Introduction

Oncocytes earlier known as Hurthle cells are thyroid follicular derived cells which are polygonal in shape, with copious eosinophilic granular cytoplasm and centrally located large nuclei with prominent nucleoli. Electron microscopy studies have shown that this appearance is because of the accumulation of numerous enlarged and globular mitochondria within it. Oncocytic cells can contain up to 5,000 mitochondria.(1)

Oncocytes are found in a wide variety of non-neoplastic and neoplastic conditions affecting the thyroid. Non-neoplastic conditions include the hyperplastic oncocytic nodules of thyroid follicular nodular disease earlier called as multinodular goitre and lymphocytic thyroiditis. Oncocytic nodules are distinguished from Oncocytic neoplasms by the absence of a capsule.(2) Oncocytic neoplasms are thyroid tumours showing more than 75% oncocytes. Neoplasms are classified as Oncocytic adenoma (OA) or Oncocytic carcinoma (OC). OAs are non-invasive, encapsulated lesions composed of oncocytic cells. OC show either capsular or vascular invasion.

The objectives of the study were-

1. To study the clinical details, age and sex incidence of Oncocytic cell lesions.
2. To document the radiological findings wherever available.
3. To analyse the concordance and non-concordance between FNA and histological diagnosis.
4. To study the histomorphological spectrum of Oncocytic cell lesions.
5. To follow up cases wherever possible.

Materials and Methods

This is a retrospective single centre study of 2 years carried out at the Department of Pathology in a tertiary care hospital. We included thyroidectomy specimens with Oncocytic cell lesions- Oncocytic nodules (ON), Oncocytic adenoma (OA) and Oncocytic carcinoma (OC). Follicular tumours with oncocytic metaplasia, oncocytic and tall cell variants of papillary thyroid carcinoma, and oncocytic variant of medullary carcinoma were excluded from the study.

Demographic and clinical data such as age, sex, chief complaints and examination findings were noted. Serum T3, T4 and TSH levels and findings on thyroid ultrasonography, wherever available, were documented. Some of the cases had previous fine-needle aspiration cytology (FNA) reports, which were documented and the slides were retrieved for examination.

The gross findings of thyroidectomy specimens, with respect to size of the lesion and appearance on cut section, were noted in all cases. The histopathology slides were retrieved and examined for the microscopic characteristics. This included size of the lesion, architecture, presence of capsule, presence of invasion and associated conditions. Follow up data was collected from patient case files.

Ethics

This study does not involve animal subjects. The identity of patients and clinical photographs are not disclosed in this manuscript in accordance to institutional ethical standards.

Results

During the study period, of a total of 360 thyroidectomy specimens, 16 showed Oncocytic cell lesions. Three cases were ON, 10 were OA, and 3 were OC. Of the 3 OC, two were minimally invasive and one was widely invasive OC. Age range was 33-74 years, and male to female ratio was 1: 4.3. Clinical details were available for 14 cases, as 2 thyroidectomy specimens were sent from an outside health care centre with no clinical details. All 14 cases presented with non-tender swelling in the neck and with normal serum T3, T4 and TSH levels. We had 10 cases with available ultrasound findings. On ultrasound, 6 lesions were hypoechoic, 2 were isoechoic and 2 were hyperechoic with cystic areas within. All lesions showed internal vascularity.

FNA reports were available for 12 cases. The comparison of diagnosis made on FNA with that on histopathology are shown in Table 1. FNA of oncocytic cell lesions was categorised by the Bethesda system for reporting thyroid cytopathology. FNA for 9 cases of OAs were available, of which 2 were diagnosed as Bethesda II, 1 as Bethesda III and 6 as Bethesda IV. Cases diagnosed as Bethesda IV showed monolayered sheets, dyscohesive clusters follicles and scattered oncocytes in background of scant colloid, as is seen in Fig 1A. Of the 2 cases of OC where FNA reports were available, one was reported as Bethesda Category V and one as Bethesda Category II. The smear diagnosed as Bethesda Category V showed papillary and microfollicular arrangement of cells with few sheets and singly scattered cuboidal cells with moderate nuclear pleomorphism, few cells showing high N:C ratio, along with intranuclear inclusion, moderate amount of cytoplasm, clumped chromatin, few showing prominent nucleoli with few lymphocytes and neutrophils in background along with haemorrhage (Fig 1B). The smear that was reported as Bethesda Category II was reviewed. On review, it was noted that the smear was of limited adequacy and showed few clusters of follicular cells with oncocytic change in background of colloid.

Fig 1(A)(B): FNA smears of Bethesda Category 4(A) and 5(B), Pap X100

On gross examination, cut section of all Oncocytic cell lesions showed grey tan fleshy areas. The median size of ON, OA and OC were 5 mm, 49 mm and 30 mm respectively.

