Hyperplastic nodules and adenomas with papillary architecture
The "papillary hyperplastic nodule" of the thyroid is usually identified in girls, usually teenagers in and around the age of menarche. These present as solitary nodules and it is unusual for them to be associated with clinical hyperfunction, although that might occur. These lesion are distinguished from papillary carcinoma in that they are totally encapsulated, often show central cystic change, have subfollicle formation in the centres of broad oedematous papillae, and do not show nuclear features of papillary carcinoma (Figure 6). Although one analysis of clonality has suggested that these are polyclonal hyperplasias (56), the detection of or TSH receptor activating mutations in such nodules suggests that they are neoplasms (18-22). Their behaviour is almost always benign. Some have advocated the name "papillary adenoma" for these tumours; while scientifically appropriate, this term carries historical connotations that some feel are unacceptable (5).
In adults, one can have a similar histologic appearance in a "hot" nodule, that is, a thyroid nodule that is associated with clinical toxicity or subclinical hyperthyroidism and iodine uptake on scan. These lesions may be solitary but are often seen in the setting of sporadic nodular goitre (see above).
On fine needle aspiration and on histologic evaluation, particularly at frozen section, papillary hyperplastic nodules or adenomas can be very alarming and lead to a false positive diagnosis of papillary carcinoma. Indeed, these entities give rise to well formed papillae but on higher magnification, the cytologic criteria for the diagnosis of papillary carcinoma, including powdery nuclear chromatin, multiple micro- and/or macronucleoli, intranuclear cytoplasmic inclusions, and linear chromatin grooves (57), are lacking.
Papillary carcinoma comprises at least 80% of thyroid epithelial malignancies diagnosed in regions of the world where goitres are not endemic. The terminology is misleading; papillary carcinomas can exhibit papillary architecture (Figure 7) but they may also have follicular (Figure 8) or mixed papillary and follicular patterns (58-62). It is now recognised that the diagnosis of papillary carcinoma is based on what the WHO has described as "a distinctive set of nuclear characteristics" (63). In contrast to true follicular carcinomas, these lesions are usually more indolent and most have an excellent prognosis with a 20 year survival rate of 90% or better (64,65).
The defining nuclear features are readily seen on cytology of fine needle aspirates as well as on histologic sections (Figure 9). They include an alteration of the size and the roundness of the normal follicular cell nucleus to one that is large and oval. Due to peripheral margination of chromatin, the centre of the nucleus has an empty appearance, which when pronounced has been termed "ground glass" (66). The chromatin and nucleolus are pushed to the edge of the nucleus. The nuclear contour is strikingly irregular, resulting in a "crumpled paper" appearance, intranuclear cytoplasmic pseudoinclusions and nuclear grooves (67,68). No one specific feature is absolutely diagnostic of papillary carcinoma; a constellation or combination of nuclear features is required for the diagnosis.
Papillary carcinomas may be multifocal; this has been interpreted as reflective of intraglandular lymphatic dissemination, but the identification of such microcarcinomas in up to 24% of the population (69) and the detection of different clonal rearrangements in multifocal lesions (70) support the interpretation of multifocal primary lesions in most patients. Nevertheless, when these lesions do invade, they show preference for lymphatic involvement with a high percentage of regional lymph node metastases.
Metastases beyond the neck are unusual in common papillary carcinoma and probably only occur in about 5 to 7% of cases.
The most useful prognostic markers in papillary carcinoma are patient variables, tumour size and extent of disease (28,29,53,71). Patients under the age of 45 usually have an excellent prognosis; in contrast those over 45 years of age generally have a poorer outlook. Sex has also been said in the past to be an important determinant of tumour biology but more recent studies have suggested that there is no major difference in the behaviour of papillary carcinoma in men compared to women. Tumour size is exceedingly important (72). Tumours less than 1 cm are common and appear to be different biologically than larger tumours (73-75); a recent study has shown that occult papillary carcinomas are identified in up to 24% of the population in thyroids that are removed for non-malignant or unrelated disease (69). In contrast, tumours greater than 1 cm are thought to be of clinical significance and those larger than 3 cm generally have a poorer prognosis than do smaller tumours. The presence of cervical lymph node metastasis, whether microscopic or identified clinically, is thought to increase the risk of recurrence of disease but has been shown to have no impact on mortality.
Extrathyroidal extension, in contrast, predicts a worse prognosis and the presence of distant metastases is the hallmark of an aggressive tumour that will bear the potential for high mortality.
Grossly, papillary carcinomas vary in size from microcarcinomas (also called small, tiny, occult and minute), which are defined as lesions measuring less than 1 cm (usually 4 to 7 mm) to large neoplasms that extend extrathyroidally beyond the thyroid capsule into surrounding soft tissue. The bulk of clinical papillary carcinomas are intrathyroidal tumours confined within the capsule of the thyroid and may have an encapsulated appearance (this is usual for the follicular variant) or an irregularly infiltrative appearance. One can see gross cystic change but usually papillary carcinoma is a firm tumor and some are calcified or even ossified.
