M

Figure 14. Tall cell papillary carcinoma is composed of a majority of tumour cells that have a height-to-width ratio that exceeds 3:1. These lesions are usually more aggressive than conventional papillary carcinomas.

gene are not thought to underlie the more common sporadic thyroid carcinomas (130,131).

Aggressive variants of papillary carcinoma include the tall cell variant and probably related lesions, the trabecular and columnar cell variant (132-137). The tall cell variant is defined as a tumor composed of cells that have a height to width ratio that exceeds 3:1 (Figure 14). They usually have complex papillary architecture and may show focal tumor cell necrosis. Tall cells generally have abundant eosinophilic cytoplasm. Columnar cells are similar to tall cells but generally are more crowded with pseudostratification and resemble endometrial lining. The two cell types tend to be found in the same tumours. Tumors that exhibit this feature in more than 30% of the tumor mass generally tend to occur in older individuals with a median age at diagnosis of 20 years older than usual papillary carcinoma, are often large lesions greater than 5 cm and often extend extrathyroidally (134). In addition to lymphatic invasion, vascular invasion is not uncommonly found in these lesions. Tumor mortality rates vary up to 25% for tall cell tumors and 90% for columnar cell carcinoma (136,138).

The management of the less aggressive forms of papillary thyroid carcinoma is controversial. Most experts advocate total thyroidectomy and radioactive iodine therapy (34,50). The rationale for total thyroidectomy is twofold, based on the frequency of bilateral carcinoma and on the need for enhancement of uptake of radioactive iodine by metastatic tumor deposits rather than residual thyroid tissue. However, as shown by the studies of Sugg et al (70), the identification of occult papillary carcinoma in the contralateral lobe is usually not attributable to intrathyroidal dissemination, which would justify further surgery for local disease. Therefore, the major indications for total thyroidectomy are the enhancement of uptake of radioactive iodine and the more sensitive use of thyroglobulin to detect persistent disease (52-54). The controversy involves the management ofpatients with low risk clinical and pathological parameters; some have advocated less aggressive management with unilateral thyroidectomy and no radioiodine therapy in this setting (49). Recent studies have identified potential markers of those more aggressive tumors that will metastasise to local lymph nodes, including loss of nuclear p27 and upregulation of cyclin D1 (139-141) and these may prove valuable to stratify patients for completion thyroidectomy and radioiodine therapy, but more studies are needed to validate these data. Since there are no controlled clinical trials that address this issue, the answer remains an empirical one. As for follicular carcinoma, external beam radiotherapy is not used in patients with papillary thyroid carcinoma, apart from those with locally advanced tumors that involve extrathyroidal soft tissues of the neck and cannot be completely resected (54,71).

HÜRTHLE CELL LESIONS

Hürthle cells in the thyroid represent a misnomer in that Dr. Hürthle originally described the parafollicular cell. The first description of oxyphilic cells in the thyroid is actually attributed to Askenazy. However, the term Hürthle cell is ingrained in the literature and it is unlikely that the historical error will even be corrected.

The Hürthle cell is derived from the follicular epithelium by metaplasia and possesses the capacity to produce thyroglobulin (142). Morphologically, Hürthle cells are characterised by large size, polygonal to square shape, distinct cell borders, voluminous granular and eosinophilic cytoplasm, prominent nucleus with "cherry-pink" macronu-cleoli. With the Papanicolau stain, the cytoplasm may be orange, green or blue. By electron microscopy, the cytoplasmic granularity is produced by large mitochondria filling the cell, consistent with oncocytic transformation (143,144). Hürthle cells have been studied by enzyme histochemistry and have been shown to contain a high level of oxidative enzymes (145,146). Somatic mutations and sequence variants of mitochon-drial DNA (mtDNA) have been identified in oncocytic thyroid carcinomas (147,148). Similar changes have been found in the nontumorous thyroid tissue of patients with oncocytic neoplasms (148), suggesting that certain polymorphisms predispose to this cytologic alteration.

Hürthle cells are sometimes considered to be a cause of concern in needle biopsies (57). When they are not the major component in a thyroid aspirate, they are not diagnostic of any given lesion. Hürthle cells are found in patients with thyroiditis as well as in several forms of thyroid neoplasia. Confusion and concern also arises with the histologic diagnosis of Hurthle cell nodules in the thyroid. Hurthle cell nodules found in the setting of thyroiditis or nodular goitre may be hyperplastic. Those lesions that arise in otherwise normal glands are usually encapsulated and are considered to be neoplastic. They can have microfollicular, macrofollicular, trabecular or solid architecture. On occasion, especially with the solid pattern and since these lesions can be extremely vascular, they may resemble medullary thyroid carcinomas and it may be necessary to resort to immunoperoxidase stains for thyroglobulin and calcitonin to obtain the correct diagnosis.

