The thyroid Hurthle (Oncocytic) cell and its associated pathologic conditions: a surgical pathology and cytopathology review.
* Context.--Hurthle cells are eosinophilic, follicular-derived
cells that are associated with a variety of nonneoplastic and neoplastic
thyroid lesions. The differential diagnosis of Hurthle cell lesions is
Objective.--To review the pathologic conditions associated with Hurthle cells in the thyroid and to discuss pathology of thyroid lesions associated with oncocytic cytology.
Data Sources.--A variety of thyroid nonneoplastic (autoimmune thyroiditis, multinodular goiter) and neoplastic conditions (Hurthle cell adenoma, Hurthle cell carcinoma) are associated with Hurthle cell cytology. In addition, there are several thyroid neoplasms that should be considered when one observes a Hurthle cell neoplasm in the thyroid (oncocytic variant of medullary carcinoma, several variants of papillary thyroid carcinoma).
Conclusions.--Oncocytic cytology is seen in a variety of thyroid conditions that are associated with a broad differential diagnosis and care must be used for accurate diagnosis. Newer molecular-based techniques may be useful for further classification of thyroid neoplasms with oncocytic pathology.
(Arch Pathol Lab Med. 2008;132:1241-1250)
Cancer cells (Properties)
Diagnosis, Differential (Methods)
Pathology, Cellular (Research)
Montone, Kathleen T.
Baloch, Zubair W.
LiVolsi, Virginia A.
|Publication:||Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2008 College of American Pathologists ISSN: 1543-2165|
|Issue:||Date: August, 2008 Source Volume: 132 Source Issue: 8|
|Topic:||Event Code: 310 Science & research|
|Geographic:||Geographic Scope: United States Geographic Code: 1USA United States|
THE HURTHLE CELL: HISTORICAL PERSPECTIVES
The Hurthle cell has consistently been the center of debate in the discussion of nonneoplastic and neoplastic lesions of the thyroid ever since it was first described in 1894 by Hurthle. (1) In fact, the cells originally described by Hurthle are now considered to represent ultimobranchial body--derived parafollicular cells or C cells. The oncocytic cells that we now consider to be the follicular-derived Hurthle cells were actually described by Askanazy in 1898. (2) Despite the fact that the cells originally described by Hurthle are likely not the Hurthle cells as considered today, the term has remained in the literature to describe follicular-derived epithelial cells with oncocytic cytology. Other terms for the Hurthle cells include oncocytic, eosinophilic, and oxyphilic cells.
THE HURTHLE CELL: HISTOLOGIC CONCEPTS
The Hurthle cell is a follicular-derived cell, which has a cytoplasm characterized as "swollen." This swelling is due in large part to the presence of numerous mitochondria in the cellular cytoplasm. (3-7) The Hurthle cell is characterized cytologically as a large cell with abundant eosinophilic, granular cytoplasm and a large hyperchromatic nucleus with a prominent nucleolus (Figure 1). We strongly feel that the Hurthle cell proliferations involving the thyroid should be composed of cells with this classic histology and that not all oncocytic cells in the thyroid are true Hurthle cells. We feel there is overinterpretation of oncocytic thyroid follicular cells as Hurthle cells in both cytologic and histologic specimens. Because historically some authors have indicated that all Hurthle cell nodules were potentially malignant, diagnosing or even mentioning these cells in a fine-needle aspiration biopsy report can lead to overreaction by the clinician and excess referrals for surgical excision; the oncocytic follicular cell contains eosinophilic (usually nongranular) cytoplasm and is slightly larger than a normal follicular epithelial cell. These cells commonly occur in nodular goiters and dominant adenomatous or hyperplastic nodules. In our opinion, the presence of these cells should not engender a diagnosis of Hurthle cell lesion.
