Nodular Hyperplasia
Sporadic nodular goitre is characterized by numerous follicular nodules with heterogeneous architecture and cytology, features that have suggested a hyperplastic rather than neoplastic pathogenesis [11, 12, 13, 14] . Nevertheless, the morphologic classification of cellular follicular nodules in nodular glands can be extremely difficult. Hyperplasia may be extremely difficult to distinguish from neoplasia. For the most part, large nodules in multinodular glands tend to be incompletely encapsulated and poorly demarcated from the internodular tissue. However, in some glands, large encapsulated lesions with relatively monotonous architecture and cytology make distinction of hyperplasia from adenoma difficult. Many pathologists have applied nonspecific terms such as "adenomatoid nodules" to describe such lesions

Molecular studies have indicated that the dominant nodules of multinodular goiters are monoclonal proliferations, and therefore represent benign neoplasms [12, 15] . It may be that these represent true adenomas arising in the background of a hyperplastic process. Moreover, most hyperfunctioning nodules are also now thought to represent clonal benign neoplasms with activating mutations of the TSH receptor or Gsa [16, 17] . The evidence of clonal proliferation in sporadic nodular goitre and the identification of ras mutations as early events in morphologically classified hyperplastic nodules in this disorder [18] indicates that the thyroid is a site for the hyperplasia-neoplasia sequence.

The neoplastic nature of these lesions raises the possibility of malignant transformation, and event that is rarely recognized clinically, since the vast majority of nodular goiters remain entirely clinically benign. However, it is important to recognize such malignant transformation, and this may be very difficult in the setting of nodular hyperplasia. This is an area where immunohistochemical markers would prove very useful.

Follicular Adenoma
Solitary follicular nodules have been unequivocally shown to be monoclonal [19, 20] and in the absence of invasive behavior or of markers of papillary carcinoma, these lesions are considered to be benign. Follicular adenomas can be classified histologically according the size or presence of follicles and degree of cellularity. The subclassification of follicular adenomas into simple, microfollicular, trabecular, oxyphil, atypical, papillary and signet ring cell types has no prognostic significance.

Atypical adenomas are highly cellular tumors with unusual gross and/or histologic appearances that suggest the possibility of malignancy but these tumors lack evidence of invasion. They may have necrosis, infarction, numerous mitoses or unusual cellularity. Many so-called "atypical adenomas" are indeed papillary carcinomas. The distinction of an encapsulated follicular variant papillary carcinoma from follicular adenoma relies on cytologic characteristics. The presence of the cytologic features of papillary carcinoma should indicate that diagnosis, despite lack of invasion, however, this is a highly subjective area that exhibits the most inconsistency in diagnostic pathology [10].

Whether some follicular nodules classified histologically as adenomas have the biologic potential to become carcinoma is not clear; aneuploid cell populations have been described in a significant percentage of these lesions, suggesting that some of these may represent carcinoma in situ.

Follicular Carcinoma
Follicular adenoma and most follicular carcinomas are indistinct with respect to their clinical presentation, radiographic appearance, cytologic findings and microscopic features. In most cases, the parenchymal component of both tumour types is essentially the same histomorphologically. The distinction between these two conditions has been considered possible only by recognition of invasion or metastasis. As indicated above, some encapsulated follicular adenomas exhibit evidence of aneuploidy and may in fact represent in situ follicular carcinomas.

Nuclear and cellular atypia and mitotic figures may be present in adenomas as well as in carcinomas and therefore cytologic characteristics are not helpful. Follicular carcinoma can only be diagnosed by the demonstration of capsular and/or vascular invasion. Follicular carcinomas are divided into groups that reflect the biology of tumour growth and metastasis. Widely invasive follicular carcinomas, which are usually identifiable as invasive grossly, and certainly are not difficult to recognize as invasive microscopically, carry a poor prognosis with a 25-45% ten year survival [21, 22] . In our experience, these tend to be insular carcinomas. In contrast, the more common scenario is that of minimal capsular invasion and patients with these tumors have an excellent prognosis. The diagnosis of follicular neoplasms requires very careful and thorough examination of the entire capsule of the follicular neoplasm by the pathologist [23]. Minimally invasive follicular carcinoma is identified by invasion through but not widely beyond the capsule. Borderline lesions include those with invasion into the capsule beyond the bulk of the lesion but not through the full thickness of the capsule. This represents another area of controversy with varying thresholds for the diagnosis of malignancy.