Hurthle cell adenomas and Hurthle cell follicular carcinomas are diagnosed when more than 75% of a lesion is composed of this cell type; the criteria for the diagnosis of lesions that are composed predominantly of Hurthle cells are the same as those applied to follicular lesions that do not contain Hurthle cells (149). The diagnosis of Hurthle cell papillary carcinoma (see below) is possible when the minimal cytologic criteria for papillary carcinoma are present (150).

FNA of Hurthle cell tumors may cause them to partially or totally infarct (151). This probably occurs because of the high metabolic activity of these cells and the delicate blood supply of these lesions that may readily become inadequate after direct trauma. A solitary tumor of the thyroid which occurs in a patient without thyroiditis and which is purely or predominantly composed of Hurthle cells on FNA should be excised, since Hurthle cell tumors show an average of 30% malignancy rate based on histology (149).

Hurthle cell hyperplasia

Hurthle cells are found in the thyroid in a variety of conditions and therefore are not specific for any particular disease. Individual cells, follicles or groups of follicles may show Hurthle cell features in irradiated thyroids, in ageing thyroids, in nodular goitre and in thyroiditis as well as in long-standing autoimmune hyperthyroidism (142). One can see these cells in chronic lymphocytic thyroiditis, in Graves' disease and in nodular goitre, where one can often find an entire nodule composed of oncocytes.

Hurthle cell adenoma and carcinoma

For many years it was felt that all Hurthle cell neoplasms of the thyroid (Figure 15) should be considered malignant since it was felt that the histology could not predict clinical behaviour. However, numerous studies have indicated that the criteria that apply to all follicular neoplasms of the thyroid also distinguish malignant from benign Hurthle cell lesions (149,152-158) . The larger the Hurthle cell lesion, however, the more likely it is to show invasive characteristics; a Hurthle cell tumour which is 4 cm or greater has an 80% chance of showing histologic evidence of malignancy (149). Nuclear atypia, which is the hallmark of the Hurthle cell, multinucleation, and mitotic activity are not useful to predict prognosis and therefore should not be used as diagnostic criteria for malignancy.

A subgroup of Hurthle cell neoplasm has been described which show some atypical features including marked nuclear anaplasia, mitoses, spontaneous infarction and

Figure 15. Hurthle cell tumours ofthyroid are usually well delineated or encapsulated lesions in which more than 75% of the tumor cells have abundant eosinophilic granular cytoplasm due to the accumulation of spherulated and dilated mitochondria. These cells are derived from follicular epithelium and the criteria used to classify them should be identical to those used for non-oncocytic lesions.

Figure 15. Hurthle cell tumours ofthyroid are usually well delineated or encapsulated lesions in which more than 75% of the tumor cells have abundant eosinophilic granular cytoplasm due to the accumulation of spherulated and dilated mitochondria. These cells are derived from follicular epithelium and the criteria used to classify them should be identical to those used for non-oncocytic lesions.

trapping of tumor cells within the capsule in the absence of a preoperative FNA. Some authors have called these "atypical Hürthle cell adenoma" or "tumour of indeterminate malignancy". The great majority of these behave in a clinically benign fashion.

Flow cytometric analyses document aneuploid cell populations in 10 to 25% of Hürthle cell neoplasms that are clinically and histologically classified as adenomas (159-161). Virtually all of these tumours behave in a benign fashion after excision. Among histologically confirmed carcinomas, patients with thyroid tumors that have diploid DNA content tend to have a better prognosis than those with aneuploid values (159,161,162). Oncocytic neoplasms show frequent chromosomal DNA imbalance, with numerical chromosomal alterations being the dominant feature (163). Activating ras mutations are infrequent in oncocytic tumors (163).

The management of Hürthle cell carcinoma is controversial (155,156,164-167). In most institutions patients undergo total thyroidectomy followed by radioactive iodine. Iodine uptake by these lesions tends to be poor. External beam radiotherapy is advocated only for locally invasive disease.

Figure 16. Oncocytic tumours with or without papillae that exhibit the nuclear features of papillary carcinoma represent Hürthle cell or oncocytic papillary carcinomas. This is an example of a follicular lesion that was not invasive, mimicking adenoma, but that harboured a ret/PTC gene rearrangement and metastasized to a local lymph node.

Figure 16. Oncocytic tumours with or without papillae that exhibit the nuclear features of papillary carcinoma represent Hürthle cell or oncocytic papillary carcinomas. This is an example of a follicular lesion that was not invasive, mimicking adenoma, but that harboured a ret/PTC gene rearrangement and metastasized to a local lymph node.