By electron microscopy, the cytoplasm of Hurthle cells contains several thousand mitochondria of varying size and shape. (3-7) The mitochondria often show dense core granules as well as filamentous inclusions. (3-7)
THE HURTHLE CELL: BIOLOGIC PERSPECTIVES
It was originally believed that the Hurthle cell is a result of senescent change within the thyroid follicular epithelial cell especially because Hurthle cells are more commonly seen in older individuals; however, that original concept cannot be any further from the truth. Hurthle cells have been shown to be less active than follicular cells and they show limited thyroglobulin production; however, they do contain high levels of oxidative enzymes. (8-11)
It has been proposed that the numerous mitochondria seen in Hurthle cells may be secondary to defects in mitochondrial DNA resulting in mitochondrial dysfunction. (12-14) Maximo et al (13,14) have identified large deletions in mitochondrial DNA in Hurthle cells in Hashimoto thyroiditis and in Hurthle cell neoplasms. In addition, point mutations in the mitochondrial genes encoding for enzymes of the mitochondrial respiratory chain have also been reported in Hurthle cell neoplasms. (13,14) It has been postulated that due to a decrease in mitochondrial activity secondary to DNA alteration, mitochondria proliferate resulting in an overall increase in their number. (14) The process of mitochondria accumulation in the cytosol of follicular epithelial cells does not occur rapidly. It is believed to occur slowly over time, which explains why Hurthle cells are rarely seen in nonneoplastic and neoplastic lesions in children. (13) In addition, accumulations would be most evident in cells with a low turnover rate such as follicular epithelial cells. Rapidly dividing cells would prevent the accumulation of mitochondria.
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NONNEOPLASTIC ENTITIES ASSOCIATED WITH HURTHLE CELL METAPLASIA
Hurthle cells are present in a variety of nonneoplastic conditions involving the thyroid and are not specific for any disease process. Hurthle cell metaplasia is seen in a variety of benign conditions such as autoimmune thyroiditis and multinodular goiter and in thyroids of patients that have been treated with head and neck irradiation and systemic chemotherapy (15-21) (Figure 2, A). In addition, the thyroids of patients with long-standing hyperthyroidism (Graves disease) may show focal or diffuse Hurthle cell change (20) (Figure 2, B). In fact, Askanazy originally described these cells in thyrotoxicosis. (2) Hurthle cells also increase with aging. (20) In some instances, one can often find an entire nodule composed of oncocytes and the distinction of hyperplasia from neoplasia can be problematic.
In many of these nonneoplastic conditions, Hurthle cells are found as isolated cells or lining one to a few follicles, but in some cases, an entire nodule may be composed of oncocytes. The classic thyroid disorder in which Hurthle cells are prominent is chronic lymphocytic thyroiditis with oxyphilia (Hashimoto disease). In virtually all cases of classic and fibrosing variants of chronic lymphocytic thyroiditis, most or all of the follicular epithelium takes on Hurthle cell cytology. (20) In fact, in our opinion, the diagnosis of classic Hashimoto thyroiditis should show the triad of lymphocytes, plasma cells, and Hurthle cells.
Most of the conditions associated with Hurthle cell change are chronic, suggesting the possibility that alteration in the follicular epithelium to take on Hurthle cell histology requires chronic stimulation. (15,18)
ONCOCYTIC THYROID NEOPLASMS
Hurthle Cell Neoplasms: General Concepts
Although oncocytic thyroid neoplasms encompass a variety of phenotypes according to the current World Health Organization classification, (22) the lesions that have produced the most debate are those with a follicular and solid pattern and the ones to which most pathologists refer to as Hurthle cell neoplasms.
As noted previously, not all nodules of Hurthle cells are neoplastic. In fact, adenomatous Hurthle cell nodules are common in multinodular goiter and are quite frequently seen in autoimmune thyroiditis. There has been considerable debate about whether these represent true neoplasms. We feel these nodules are metaplastic and should not be included in studies discussing Hurthle cell neoplasms. Hurthle cell nodules are distinguished from Hurthle cell neoplasms by the absence of a complete lesional capsule. Some experienced pathologists believe that Hurthle cell nodules in thyroiditis can be distinguished as metaplastic or neoplastic by the presence of intralesional lymphocytes in the former. Although there is a trend in this direction, our experience is that this is not an absolute criterion as we have recognized angioinvasive Hurthle cell carcinomas arising in chronic thyroiditis in which lymphocytes were percolating through the cords of tumor cells.