The concept of unencapsulated follicular carcinoma was raised by the identification of tumors that lack a capsule. In one report of four such cases, one patient developed metastases, and this gave rise to citations of a 25% metastatic rate by such lesions [24]. However, this has not been substantiated in larger series and this concept has largely been abandoned.

Patients with minimally invasive follicular carcinomas are on average about 10 years younger than those with widely infiltrative carcinomas and since traces of capsule are found in about 24% of widely invasive lesions, it is possible that encapsulated follicular carcinoma is a precursor of the widely invasive lesion [25]. Minimally invasive carcinomas have ten year survival rates of 70-100% [26] and therefore some argue that this disease does not warrant the painstaking search for microscopic invasion that distinguishes it from follicular adenoma. Nevertheless, the investigators that have reported these promising data have treated their patients for carcinoma rather than for benign disease. Rather than endorsing a cavalier approach that would entail less work for the pathologist, it behooves us to recognize the presence of potential malignancy, to treat the patient appropriately [27], but also to identify the excellent prognosis that these lesions carry after appropriate management.

Vasculoinvasive follicular carcinomas are aggressive and require management accordingly. While vascular invasion is more reliable for the diagnosis of malignancy, again the criteria are vague. Vascular invasion cannot be evaluated within the tumour and therefore again the circumference of the lesion is the site that warrants careful examination. Bulging of tumour under endothelium does not qualify as vascular invasion if the endothelium is intact. Nests of tumour cells within an endothelial lumen generally are accepted as representing invasion. However, it is recognized that artefactual implantation of tumour cells into blood vessels can occur during the surgical procedure or sectioning. Therefore, endothelium covering invasive tumour cells or thrombus adherent to intravascular tumour is required to distinguish true invasion from artefact.

The significance of this diagnosis must be interpreted in light of clinical data that assess the behavior of this disorder. The dominant determinant of cause-specific mortality in patients with follicular carcinoma is the presence of distant metastases [28, 29, 30] . Most studies have indicated that morbidity and mortality for patients with non-metastatic encapsulated follicular carcinoma is very low and correlates better with patient age than with any other parameter. Some have suggested that capsular invasion alone does not alter the incidence of distant metastases or cancer-related death.

Since the incidence of follicular carcinoma is low [31], most investigators still advocate total thyroidectomy and radioactive iodine therapy [27, 32, 33] . The rationale for total thyroidectomy is not bilateral carcinoma; multifocal disease in follicular carcinoma is exceedingly rare and the identification of occult papillary carcinoma in the contralateral lobe is not an indication for further surgery [34]. The only logical rationale for completion thyroidectomy is to allow selective uptake of radioactive iodine by metastatic tumour deposits rather than by residual thyroid gland. Uptake of radioactive iodine by distant metastases is a favorable prognostic factor and is improved by pre-therapeutic total thyroidectomy, resulting in improved survival [35, 35, 36, 37] . In contrast, external beam radiotherapy is not thought to be of use in patients with differentiated thyroid carcinoma, apart from those with locally advanced tumors such as widely invasive follicular carcinomas that involve extrathyroidal soft tissues of the neck and cannot be completely resected [37].

The last few decades have seen a decrease in the incidence of follicular thyroid carcinoma, probably due to dietary iodine supplementation [31]. However, misdiagnosis of this tumour continues. Benign lesions, such as partly encapsulated hyperplastic nodules or nodules exhibiting pseudo-invasion after fine needle aspiration [38], are often over-diagnosed as malignant; papillary carcinomas with follicular architecture are often misinterpreted as follicular carcinoma. The clinical features, pathophysiology and biological behavior of follicular cancer differ significantly from those of the entities with which it is often confused. Only careful histopathologic classification will allow correct evaluation of treatment options and prognosis.

Papillary Carcinoma
Papillary carcinoma comprises at least 80% of thyroid epithelial malignancies diagnosed in regions of the world where goiters are not endemic. The terminology is misleading; papillary carcinomas can exhibit papillary architecture but they may also have follicular or mixed papillary and follicular patterns [3, 5, 39, 40, 41, 42, 43, 44, 45, 46] . It is now recognized that the diagnosis of papillary carcinoma is based on what the WHO has described as "a distinctive set of nuclear characteristics" [2]. 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 [35, 47, 48] . 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 [21, 22, 35, 49] . 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 behavior of papillary carcinoma in men compared to women. Tumour size is exceedingly important [50]. Tumors less than 1 cm are common [51] and appear to be different biologically than larger tumors [52, 53, 54] . In contrast, tumors 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 tumors. 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.