Hürthle cell papillary carcinoma

Many Hürthle cell tumors, whether benign or malignant, show papillary change which is really a pseudopapillary phenomenon, since Hürthle cell neoplasms have only scant stroma and may fall apart during manipulation, fixation and processing.

True oxyphilic or Hürthle cell variant of papillary carcinoma has been reported to comprise from 1 to 11% of all papillary carcinomas (144,168-173). These tumors have papillary architecture, but are composed predominantly or entirely of Hürthle cells (144,174). The nuclei may exhibit the characteristics of usual papillary carcinoma (169,175) (Figure 16), or they may instead resemble the pleomorphic nuclei of Hürthle cells, being large, hyperchromatic and pleomorphic (63,170). The clinical behaviour of this rare subtype is controversial; some authors have reported that they behave like typical papillary carcinomas (63,150,172,174,175), while others maintain that the Hürthle cell morphology confers a more aggressive behaviour (176,177) with higher rates of 10 year tumor recurrence and cause-specific mortality (170). This suggestion of aggressive behaviour may be attributed to inclusion of tall cell variant papillary carcinoma in the group of Hurthle cell carcinomas.

One morphologic subtype of Hurthle cell papillary carcinoma which, because of a characteristic cystic change and extensive lymphocytic infiltration into the cores of the papillae of the tumour, has a striking histological resemblance to papillary cystadenoma lymphomatosum of the salivary gland and has been called "Warthin-like tumour of the thyroid" (178). This lesion occurs in the setting of chronic lymphocytic thyroiditis, predominantly in women, and is associated with a similar prognosis to usual papillary carcinoma.

The diagnosis of Hurthle cell follicular variant papillary carcinoma remains controversial. Many of these lesions have been diagnosed in the past as Hurthle cell adenoma, however, reports of aggressive behaviour suggested that this diagnosis could not be trusted (156,179). The application of ret/PTC analysis by RT-PCR allowed recognition of a follicular variant of Hurthle cell papillary carcinoma as a group of lesions with no invasive behaviour at the time of diagnosis but that harboured a ret/PTC gene rearrangement (180,181). Many of these lesions exhibit irregularity of architecture with hypereosinophilic colloid and nuclear features of papillary carcinoma, but these can be obscured by the hyperchromasia and prominent nucleoli of oncocytic change. Nevertheless, they can be recognised when there is a high index of suspicion and with the addition of immunohistochemistry for HBME-1, galectin-3, CK19 and ret or by RT-PCR studies of ret rearrangements. These tumours have the potential to metasta-sise (182), explaining the occurrence ofmalignancy in patients with a histopathological diagnosis of adenoma.

Nodules associated with hashimoto's thyroiditis

In 1912, Hashimoto described a well-defined clinicopathologic syndrome consisting of goitre, hypothyroidism, and lymphocytic thyroiditis. It is now generally accepted that the form of lymphocytic thyroiditis known as Hashimoto's thyroiditis is of autoimmune aetiology (183,184). Patients have antibodies to thyroglobulin and to thyroid peroxidase (also know as "microsomal antigen") (185). Some patients also have antibodies to a colloid component other than thyroglobulin "second colloid antigen") and, occasionally, to thyroid hormones. Patients with this disorder are most often women (female-male ratio is 10:1) between 30 and 50 years of age. They typically develop a diffuse, lobulated, asymmetrical, nontender goitre. Most patients with long-standing disease are hypothyroid. Occasionally there is a transient episode of hyperthyroidism known as "Hashitoxicosis" early in the course of the disease; this has been attributed to release of stored hormone during tissue destruction or to stimulation by antibodies to the TSH receptor (185).

The presence of thyroid growth-stimulating immunoglobulins (TGI) in these patients and/or compensatory TSH excess due to tissue destruction and hypothy-roidism have been implicated in the development of hyperplastic nodules that present as discrete masses in patients with this disorder. Aspiration of these lesions yields an admixture of epithelial cells and inflammatory cells (57). The hallmark is the Hurthle cell, a follicular epithelial cell that is characterised by abundant granular cytoplasm and a nucleus often with prominent "cherry pink" nucleolus. The background is composed of small and large lymphocytes, plasma cells, germinal centre fragments and macrophages with or without tangible bodies. Follicular cells and colloid are usually scant but may show nuclear atypia with irregular nuclear contours and prominent grooves.