By definition, Hurthle cell neoplasms are composed of 75% or greater Hurthle cells. A variety of thyroid neoplasms are characterized as having oncocytic cytology. These include benign (Hurthle cell adenoma, granular cell tumor) and malignant (Hurthle cell carcinoma) neoplasms, variants of papillary thyroid carcinoma (PTC) (tall cell variant, oncocytic variant, and Warthin-like variant), and the oncocytic variant of medullary carcinoma.
There was a significant debate in the early endocrine and surgery literature on the incidence of malignancy in Hurthle cell neoplasms. (23-48) Some authors cite that 80% or more of these lesions are benign (especially when studies have included Hurthle cell adenomatous nodules), whereas others considered all Hurthle cell neoplasms as malignant. The latter finding was proposed because the initial studies on Hurthle cell tumors showed that even lesions that were initially diagnosed as benign acted in a malignant fashion. Throughout the years though, with good follow-up studies and refinement of the criteria for malignancy in encapsulated thyroid neoplasms such as capsular and/or vascular invasion as well as the establishment of molecular techniques that have identified oncocytic follicular variants of papillary carcinoma, it has been clearly established that there are Hurthle cell neoplasms that act in a benign fashion as well as those that act in a malignant fashion. (34,36,44-48)
Studies that include multiple Hurthle cell nodules found in the background of goiter or chronic lymphocytic thyroiditis indicate that more than 80% of Hurthle cell neoplasms are benign. (28,32,40) However, other studies that exclude these unencapsulated Hurthle cell nodules have shown that the rate of malignancy is higher in Hurthle cell than classic follicular neoplasms (2%-3% vs 30%-45%). (4,36,44-48)
Grossly, Hurthle cell neoplasms are usually solitary and show at least partial encapsulation. They are distinctly mahogany brown due the abundant mitochondrial cytochrome content. Lesions may vary significantly in size from one to several centimeters. Similar to oncocytic neoplasms in other organs, a central scar may be evident. Hemorrhage and necrosis may be grossly seen especially in lesions that have undergone preoperative fine-needle aspiration biopsy; massive infarction either spontaneously or following fine-needle aspiration biopsy has been reported in Hurthle cell tumors. (49-51) The infarction can be extensive, leading to severe hampering of the histologic assessment. The presence of spontaneous infarction does not equate with malignancy.
Microscopically, Hurthle cell neoplasms should be composed of at least 75% Hurthle cells. A variety of patterns of growth may be seen such as macrofollicular, follicular, trabecular, solid, and pseudopapillary. (44) Many tumors will show a variety of these patterns of growth. The pattern of growth is usually follicular, but it also can be trabecular or solid. Hurthle cell neoplasms, both benign and malignant, have a tendency to show pseudopapillary change, which is felt to be an artifact from fixation and tissue processing. Hurthle cell neoplasms may show dystrophic calcifications, which may even be psammomatous in nature. Importantly, these psammoma-like or pseudopsammoma bodies are present within colloid and are often not lamellated (20,21) (Figure 3). We consider these calcifications to represent an unusual reaction in the micro milieu in which biochemically modified colloid produced by the Hurthle cells attracts calcium, which precipitates in it. Psammoma bodies in epithelial cells or in the thyroid interstitium should alert the pathologist to the high probability of papillary carcinoma elsewhere in the gland.