On histology, Oncocytic cell lesions showed various patterns. Some had different patterns within the same lesion. All lesions showed microfollicular pattern. Trabecular pattern was seen in 8 lesions. Other patterns that were observed were nested (n=4), solid (n=3) and papillary pattern (n=1). Fig 2, 3 and 4 show photomicrographs of ON, OA and OC respectively.

Fig 2: Oncocytic nodule, H&E X40

Fig 3: Oncocytic adenoma, H&E X40

Fig 4: Oncocytic carcinoma, H&E X40

We observed that coexisting thyroid conditions in some of the cases. 4 cases showed lymphocytic thyroiditis. 4 cases showed papillary neoplasm, including in a case of OC, which had a coexisting papillary microcarcinoma.

Follow up was done for 12 cases, ranging for period of 2 to 25 months. The other 4 cases were either lost to follow up or details were unavailable. One case of OA expired post-op due to unrelated cause. Patients with OC and lesions with associated papillary thyroid carcinoma underwent iodine-131 therapy, 4 to 6 weeks after surgery, and are presently doing well. Patients with benign Oncocytic cell lesions had no fresh complaints.

Discussion

Oncocytes/ Hurthle cells are oncocytic cells found in the thyroid. Oncocytes have numerous mitochondria, which imparts a finely granular deeply eosinophilic appearance to the cytoplasm. Oncocytes have been found to arise in various tissues, including other endocrine glands, like pituitary and parathyroid glands, exocrine glands like salivary glands, lacrimal glands and pancreas, as well as nasal and buccal mucosa and epithelia lining larynx. Thyroid oncocytic cells were first described by Karl Hurthle, in canine thyroids in 1894.(3) It was subsequently realised that the cells Hurthle described were the parafollicular C cells. The true oncocytic cells of thyroid follicular epithelium was described by Max Ashkanazy in 1898, in a case of Graves’ disease.(4) However, the term “Hurthle cell” was still used in literature until the recent World Health Organization (WHO) histologic classification of thyroid neoplasms fifth edition has replaced the term “Hürthle cells” with “oncocytic” cells. Oncocytic cells are follicular in origin since these cells show thyroglobulin immunoreactivity and presence of TSH receptor adenylate cyclase system.

As mentioned above, lesions composed of oncocytes include Oncocytic nodules and Oncocytic neoplasms. Oncocytic nodules are found in thyroid follicular nodular disease and lymphocytic thyroiditis, particularly Hashimoto’s thyroiditis. Initially, all Oncocytic neoplasms, irrespective of size, were regarded as malignant. Subsequently, it was shown, that Oncocytic adenomas without capsular or vascular invasion were benign. Now, it has been proved that greater than 80% of oncocytic cell lesions are benign.(1) In our study, 86% cases of oncocytic cell lesions were benign.

The incidence of oncocytic cell lesions varies in different studies due to variation in defining criteria. Some studies have shown frequency to be 4.5-10% (5) and in our study, 4.02% of thyroid nodules were identified as Oncocytic cell lesions. OCs constitute approximately 5% of all differentiated thyroid carcinomas.(6)

On literature review, the median age of Oncocytic neoplasms in our study correlated with studies by Pisanu et al.(6), Barnebei et al.(7), Zhou et al.(8), and Stojadinovic et al.(9) These studies show female preponderance, which was also observed in our study. Sugino et al.(10), Melck et al.(11) and Petric et al.(12) found male gender to be significantly associated with malignancy. Melck et al.(11), Pisanu et al.(6), and Lee et al.(13) showed that larger tumour size is associated with malignancy, whereas studies by Petric et al.(12) and Sugino et al.(10) found no significant association with size. In our study, all cases of OC were female, and tumour size were similar to those of benign lesions, and hence no significance with gender or tumour size was noted.

On ultrasound, Oncocytic neoplasms have been reported to show a spectrum of sonographic appearances from predominantly hypoechoic to hyperechoic lesions and no internal flow to extensively vascularized lesions.(14) Differentiation of benign and malignant Oncocytic neoplasms is beyond the resolution of sonography. In our study, varied sonographic appearances were seen, which did not have any association with their histological diagnosis.

