Clinico-pathological prognostic factors

Several authors have studied various clinical factors in large groups of patients and have devised treatment and prognostic schemes based on these factors. Most studies use cancer-related death as an end point. Because tumour recurrence rates reflect cancer cancer-related clinical problems, it is unfortunate that this parameter has not been well examined. Various clinical parameters used in these studies are:

8.2.1. Age

Age at tumour diagnosis has been found to be the most important prognostic factor in DTC [8.4, 8.11, 8.12]. It is shown that there is a linear increase in tumour recurrence and death with age, especially after age 40. Older patients often present with more aggressive tumours, more frequent distant metastases, and aggressive histological variants, thus leading to an unfavourable disease course [8.4, 8.5]. Children above the age of 10 and adolescents have an excellent prognosis even in the presence of extensive local disease and distant metastasis.

However, children under 10 years of age with DTC usually exhibit more advanced disease and a high risk of disease-related mortality than children over 10 years of age [8.11, 8.13-8.15].

8.2.2. Gender

Tumours in men follow a more aggressive clinical course compared to women [8.7, 8.16]. A study of 1257 patients by Lin, et al. [8.16] showed that male patients with papillary carcinoma were more prone to distant metastasis. These results were also corroborated by a Canadian study of 1578 patients [8.17]. However, some large studies have failed to show any correlation between gender and prognosis of DTC [8.4, 8.5].

8.2.3. Size

The size of papillary carcinoma of thyroid can range from less than 1 cm to a tumour replacing the entire thyroid lobe [8.1, 8.2, 8.13]. Tumours measuring less than 1 cm or less are defined as microcarcinoma by the World Health Organization (WHO) [8.18]. It has been shown that tumour size is a dependable prognostic factor in DTC (19). Although papillary microcarcinoma rarely show nodal metastases [8.20] while large tumours (4 cm or more) are often associated with extrathyroidal extension [8.16]. However, it is unclear from published studies that tumour extension rather than size is an important factor affecting the prognosis.

8.2.4. Multifocality

In cases of papillary cancer, multiple foci of tumour may be present within one lobe or both lobes [8.2, 8.21]. This is a cited reason for total thyroidectomy in patients with papillary cancer [8.19, 8.22]. Some authors believe that these multiple foci represent intraglandular spread of tumour via lymphatics [8.1, 8.2] however, others have shown by RET-PTC analysis that these foci are separate tumours and not a progeny of one clone [8.23]. Multifocal tumours have an increased propensity to metastatise to lymph nodes, have persistent local disease, regional recurrences, distant metastases and mortality [8.2, 8.24].

8.2.5. Vascular invasion

Historically, this factor has not been analysed in detail as a prognostic factor in DTC especially in papillary cancers. Gardner, et al. [8.25] showed tumours associated with intrathyroidal and/or extrathyroidal vascular invasion are associated with an increased incidence of distant metastases and recurrence.

8.2.6. Extrathyroidal extension

Both papillary and follicular carcinoma can have extrathyroidal extension [8.1, 8.13]. It has been shown that tumours associated with gross extrathyroidal extension (noted by the surgeon or by preoperative evaluation) have a worse prognosis than those confined to the thyroid [8.5, 8.26]. A study from Memorial Sloan Kettering Cancer Centre of 931 patients found that on multivariate analysis, extrathyroidal extension is one of the adverse prognostic factors [8.27].

Similar findings have been reported from other large referral centres [8.28, 8.29].

8.2.7. Degree of tumour differentiation

Most DTC are low-grade tumours, thus, grading of these tumours has not been successful [8.6]. Some DTC can show focal areas of less differentiated tumour (solid growth, focal necrosis, mitoses), which have been denoted as foci of ‘poorly differentiated’ carcinoma.

According to these reports the presence of significant amounts (>10% of tumour mass) of these foci may adversely affect patient prognosis [8.30].

8.2.8. Metastases

Lymph node metastases are more common in papillary carcinoma than in follicular carcinoma [8.1, 8.13]. The reported rates for lymph node involvement in papillary carcinoma can be as high as 80% [8.1, 8.13, 8.16]. Some studies have suggested that lymph node involvement in papillary carcinoma is an adverse prognostic factor, whereas, others have found no prognostic significance [8.4, 8.5, 8.7, 8.31]. Mazaferri, et al. [8.7] found lymph node involvement to be highly predictive of tumour recurrence and cancer-related death. Hughes, et al. [8.32] found

that nodal involvement was dependent on age at the time of tumour diagnosis and was not an independent prognostic factor. Miralle, et al. [8.33] suggested vascular invasion, male, absence of tumour capsule, and perithyroidal involvement as predictive of presence of nodal disease by univariate analysis. However, by multivariate analysis only absence of tumour capsule and perithyroidal tissue involvement was predictive of nodal disease. Distant metastases to lung and bones can also adversely affect prognosis in DTC. These are more common in follicular than papillary carcinoma [8.13, 8.24]. Ruegemer, et al. [8.34] showed that distal metastases had increased mortality rates (up to 75%) in cases of follicular and Hurthle cell carcinoma and 82% of these died of their disease within 5 years.