One of the most difficult aspects of examining Hurthle cell neoplasms is to determine whether the lesion is benign or malignant. Size in and of itself is not predictive of behavior, although larger lesions have a higher incidence of malignancy. (34,36,44-48) It is quite clear that pathologic criteria for malignancy, such as vascular and capsular invasion, can predict the clinical behavior of these tumors. (34,36,44-48) Nuclear atypia, multinucleation, cellular pleomorphism, mitoses, or histologic pattern of the lesion are not determinants of malignancy. (44) The main criteria for malignancy include the presence of capsular and/or vascular invasion (Figure 4, A through C). Like follicular carcinomas, Hurthle cell carcinomas can be classified as minimally invasive, angioinvasive (invasion of vessels in and/or beyond the lesional capsule), or widely invasive. Minimally invasive tumors show invasion into and/or though the lesional capsule focally. In our opinion, minimally invasive tumors should not have evidence of angioinvasion. Using this strict definition, the prognosis of minimally invasive Hurthle cells should be excellent. Tumors with minimal capsular invasion but evidence of vascular invasion should be classified as angioinvasive and the number of foci of vascular invasion quantified if possible. Ghossein et al (52) recently reported on 50 patients with encapsulated Hurthle cell carcinomas. They identified the most important risk factor for recurrent disease was the presence of vascular invasion. More specifically, 4 or more areas of vascular invasion was associated with a significantly higher risk of recurrence in otherwise encapsulated Hurthle cell carcinomas. Widely invasive tumors have extensive transcapsular and vascular invasion.
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As noted previously, Hurthle cell neoplasms have a tendency to undergo spontaneous necrosis or show extensive degenerative necrosis following fine-needle aspiration biopsy. In these situations, viable lesional cells are often not present and it is difficult to fully evaluate the lesion pathologically. Therefore, it may be very difficult for the pathologist to determine whether the lesion is benign or malignant. In our opinion, unless there is unequivocal vascular invasion seen in the tumor capsule or beyond, the pathologist should not diagnose carcinoma in an otherwise infarcted Hurthle cell tumor. Our recommendation for reporting in these situations is as follows: "completely necrotic thyroid neoplasm without evidence of definitive vascular invasion" with a comment explaining that it is difficult to determine the behavior of this completely infarcted tumor.
It is believed by some authors that transformation of poorly differentiated and anaplastic forms may occur in some Hurthle cell carcinomas. (53-55) This is supported by the rare finding of Hurthle cell tumors in association with anaplastic carcinomas (55) (Figure 5). This association has led to the speculation that Hurthle cell neoplasms can behave in a manner similar to low-grade papillary and follicular cancers, that is, they can undergo transformation to high-grade malignancies. The frequency of this occurrence is unknown and the transformation is more commonly seen in recurrences and metastases than in primary tumors.
The term atypical Hurthle cell adenoma or indeterminate Hurthle cell tumor is used to describe lesions with atypical features that do not fulfill criteria for malignancy. (44,47,48,56) These features include
marked cytologic atypia, mitotic activity, spontaneous infarction, necrosis, hemorrhage, and/ or trapping of tumor cells within the lesion's capsule in tumors that have not been aspirated preoperatively. Longterm follow-up (median, 10-13 years) indicates that even these atypical Hurthle cell tumors behave in a benign fashion. (44)
Although Hurthle cell carcinomas are believed to be similar to follicular carcinomas, they have a tendency to behave clinically different in some series. (44) Metastases to regional lymph nodes are reported in Hurthle cell carcinomas (although some of these series may include oncocytic follicular variants of PTCs). (34,36,44-48) In addition to lymph node metastases, Hurthle cell carcinomas spread hematogenously, most commonly to the lungs, liver, and bone. Survival rates for histologically proven carcinomas range from approximately 50% to 60% at 5 years; however, late recurrences and metastases are not rare. (43)
Flow cytometric analysis of Hurthle cell tumors indicates that this technique cannot discriminate between benign and malignant Hurthle cell neoplasms because adenomas may show aneuploidy and cancers may be diploid. (26,57-60) However, in the histologically defined carcinomas, flow cytometric data may provide prognostic aid--carcinomas that show an aneuploid pattern histologically may behave more aggressively than those that are diploid. (57,58)
Most patients undergo total thyroidectomy for treatment of Hurthle cell carcinoma. Following surgery, patients are often treated with iodine 131 therapy but Hurthle cells show low uptake of iodine. It is believed that stage for stage, Hurthle cell carcinomas behave more aggressively than follicular carcinomas. Nishida et al (61) used a 3-tiered system and classified Hurthle cell carcinomas as "moderate" grade to recognize the clinical difference with "low grade" papillary and follicular cancers and "high grade" anaplastic tumors.