FNA is currently one of the first line investigations done in the evaluation of thyroid nodules. Oncocytes are frequently seen in FNAs of thyroid and can pose diagnostic difficulties. The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC)(15) recognises that oncocytic cell-rich aspirates can fall under various Bethesda categories, depending on the abundance and cellular morphology of these cells. Smears diagnosed as Bethesda Category II show oncocytes admixed with normal (non-Hurthle/ oncocytic cell) macrofollicles usually in a background of abundant colloid. In lymphocytic thyroiditis, there is scant colloid but singly scattered and sheets of oncocytic cells along with numerous polymorphous lymphocytes, plasma cells, tingible body macrophages, and lymphohistiocytic aggregates. Oncocytic neoplasms are categorized under Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance (AUS/FLUS), Oncocytic cell type (AUS-H) (category III) or as Follicular Neoplasm/Suspicious for Follicular Neoplasm (FN), Oncocytic cell type (FN-H) (category IV). The smear reported as Bethesda III in our study showed clusters and few scattered thyroid follicular cells along with oncocytes with anisonucleosis, dispersed chromatin and prominent nucleoli along with neutrophils and lymphocytes in a background of scant colloid admixed with hemorrhage. Bethesda IV aspirates are usually moderately to markedly cellular, composed almost exclusively of clusters of singly scattered oncocytes.(15)

Some studies propose that features suggestive of neoplasia in cytology smears are presence of architectural atypia in the form of non-macrofollicular groups or dyscohesive/single cells, transgressing blood vessels and absence of lymphocytes.(16) Alaedeen et al.(17) showed that FNAs from non-neoplastic oncocytic cell lesions did not show any specific features that could distinguish them from neoplasms and no cytologic feature reliably excluded neoplastic disease. In their study, atypia was not of value in predicting the behaviour of nodular Oncocytic cell lesions.

On histology, Oncocytic neoplasms can display varying growth patterns, including follicular, solid, trabecular and pseudopapillary. True papillary pattern has also been reported, and in these cases identifying nuclear features help distinguish them from oncocytic variant of papillary carcinoma. Concentric calcifications of the colloid resembling psammoma bodies are often seen. Some oncocytes can show nuclear grooves. Oncocytic neoplasms have a propensity to undergo infarction post FNA. These cases may present diagnostic difficulties as they cause irregularities in the capsule and mimic invasion.(18)

According to the World Health Organization Classification of Tumours of Endocrine Organs,(19) OCs are classified as minimally invasive, encapsulated angioinvasive and widely invasive. In our study, 2 cases were minimally invasive and 1 was widely invasive. It has been shown that vascular invasion is an important prognostic factor.(20)

In our study, 4 lesions had an associated papillary microcarcinoma/carcinoma of which 3 were Oncocytic neoplasms. Such associations were also noted by Pisanu et al.(6) and Barnabei et al.(7) in their studies on Oncocytic/ Hurthle cell tumours.

Table 2 shows the different observations made in other studies on Oncocytic cell lesions of the thyroid.

Molecular studies show that alterations in mitochondrial DNA in Oncocytes/ Hurthle cells such as point mutations and large deletions, which cause impaired oxidative phosphorylation and ATP synthesis leading to accumulations of mitochondria within the cell. Defects in Cytochrome c oxidase complex IV, the terminal enzyme of the respiratory electron transport chain and mitochondrial DNA deletions are also seen in oncocytes of Hashimoto thyroiditis. Nuclear DNA alterations occur less frequently in Oncocytic neoplasms compared to other follicular cell–derived neoplasms.(16) Studies have also shown TERT promoter mutations in oncocytes, which is seen more often in widely invasive OCs as compared to minimally invasive OCs.(20)

There is considerable controversy in literature regarding the clinical behaviour of OCs. Some studies(21,22) have shown that the biologic behaviour of OC is very aggressive with more frequent lymph nodes, distant metastasis and higher likelihood of recurrence. Haigh PI, et al.(23) Bhattacharyya et al.(24) Rogounovitch et al.(25) believe that OC behave similar to non-Hurthle/ oncocytic counterparts as they found no statistically significant difference between them regarding size, extrathyroidal extension, nodal or distant metastasis, local recurrence, and patient survival. Though it has been shown that OCs are not very sensitive to radioactive iodine, total thyroidectomy followed by radioactive iodine is still the standard of care for most patients.

Conclusion

Oncocytes/ Hurthle cells are found in non-neoplastic and neoplastic lesions of the thyroid. Our study showed that radiology and FNA were not useful in differentiating various Oncocytic cell lesions. Accurate diagnosis can be made on histopathology by observing the surrounding thyroid for capsule, vessels, lymphocytes and colloid. In case of Oncocytic neoplasms, extensively sampling the lesion and looking for capsular and vascular invasion s mandatory. While the significance of oncocytes in thyroid pathology is currently uncertain, identifying malignant lesions is of utmost importance.

Acknowledgments

We would like to express our deepest gratitude to all the teaching staff and laboratory personnel of the Department of Pathology, Kasturba Medical College, Manipal for their relentless support in completing this research work. This research has not been funded.

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