The follicular variant of papillary carcinoma has been recognized more frequently in the past 20 years [2, 3, 5, 55, 56, 57] . This lesion comprises more than 50% of papillary cancers in our experience. It has either been misdiagnosed as follicular carcinoma or under-diagnosed as follicular adenoma or atypical adenoma. Any lesion with follicular architecture and characteristic nuclear features of papillary carcinoma should be classified as this tumor. However, the threshold for this diagnosis is extremely inconsistent [6, 7, 8, 9, 10] . The presence of cytologic atypia may raise the possibility of papillary carcinoma without being sufficiently convincing for unequivocal diagnosis. In such cases, specific markers of this tumour as well as other markers if malignancy may be useful.

The management of the less aggressive forms of papillary thyroid carcinoma is controversial. Most experts advocate total thyroidectomy and radioactive iodine therapy [27, 33] . 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 tumour deposits rather than residual thyroid tissue. However, as shown by the studies of Sugg et al [58], 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 [35, 36, 37] . The controversy involves the management of patients with low risk clinical and pathological parameters; some have advocated less aggressive management with unilateral thyroidectomy and no radioiodine therapy in this setting [32]. There is a clear need for potential markers of those rare more aggressive tumors that will metastasize to local lymph nodes to stratify patients for completion thyroidectomy and radioiodine therapy. 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 [37, 49] .

The Role of Immunohistochemistry
It is obvious that the diagnosis of malignancy in well-differentiated encapsulated follicular-patterned tumors rests on subjective criteria. The search for objective markers of malignancy is therefore of great importance and reliable candidates will prove very useful for diagnosis and patient management.

The search has yielded one very specific but highly enigmatic candidate. HBME-1, a marker of mesothelial cells, is immunohistochemically detected in more than 40% of thyroid follicular malignancies of papillary or follicular differentiation [59, 60, 61] and has been used successfully in cytology studies as well as histopathologic evaluation of thyroid nodules [60, 61] . The problem with this marker is that is identifies an unknown antigen.

Recent studies have advocated the use of galectin-3 as another marker of malignancy [62, 63, 64] . However, this has not been a reliable marker in the hands of some investigators [65]. In our experience this marker also stains normal, hyperplastic and inflamed thyroid tissue, but positivity in malignancies is more diffuse and strong. These data should limit the application of this technique for cytology but this has not been widely recognized [66].

Stains for high molecular weight cytokeratins, particularly cytokeratin 19 (CK19) may be useful to diagnose a follicular-patterned papillary carcinoma. This technique, also considered controversial [67, 68] , has been shown to be useful when applied to paraffin sections with microwave antigen retrieval [69] . The results of these studies indicate that moderate to strong diffuse staining is confined to papillary carcinoma 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 papillary carcinoma has been further advanced by the recognition of a family of gene rearrangements that are specific to papillary carcinoma [70]. The ret/PTC oncogenes (1 through 15, depending on the site of rearrangement, reviewed in [71] ) 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 [72, 73, 74, 75, 76] . The rearrangements result in constitutive tyrosine kinase activation and translocation of the fusion protein to the cytoplasm [77]. Animal models have shown the tumorigenicity of these fusion proteins [78, 79] ; the rearrangements are common in radiation-induced tumors [80, 81, 82, 83, 84] but are also found in sporadic papillary carcinomas [85, 86, 87, 88] and appear to be an early event in tumour development [89]. 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 [58]. Again, a negative stain is not useful. 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 [90] and application of this technique enhances the cytological diagnosis of papillary carcinoma.

The diagnosis of Hürthle cell follicular variant papillary carcinoma remains controversial. Many of these lesions have been diagnosed in the past as Hürthle cell adenoma, however, reports of aggressive behavior suggested that this diagnosis could not be trusted [91, 92] . The application of ret/PTC analysis by RT-PCR allowed recognition of a follicular variant of Hürthle cell papillary carcinoma as a group of lesions with no invasive behavior at the time of diagnosis but that harbored a ret/PTC gene rearrangement [93, 94] . 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 recognized when there is a high index of suspicion and with the addition of immunohistochemistry for HBME-1, galectin-3, CK19 and ret. These tumors have the potential to metastasize [95], explaining the occurrence of malignancy in patients with a histopathological diagnosis of adenoma. This concept requires a re-evaluation of the approach to oncocytic lesions of thyroid [96], including the application of other markers of malignancy such as HBME-1 and galactin-3 [97].