Molecular Pathology of Oncocytic Thyroid Neoplasms in General
All forms of thyroid neoplasia most likely have an oncocytic component. This has been shown by several different studies. For instance, BRAF FV600E mutations are seen in many usual-type PTCs as well as oncocytic variants of PTC, whereas oncocytic follicular variants of papillary carcinoma do not show this abnormality. (62,63) In addition, ret proto-oncogene/papillary thyroid carcinoma (RET/PTC) rearrangements have been demonstrated in oncocytic papillary carcinomas but not always in oncocytic follicular variants of PTC. (64,65) However, Cheung et al (66) and Belchetz et al (67) were able to reclassify follicular lesions that would have been interpreted as Hurthle cell adenomas as oncocytic follicular variants of papillary carcinoma based on nuclear features and the presence of RET/PTC rearrangements. Belchetz et al (67) also observed that some of their lesions with the RET/PTC rearrangements showed lymph node metastases and behaved more like papillary carcinomas. None of the Hurthle cell carcinomas or the adenomas included in their study contained RET/PTC rearrangements. Recently, Sheu et al (68) observed that carriers of the C allele of the common C825T polymorphism in guanine nucleotide binding protein 3 gene appear to have an increased risk of developing oncocytic thyroid tumors. They propose that this polymorphism may be a factor favoring the development of oncocytic thyroid tumors, although the biologic mechanism remains obscure. They believe that there may be a genetic predisposition of patients to develop oncocytic thyroid neoplasms. Whether this is somehow related to the mitochondrial DNA alterations seen in oncocytic thyroid tumors remains to be seen. Gasparre et al (69) have recently shown that disruptive mutations in mitochondrial DNA were found in complex I subunit genes in Hurthle cell neoplasms and this finding appears to be a marker for thyroid oncocytic tumors. Maximo et al (70) have recently identified somatic missense mutations in GRIM19 in approximately 11% of sporadic Hurthle cell carcinomas. GRIM19 is believed to promote apoptosis as part of the interferon [beta] and retinoic acid induced pathway of cell death, is a negative regulator of cell growth, is involved in mitochondrial metabolism, and is linked in part to mitochondrial complex I assembly.
Interestingly GRIM19 is located at 19p13.2. The TCO gene locus, which has been linked to familial Hurthle cell neoplasms, has also been mapped to this locus. (71,72) Baris et al (73) have shown that oncocytic follicular neoplasms show distinct differences in gene expression as compared with usual-type PTC. For one thing, Hurthle cell carcinomas more commonly express genes associated with mitochondrial and cellular metabolism. In addition, this group observed that overexpression of the respiratory chain complexes III and IV seems to be specific to the development of oncocytic follicular carcinomas. Bonora et al (74) recently have found that there are variations in the inner mitochondrial membrane transporter TIMM44 in patients with oncocytic thyroid tumors. All of these studies seem to indicate that there is a genetic predisposition to develop oncocytic thyroid tumors.
Oncocytic Variant of PTC
The Hurthle cell variant of papillary carcinoma comprises approximately 10% of cases of PTC. This tumor is characterized histologically by the presence of oncocytic cells with the classic nuclear features of PTC usually arising in a background of chronic lymphocytic thyroiditis with oxyphilia (Hashimoto thyroiditis). (75-80) Most lesions are well circumscribed, are encapsulated, and often show at least a focal papillary growth pattern. There may be areas of follicular growth and in some cases the follicular pattern may be the predominant growth pattern. Cytologically, the tumor cells show abundant eosinophilic cytoplasm and classic papillary carcinoma nuclei as noted previously (Figure 6). In some cases, the nuclei have a tendency to localize to the apex of the cells. The differential diagnosis includes Hurthle cell neoplasms and the tall cell variant of PTC. Hurthle cell neoplasms, both benign and malignant, have a tendency to show pseudopapillary change, which is felt to be an artifact from fixation and tissue processing. The Hurthle cell variant of PTC shows true papillae with fibrovascular cores. In addition, the Hurthle cell variant of papillary carcinoma shows classic nuclear changes of PTC. The eosinophilic cells in Hurthle cell variant are not twice as tall as they are wide, a feature that aids in distinguishing this histologic variant of papillary carcinoma from the tall cell variant, which usually behaves in a much more aggressive fashion. Although the lesions are often confined to the thyroid, extrathyroid spread as well as the presence of lymph node metastases have been reported. By molecular analysis, the oncocytic variant of PTC shows RET/PTC gene rearrangements. (62,63) Trovisco et al (62) were able to identify BRAF mutations in oncocytic variants with papillary or papillary/follicular growth, whereas tumors with just follicular growth did not show BRAF mutations suggesting that the follicular oncocytic variants are genetically different from the papillary oncocytic variants. Abrosimov et al (81) observed MUC1 and cyclin D1 expression (a target of the Wnt pathway) in 100% of tall cell, columnar cell, and oncocytic variants of PTC and almost 80% of Warthin variants but only 27% of follicular variants. These data again show that the follicular variants appear to be distinct genetically from the oncocytic variants.