The appearance of the thyroid involved by Hashimoto's thyroiditis is variable. The gland is usually enlarged and can weigh more than 200 g. It is composed of firm, lobulated, rubbery tissue with a homogeneous, pale grey, fleshy cut surface that lacks colloid translucence and resembles lymphoid tissue. Microscopically, the gland is diffusely infiltrated by mononuclear inflammatory cells, including lymphocytes, plasma cells, immunoblasts, and macrophages. Lymphoid follicles contain well-formed germinal centres. The glandular epithelium exhibits variable degrees of damage. Residual follicles are either atrophic, with sparse colloid and flattened epithelium or exhibit oxyphilic metaplasia, the accumulation of abundant eosinophilic granular cytoplasm characteristic of Hurthle cells (142). Follicular epithelial cells may also exhibit marked cytologic atypia that can be characterised by irregular nuclear membranes, grooves and even clearing of nucleoplasm. These features which in the face of inflammation are considered reactive, mimic papillary carcinoma (3,5). Areas of squamous metaplasia may be found (186). As the disease evolves, fibrosis becomes more conspicuous and in some patients, there is progression to the "fibrous variant" with less prominent lym-phocytic infiltration, more prominent squamous metaplasia, and intense fibrosis that almost totally replaces thyroid tissue (187).

The nodules that usually precipitate surgical intervention are cellular areas composed of follicles with variable colloid storage. It is not uncommon for them to be composed predominantly of Hurthle cells and they may be difficult to distinguish from adenomas. The cytologic atypia that resembles that of papillary carcinoma and the fibrosis that can trap follicular epithelium create difficult diagnostic problems. The distinction of thyroid cancer from a reactive process or hyperplasia can be extremely difficult. Application of special techniques is particularly important in this setting. Stains such as HBME-1, galectin-3, CK 19 and ret can be of assistance.

Recent data indicate that glands with Hashimoto's disease express ret/PTC gene rearrangements (188). In the author's experience, this is the case when there are nodules of Hurthle cells or micropapillary carcinomas in the tissue submitted for examination, but not if these lesions are carefully excluded from the inflamed tissue examined (70). In general, ret/PTC expression in Hurthle cell nodules in this setting identifies gene rearrangements that correlate with other features of papillary carcinoma.

Sudden and rapid enlargement of a nodule in a patients with Hashimoto's thyroiditis may indicate the development of primary thyroid lymphoma which occurs usually in this setting.

POORLY DIFFERENTIATED (INSULAR) CARCINOMA

Poorly differentiated or insular carcinoma is a tumour of follicular cell origin which mimics the architecture of medullary thyroid carcinoma (189-191). The tumour may

Figure 17. Insular or poorly differentiated carcinoma derived from follicular epithelium can mimick medullary carcinoma since it has a solid nesting architecture. Individual tumour cell necrosis is usually present.

Figure 17. Insular or poorly differentiated carcinoma derived from follicular epithelium can mimick medullary carcinoma since it has a solid nesting architecture. Individual tumour cell necrosis is usually present.

have a central nidus that is encapsulated but usually the lesion exhibits frank capsular invasion and forms satellite nodules in the surrounding thyroid. The tumour architecture is characterised by large well-defined solid nests; it is largely devoid of follicular architecture and devoid of colloid (Figure 17). The tumor cells are usually small and uniform in size and there is a variable degree of mitotic activity. Sclerosis can mimic amyloid, however, congo red stains are negative and immunohistochemical stains for calcitonin, chromogranin and CEA are negative. In contrast the tumors are uniformly positive for thyroglobulin, confirming the follicular cell differentiation of this neoplasm. In contrast to anaplastic carcinomas, there is little pleomorphism and no bizarre, giant, or multinucleated cells are found, however, mitotic activity is identified. Single cell necrosis is a defining feature, but geographic necrosis is unusual.

Insular carcinoma behaves in an aggressive fashion and is often lethal. This is the lesion that most often is identified in cases that have been diagnosed as "widely invasive follicular carcinoma". Most aggressive Hurthle cell lesions show insular growth and focal tumor cell necrosis. Vascular invasion and or metastases are frequent at the time of diagnosis. Insular carcinoma therefore occupies a position both morphologically and biologically between differentiated papillary or follicular carcinoma and anaplastic thyroid carcinoma. These tumors are not uncommonly found associated with well differentiated carcinoma (either papillary or follicular) and the insular growth is thought to represent a dedifferentiation phenomenon. Since this entity has only been recognised relatively recently and the clinical literature does not include studies of this tumor type as a separate entity, appropriate clinical management remains to be established.

Clear cell carcinoma is a rare finding in the thyroid and raises important differential diagnoses. The identification of any clear cell lesion should alert the pathologist to the possibility of metastasis, particularly from renal or adrenal tumors (5). However, primary clear cell tumors of thyroid follicular cells occur and are thought to be due to accumulation of glycogen, lipid or even mucin (5). Proof that these represent follicular cells is obtained from thyroglobulin and TTF-1 staining. The term "clear cell tumor" should be restricted to lesions in which more than 75% of the tumor cells show this change.

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