More recently, activating mutations in BRAF were identified as another common feature of papillary thyroid carcinomas [98, 99, 100, 101, 102, 103, 104, 105, 106] . All of the mutations thus far described in this disorder affect nucleotide 1796 in exon 15, resulting in a thymidine to adenine transversion which translates into a valine to glutamate substitution at residue 599. Interestingly, classical papillary carcinomas have a high incidence of this mutation, but it seems to be rare in follicular variant lesions that are more of a diagnostic dilemma, and a few of these lesions have been reported to harbor a mutation of residue 600 [105]. BRAF belongs to the RAF family of serine/threonine kinases and is located downstream of Ras and upstream of mek in the classical MAPK signaling cascade, and since this pathway is activated by tyrosine kinase receptors including ret, it likely results in convergence of altered signal transduction. However, this molecular alteration, while highly specific, cannot be detected by immunohistochemistry as yet. Similarly, telomerase activity has been identified as a diagnostic and prognostic factor in thyroid tumors [107, 108] , but there is as yet no immunohistochemical test for this application.

The controversy concerning the management of patients with low risk clinical and pathological parameters revolves around the indication for less aggressive management with unilateral thyroidectomy and no radioiodine therapy in this setting [32]. Recent studies have identified potential markers of those more aggressive tumors that will metastasize to local lymph nodes, including loss of nuclear p27 and upregulation of cyclin D1 [109, 110, 111] and these may prove valuable to stratify patients for completion thyroidectomy and radioiodine therapy, but more studies are needed to validate these data. Another prognostic marker in papillary carcinoma is loss of bcl-2 protein [112].

Another molecular marker with application to prognostication of follicular carcinoma is a gene rearrangement that involves the thyroid transcription factor Pax 8 and the peroxisome proliferator-activated receptor g (PPARg) gene [113]. Normal thyroid follicular cells express Pax 8 at high levels; this transcription factor is essential for thyroid development, involved in regulating expression of the endogenous genes encoding thyroglobulin, thyroperoxidase, and the sodium/iodide symporter. PPAR g , a transcription factor that is implicated in the inhibition of cell growth and promotion of cell differentiation, is also expressed by normal thyroid follicular epithelium. However, this in-frame rearrangement results in a fusion protein that likely interferes with the normal function of both differentiating factors, thereby explaining its potential role in thyroid tumorigenesis. The rearrangement is most reliably detected using fluorescence in situ hybridization (FISH) technology to identify the translocation of the two genes that are normally localized on chromosomes 2q13 (Pax 8) and 3p25 (PPAR g ). The presence of overexpressed protein can also be identified using immunostains for PPARg where strong nuclear staining identifies tumors harboring a translocation. Although follicular carcinomas of thyroid are rare [31], and the numbers of cases studied has been small, it appears to be a useful tool for the diagnosis of malignancy in thyroid follicular lesions, particularly to predict vascular spread and aggressive behavior [114]. Nevertheless, it remains controversial, with some reports of positivity in benign lesions [115, 116] , and some studies have shown correlation with malignancy but better prognosis [117].

Other markers that may have potential for more accurate diagnosis and therapy of thyroid lesions include hepatocyte growth factor (HGF) and its receptor met [118], thyroid peroxidase (TPO) [119], CITED-1 [120], cyclooxygenase-2 (COX-2) and thromboxane [121], CD44V6 and CD 57 [122], CD82 [123], HMGI(Y) [124], MUC1 [125] and the novel S100C [126].

It is evident that no single marker can identify all malignant follicular-patterned lesions, therefore various combinations of markers have been proposed. The use of HBME-1, high molecular weight cytokeratins and ret provides a set of immunohistochemical markers that aids in the diagnosis of papillary carcinoma in equivocal cases [127]. Other combinations have also been suggested, including galactin-3 and TPO [119], galactin-3, fibronectin-1, CITED-1, HBME-1 and CK19 [128] .

As these and other markers are characterized and validated, directed in the future by molecular profiling of thyroid lesions with characteristic morphology, behavior and outcome [129], they will become available as routine immunohistochemical markers that will provide a more accurate, scientific and clinically relevant consultation report from the pathologist for cytology and surgical pathology procedures.

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