Stage for stage, the prognosis of patients with the oncocytic variant of PTC is similar to that of patients with conventional PTC. Oncocytic variant of PTC has reduced capacity to uptake radioactive iodine and is therefore less responsive to radioactive iodine therapy. (75,78-80)
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Recently, Mai et al (82) examined 19 cases of encapsulated Hurthle cell neoplasms with papillary architecture that lacked nuclear features of papillary carcinoma. In their study, they identified proliferative activity in the neoplastic cells associated with the papillary architecture and felt the papillary changes were part of the lesion and not a degenerative process as described in some oncocytic tumors. All 19 of their patients were free of disease with follow-up (1-19 years after diagnosis). This group believes the term papillary variant of oncocytic (Hurthle cell) adenoma should be used to describe these overall benign-acting oncocytic lesions. (82)
Warthin-like Variant of PTC
The Warthin-like PTC is a variant that is characterized by a papillary growth of oncocytic cells with classic nuclear features of PTC and an associated brisk lymphoplasmacytic infiltrate in the papillary stalks. (83,84) The variant is so-named because of its close resemblance to parotid gland Warthin tumor (Figure 7, A and B). These tumors often have an associated chronic lymphocytic thyroiditis with oxyphilia in the background thyroid. The differential diagnosis includes the tall cell variant of PTC; however, despite the oncocytic cells, the cells are not twice as tall as they are wide. The prognosis of this lesion is similar to that reported with typical PTC. We have seen unusual cases of Warthin-like PTC transition to tall cell PTC at its invasive edge and then invade into extrathyroidal soft tissues. The clinical behavior of such lesions (based on anecdotal observations) seems to more closely follow that of Warthin-like papillary carcinoma than the tall cell phenotype.
Trovisco et al (62) identified BRAF mutations in 75% of Warthin-like PTCs versus 46% of usual-type PTCs. In contrast though, Sargent et al (85) observed BRAF mutations only rarely in a variety of papillary carcinomas arising in a background of chronic lymphocytic thyroiditis and not in Warthin variant.
Tall Cell Variant of PTC
In 1976 Hawk and Hazard (86) described a variant of PTC that was characterized by carcinoma cells with classic papillary carcinoma nuclei but abundant cytoplasm in which the cells were 3 times as tall as they were wide. The distinction between this tall cell variant and the usual variant of papillary carcinoma proved to be important because the tall cell variant showed a more aggressive behavior and because tumors were large, more often showed extrathyroid extension, and showed a propensity for vascular invasion (86,87) (Figure 8, A and B). The cells in this tumor are described as tall, with the most recent definition indicating their height is at least 3 times their width and most of them have an eosinophilic cytoplasm. However, the tumor cells are less granular than Hurthle cells. There has been debate about the amount of tall cells needed to make a diagnosis of tall cell variant of PTC. We prefer a diagnosis of tall cell variant when tumors show more than 70% tall cells in the lesion; however, it is wise to mention any tall cell differentiation if seen in a papillary carcinoma. In addition, when these lesions show anaplastic transformation, they give rise to spindle cell squamous carcinomas (88) (Figure 8, C). Squamous change of the tall cells may be seen in recurrent tall cell papillary carcinomas and precede by months or years the development of anaplastic spindle cell squamous carcinoma.