Microscopically, papillary carcinomas classically are composed of papillae but virtually all contain follicular elements. Ghosts of dead papillae or infarcted papillae calcify with a concentric whorled pattern that is characteristic of psammoma bodies (Figure 10); these are found in 40 to 50% of classical papillary carcinomas, either in the tumour stroma or in the surrounding non-tumourous thyroid, but they are distinctively uncommon in lesions with follicular architecture.
Inflammatory infiltrates within papillary carcinomas and in the surrounding thyroid parenchyma have been noted by several authors, although the prognostic significance of this is not clear (76,77). Some people have postulated that this inflammatory infiltrate
may indicate host-tumour immune interactions that are responsible for the general indolence of this type of thyroid carcinoma (76).
Although there are reports to the contrary, the exact histological variant of papillary carcinoma usually cannot be predicted from the appearance of the fine needle aspirate (78). Nevertheless, the histologic distinctions, which are characteristic (3,5,63,79-81), are of prognostic value.
Papillary microcarcinoma (75), cystic and encapsulated variants of papillary carcinoma (82) have an apparently better prognosis than usual papillary carcinoma.
The follicular variant has been recognized more frequently in the past 20 years (5,63,83,84). It has either been misdiagnosed as follicular carcinoma or underdiagnosed as follicular adenoma or atypical adenoma. Any lesion with follicular architecture and characteristic nuclear features of papillary carcinoma should be classified as this tumor. Infiltrating areas and metastases may exhibit a more striking papillary appearance and may even have psammoma bodies. It is unclear what the ultimate biological and clinical behaviour of follicular variant is, since some of these may be underdiagnosed as atypical adenomas and it is likely that the initial reports of this tumour included the aggressive biological spectrum of this variant.
The presence of cytologic atypia may raise the possibility of papillary carcinoma without being sufficiently convincing for unequivocal diagnosis. In some cases the changes may be induced by previous needle biopsy. The presence of haemorrhage, granulation tissue and hemosiderin laden-macrophages, inflammation and foreign body giant cells and even foreign material should point to this possibility. There may be calcification that can be mistaken for psammoma bodies. Various metaplastic changes occur. These changes have been described with the acronym WHAFFT which stands for "Worrisome Histological Alterations Following FNA of Thyroid" (55). The diagnosis of papillary carcinoma should not be made in this situation unless the lesion is entirely unequivocal.
In cases where the features are suggestive of papillary carcinoma but not entirely diagnostic, specific markers of this tumour as well as other markers if malignancy may be useful. A proportion of malignancies of thyroid follicular epithelium stain for HBME-1 (35-37)and some investigators have advocated the use of galectin-3 as a marker of thyroid carcinoma (38-41). Stains for high molecular weight cytokeratins may be useful. This technique, also considered controversial in the past, has recently been shown to be useful when applied to paraffin sections with microwave antigen retrieval (85). The results of these studies indicate that moderate to strong diffuse staining is confined to papillary carcinoma (Figure 11) whereas follicular neoplasms and hyperplastic nodules are negative or show only focal staining in areas of reaction to degeneration or previous fine needle aspiration biopsy. Nevertheless, only approximately 60% of papillary carcinomas are positive; a positive stain is therefore helpful, but negative stains are unable to assist in the diagnostic process.
The diagnosis of this entity has been further advanced by the recognition of a family of gene rearrangements that are specific to papillary carcinoma (86). The ret/PTC oncogenes (1 through 15, depending on the site of rearrangement, reviewed in (87)) are the result of DNA damage with rearrangements that transpose various cellular genes adjacent to the gene encoding the intracellular tyrosine kinase domain of the ret protooncogene (88-92). The rearrangements result in constitutive tyrosine kinase activation and translocation of the fusion protein to the cytoplasm (93). Animal models have shown the tumorigenicity of these fusion proteins (94-96); the rearrangements are common in radiation-induced tumors (97-101) but are also found in sporadic papillary carcinomas (102-105) and appear to be an early event in tumour development (106). Immunohistochemical staining with antisera directed against the carboxy terminus of ret allows rapid and clinically useful detection of this marker of papillary carcinoma which is present in almost 80% of occult papillary microcarcinomas and approximately 50% of clinically detected lesions (70). Again, a negative stain is not useful, however, the combination of high molecular weight cytokeratins and ret provides a set of immunohistochemical markers that aids in the diagnosis of papillary carcinoma in equivocal cases (107). At the moment, antisera or antibodies to ret offer inconsistent detection of these rearrangements and molecular diagnostics using RT-PCR remain the gold standard of this diagnostic tool. This methodology has been applied to FNA specimens when collected in suspension (108) and application of this technique enhances the cytological diagnosis of papillary carcinoma.
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