to the capsule and/or areas with unconvinced vascular invasion. ¹

Apart from conventional FTC, the current World Health Organization (WHO) classification lists several histological subtypes, including the oncocytic variant, with large eosinophilic cytoplasm and the clear cell variant, as exemplified by cells with lucid vacuolization of the cytoplasm in >50% of the tumor cells. ¹ The clear cell phenotype has previously been described for FTAs (ccFTAs), FTCs (ccFTCs), and papillary thyroid carcinomas (ccPTCs), but not for FT-UMP.^1-6 The most comprehensive studies yet report clear cell change in frequencies ranging from less than 1% to 3% of primary thyroid carcinomas (most often in FTCs, more seldom in PTCs).^2-8 The reason for the clear cell phenotype is believed to be intracytoplasmic deposits of glycogen, lipids or colloid vacuoles, but the causal mechanism for this aberrancy is not fully elucidated.^6,9 For ccFTCs, the underlying genetics partly mirrors the findings in conventional follicular tumors, with RAS mutations and PAX8-PPARG rearrangements reported, but also surprisingly TP53 mutations in individual cases.^8,10 The histologic manifestation of clear cell change seems to carry little prognostic implication but could constitute a major differential diagnostic problem for both cytologists and pathologists.^1,8,11 Especially, medullary thyroid carcinoma, metastatic renal cell and parathyroid carcinoma must be ruled out before a diagnosis of a clear cell follicular thyroid tumor can be established. ¹

In this report, we present a rather unique finding of a clear cell variant follicular thyroid tumor with uncertain malignant potential (ccFT-UMP). To our knowledge, this entity has neither previously been reported in the scientific literature nor is it described in the 2017 WHO classification of endocrine tumors. ¹ We therefore believe the description of this histological subtype could be of value to the scientific community.

Materials and Methods

Results

The postoperative gross examination revealed an encapsulated 30 mm large tumor with a solid, white to grey cut surface. No gross evidence of capsular invasion was found. The tumor was submitted entirely for histology in 12 cassettes. The histopathological evaluation revealed a well-circumscribed and encapsulated lesion, in which the tumor cells exhibited a clear cell phenotype with clear cytoplasm, small nuclei with a light chromatin and distinct nucleolus in the vast majority of the tumor cells (Figure 1A and B). No PTC associated nuclear features were detected. The tumor cells were predominantly arranged in a microfollicular growth pattern, with focal areas organized in solid and trabecular sheets. No mitotic figures in 10 high-power fields (HPFs) and no tumor necrosis were observed. Several foci with intracapsular tumor cell deposits as well as areas with questionable vascular invasion was reported (Figure 1C-F), but no evident invasion through the entire capsular diameter were identified. Immunohistochemical stainings with vascular endothelial markers (CD31, ERG) were performed, but no area with evident vascular invasion was found. The tumor was removed with negative surgical margins.

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Figure 1.

Histological and immunohistochemical profile of the clear cell FT-UMP (follicular tumor of uncertain malignant potential). All photomicrographs are magnified 100 times (×100) unless otherwise specified. (A, B) Hematoxylin-eosin stain depicting the clear cell features of the FT-UMP at ×100 and ×400 magnifications, respectively. (C-F) Hematoxylin-eosin stains showing areas with disputable engagement of intracapsular blood vessels. Arrows mark the tumor foci of interest. None of the foci were confirmed with endothelial cell markers. (G, H). Thyroglobulin and TTF1 immunohistochemistry, respectively, revealing strong staining for tumor cells, verifying the lesion as primary in the thyroid (magnification ×400). (I) Immunohistochemistry with anti-Ki-67, displaying an augmented proliferation index of 11% (magnification ×400).

Immunohistochemical analyses are exemplified in Figure 1G-I and revealed the tumor cells positive for CKMNF116, thyroglobulin, TTF1, PAX8, PTEN, and vimentin, whereas no immunoreactivity was seen for CD10, RCC, EMA, chromogranin A, calcitonin, PTH, GATA3, HMBE1, and BRAF V600E. The p53 immunoreactivity was mixed (approximately 50% strongly positive cells) and did not suggest an underlying TP53 gene mutation. The Ki-67 index was 11%. periodic acid–Schiff (PAS) stain and PAS-diastase stainings could not visualize intracytoplasmatic polysaccharides or mucin within the clear cells. The immunohistochemical results supported the tumor as thyroid-derived, and excluded metastatic renal cell carcinoma (RCC), medullary thyroid cancer (MTC), and a parathyroid tumor. Given the microfollicular growth pattern, the lack of PTC-associated nuclear features and the immunophenotype above, the tumor was suspected to constitute a follicular thyroid neoplasm. As the relationship between the tumor and the intracapsular blood vessels was uncertain, the final diagnosis was a clear cell variant of an FT-UMP.

At our institution, all cases of FT-UMP are tested for mutations in the TERT gene promoter region as a part of the clinical workup of these patients, as the C228T and C250T mutations have been associated to relapses and future distant metastases in the FTA and FT-UMP groups.^12-16 Thus, these mutations can serve as prognostic markers for a specific subset of patients with follicular thyroid tumors with unclear histology. In the current case, no TERT promoter mutation could be identified, and the decision was taken during a multidisciplinary tumor board conference to discharge the patient to his home, with no further clinical controls required. The patient is well with no signs of disease or postoperative complications 4 months after surgery.

Discussion

Clear cell changes in thyroid tumors are unusual and the number of reported cases is very low, making the scientific community dependent on large, international multicenter case description studies as well as individual case reports from single institutions to obtain an overview of the field.^2-8. Although based on a small number of cases, ccFTCs seem to carry comparable prognosis as conventional FTCs, and apart from TP53 mutations, ccFTCs have similar genetic phenotype.^8,10 Similarly, FTAs with clear cell changes might not constitute a less indolent tumor than conventional FTAs. ¹

Our case is rather unique in several aspects. It is to our knowledge the first report of an FT-UMP with clear cell change, and moreover it is histologically distinctive from the majority of clear cell thyroid neoplasias, as the tumor cells exhibited a uniformly clear cell morphology, and not just focally as previously reported. ⁸ According to our electronic records at the Karolinska University Hospital, a national tertiary center for endocrine tumors, we performed 8849 thyroidectomies between the years 1992 and 2017. Of these, seven cases were registered as exhibiting tumors with clear cell changes present in the vast majority of tumor cells; 6 cases were metastatic renal cell carcinoma and 1 case was a clear cell variant of a toxic follicular adenoma. Considering the amount of follicular neoplasias diagnosed at our institution during the same period (n = 1219), the frequency of clear cell changes in follicular thyroid tumors at our institution is exceedingly low (<0.1%).

Whether this tumor carries malignant potential or not is debatable as the elevated Ki-67 proliferation index and the intracapsular engagement would suggest an aggressive phenotype, but the ensuing TERT promoter mutational screening was negative and partly argues against this assumption. According to the current WHO classification, clear cell follicular tumors are considered either benign or malignant, and no gray zone cases have been previously reported. Given the unique cytological and histological attributes of this lesion, we believe that practicing cytologists and pathologists should be aware of this very rare FT-UMP subtype.