Ghossein et al (89) recently compared the behavior of tall cell variant of papillary carcinoma (as defined as >50% tall cells in their study) without extrathyroidal extension with usual-type PTC. In their study, they observed that tall cell variants even without the adverse feature of extrathyroid extension were more likely to develop lymph node and distant metastases and they concluded tall cell variant of PTC without extrathyroidal extension is a more aggressive variant of papillary carcinoma independent of age, gender, and tumor size. Adeniran et al (90) identified BRAF mutations more commonly than RET/PTC and RAS mutations in tall cell variants of PTC.
Oncocytic Variant of Medullary Thyroid Carcinoma
Some medullary thyroid carcinomas are composed of large cells with finely granular cytoplasm and superficial study can suggest a Hurthle cell lesion. (91) However, the nuclear characteristics are different because most medullary carcinomas have uniform, small nuclei unlike the pleomorphic nuclei in the Hurthle cell tumors. The cytoplasmic granularity is less pronounced in medullary lesions, and the latter rarely demonstrate intense eosinophilia. In any questionable case, of course, immunohistochemical staining for calcitonin and thyroglobulin will aid in reaching the correct diagnosis.
Granular Cell Tumor
Granular cell tumor is a rare tumor most likely of Schwann cell origin. Approximately 50% of the cases have been reported in the head and neck region. They can occur in other organs, including respiratory tract, gastrointestinal tract, genitourinary tract, vulva, and breast. Rarely these tumors can occur in thyroid or adjacent to the thyroid and clinically present as thyroid masses. (92) Most reported tumors in the thyroid occur in women, behave in a benign fashion, and can be treated with lobectomy.
FINE-NEEDLE ASPIRATION BIOPSY OF HURTHLE CELL LESIONS
Hurthle cells of the thyroid in cytologic specimens appear as large polygonal cells with ample eosinophilic granular cytoplasm and central or occasionally eccentrically placed nuclei containing prominent nucleoli. The cell borders appear sharply demarcated and one may see empty space between 2 Hurthle cells similar to "windows" seen in mesothelial cells. Intranuclear grooves can be seen in Hurthle cells in Papanicolaou-stained smears and monolayer preparations (93,94) (Figure 9, A and B).
Hurthle cells can be a prominent component in fineneedle aspiration (FNA) specimens from Hurthle cell adenomas and carcinomas, Hurthle cell nodules in Hashimoto thyroiditis, adenomatoid nodules with Hurthle cell metaplasia, and nodules arising in a background of Graves disease. (95) Because Hurthle cells can be present in both nonneoplastic and neoplastic thyroid lesions it can be diagnostically challenging to differentiate between these two in thyroid FNA specimens. (93,96,97)
Nonneoplastic Hurthle Cell Lesions
Hyperplastic/adenomatoid nodules in multinodular goiter and Hashimoto thyroiditis can show a preponderance of Hurthle cells. In the former, the background usually shows watery colloid and macrophages; however, of utmost importance is the presence of a second cell population of small follicular cells containing scant cytoplasm and small nuclei with dense chromatin. (98,99) The Hurthle cells may demonstrate intranuclear grooves and even focal nuclear chromatin clearing; however, the nuclei are round in shape with prominent nucleoli and other features of papillary carcinoma are not seen. (99) The FNA specimens from a Hurthle cell nodule in Hashimoto thyroiditis usually show Hurthle cells arranged in sheets, follicular groups, and singly scattered cells and lymphocytes. The latter are seen scattered in the background or arranged in loosely cohesive lymphoid follicles. The most important feature is that the lymphocytes are also seen percolating among the majority of cell groups. (100-102) In our experience this is an important feature that distinguishes neoplastic versus nonneoplastic Hurthle cell lesions arising in a background of chronic lymphocytic thyroiditis. Hurthle cells in Hashimoto thyroiditis can display nuclear atypia that mimics papillary cancer, that is, intranuclear grooves, nuclear chromatin clearing, and rarely intranuclear inclusions. One must be aware of this and exercise caution in diagnosing PTC in Hashimoto thyroiditis. Usually the Hurthle cells with these atypical nuclei still maintain a round shape with smooth nuclear membrane and prominent nucleoli. Some authors have suggested that immunostains for cytokeratin 19, HBME-1, and galectin-3 can be helpful in solving this diagnostic dilemma; however, others have shown that follicular and Hurthle cells in Hashimoto thyroiditis can show positive immunostaining with all the previously mentioned markers. (103)
Hurthle Cell Neoplasm
Fine-needle aspiration cytology cannot differentiate between Hurthle cell adenoma and carcinoma because this distinction is dependent on demonstration of capsular and/or vascular invasion by histopathologic examination. Therefore, cytopathologists can only render a diagnosis of Hurthle cell lesion/neoplasm. These specimens demonstrate a monotonous population of Hurthle cells comprising more than 90% of the specimen. The cells are seen arranged in sheets, follicular groups, and singly scattered cells. Some authors have suggested that on the basis of nuclear atypia such as prominent nucleoli, high nuclear-cytoplasmic ratio, and nuclear pleomorphism one can differentiate between Hurthle cell adenoma and carcinoma (97); however, others have refuted these observations. It has been shown that transgressing vessels and intracytoplasmic lumina are more commonly seen in neoplastic rather than nonneoplastic lesions. (93,104) Others have shown that transgressing vessels are a more reliable criterion for the diagnosis of Hurthle cell neoplasm as compared with intracytoplasmic lumina. (93) In our experience, monotonous population of Hurthle cells comprising more than 90% of the specimen is a reproducible and reliable criterion for the diagnosis of Hurthle cell neoplasm.
FNA Biopsy of Papillary Hurthle Cell Carcinoma With Lymphocytic Stroma
("Warthin-like Tumor" of the Thyroid)
This variant of papillary cancer displays peculiar morphology that closely resembles the papillary cystadenoma lymphomatosum or "Warthin tumor" of the salivary gland. It is usually seen in the thyroids affected by chronic lymphocytic thyroiditis. The key histologic features include oncocytic follicular epithelium arranged in papillae with nuclear features of papillary carcinoma and a brisk infiltrate of lymphocytes and plasma cells in the cores of papillary stalks. The FNA specimens from such tumors show oncocytic cells with nuclear features of papillary carcinoma with an admixture of lymphocytes. The FNA specimen and the histologic sections from Warthin-like papillary carcinoma can pose difficulties in distinguishing these lesions from florid chronic thyroiditis itself, Hurthle cell nodules in chronic lymphocytic thyroiditis, Hurthle cell tumors, tall cell variant of papillary carcinoma (PTC), and oncocytic variant of medullary carcinoma. (84,105)
The biologic behavior of these Warthin-like tumors is similar to usual papillary carcinoma when compared for tumor size and stage.
CYTOLOGY OF TALL CELL VARIANT OF PAPILLARY CARCINOMA
Cytology specimens of this tumor usually show elongated cells with sharp cytoplasmic borders, granular eosinophilic cytoplasm, and variably sized nuclei with nuclear features of papillary carcinoma. The nuclear features of papillary carcinoma are usually abundant in aspirates of tall cell variant as compared with that of classic PTC. Thus, nuclear grooves and inclusions are readily identifiable. Some authors have reported presence of intraepithelial neutrophils in aspirates from cases of tall cell variant of PTC. This tumor can be confused with Hurthle cell tumor on cytology due to cytoplasmic eosinophilia; however, the nuclear features should help in differentiating between these two tumors. (106,107)
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Accepted for publication March 11, 2008.
From the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Kathleen T. Montone, MD, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 3400 Spruce St, 6 Founders, Philadelphia, PA 19104 (e-mail: firstname.lastname@example.org).
Kathleen T. Montone, MD; Zubair W. Baloch, MD, PhD; Virginia A. LiVolsi, MD
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