8.2.9. Treatment

Many thyroidologists and surgeons recommend that DTC should be treated by near-total thyroidectomy and ablation of the thyroid remnant by post-operative radioiodine (¹³¹I) treatment [8.7, 8.19, 8.35]. Near-total thyroidectomy is preferred by many clinicians over partial thyroidectomy because of the following: a) multicentricity in papillary cancer, b) frequent nodal disease, c) highly invasive nature of follicular carcinoma, and d) difficulty in ablation of large thyroid remnant by ¹³¹I. At present, there are several nonrandomized published reports which show that this treatment significantly reduces tumour recurrence, improves survival, and facilitates follow-up [8.7, 8.16, 8.19, 8.35, 8.36]. It has been shown that tumour recurrence can occur in thyroid remnant in 20% of patients and distant metastases are more common after subtotal than total thyroidectomy [8.35, 8.37, 8.38]. In light of these studies exploring the effects of mode of treatment on prognosis in DTC, many clinicians believe that an initial aggressive management may lead to disease free survival in more than 90% of patients [8.7, 8.39]. In young patients with small tumours (<1.5 cm), and no evidence of thyroid capsule invasion or metastases, a conservative approach has been recommended.

Total thyroidectomy and radioiodine treatment have not been shown to improve prognosis in this low risk group of patients [8.28].

8.2.10. Tumour markers

Thyroglobulin (Tg) is expressed by all DTC therefore Tg measurement can be used as a postoperative tumour marker, especially when normal thyroid tissue has been eliminated by surgery or radioactive iodine ablation therapy. Postoperative Tg is usually measured during thyrotropin (TSH) stimulation (endogenous or recombinant TSH) and has been found to be more sensitive for detecting disease than basal Tg measurements. This method also indicates TSH sensitivity of the tumour. It has been shown that changes in serum Tg represent evolution of disease (change in tumour mass) after initial treatment [8.7, 8.40].

8.2.11. Tumour subtype

Papillary carcinoma is the most common form of DTC and patients with this tumour fare better than those with follicular thyroid carcinoma. The reported 10-year survival is 95% in papillary carcinoma and 80% in follicular carcinoma. However, this is dependent on histological subtypes of papillary carcinoma. In addition, survival figures in follicular carcinoma decline if Hurthle cell carcinomas are included. Despite these reported differences studies have shown that if the patients are stratified by their age and disease stage, survival curves for both papillary and follicular carcinoma are similar [8.2, 8.5, 8.7, 8.13, 8.41].

At present, numerous histological variants/subtypes of papillary carcinoma have been

prognosis. A better prognosis is seen in encapsulated, cystic or microcarcinoma papillary cancer, whereas an aggressive clinical behaviour is seen in tall cell, columnar cell, and diffuse sclerosing variant [8.1, 8.2, 8.3, 8.13].

Tall cell variant of papillary carcinoma derives its name from the presence of elongated tumour cells (the height of individual cell being twice the width) with nuclear features of papillary carcinoma. Hawk and Hazard [8.42] initially reported this tumour in 1976. These tumours are usually of large size (>5 cm), present at older age and have a strong male predilection. These tumours exhibit a strong tendency toward extrathyroidal extension, vascular invasion, local recurrence, distant metastases and cause disease-associated death in about 25% of patients [8.1, 8.13, 8.43].

Columnar cell carcinoma is a unique variant of papillary carcinoma. It is characterized by papillary architecture and nuclear stratification with prominent subnuclear cytoplasmic vacuolation resembling early secretary endometrium [8.13]. These tumours usually are aggressive and exhibit extrathyroidal extension, regional and distant metastases and a fatal outcome [8.44]. Recently, an encapsulated variant of this tumour have been described. These tumours are confined to the thyroid and show better prognosis compared to the initially described cases [8.45, 8.46].

Papillary microcarcinoma is defined as tumour measuring 1 cm or less in size [8.18]. A majority of these tumours are incidental findings during autopsy examination of thyroid or histological examination of thyroid lobe(s) resected for benign thyroid disease or as a part of surgical dissection of tumours of neighbouring head and neck organs (i.e., larynx) [8.20, 8.47]. Papillary microcarcinoma can be seen as a unifocal or multi-focal disease [8.1, 8.47].

The latter have been shown to be commonly associated with lymph node metastases and local recurrences. Therefore, it is recommended that hemithyroidectomy is adequate for unifocal tumours, whereas, multifocal tumours should be treated by total thyroidectomy [8.13, 8.20, 8.48-8.50]. Lupoli, et al. [8.51] recently described a familial form of this tumour in seven patients of which five tumours were multifocal and three showed vascular invasion.

Diffuse sclerosing variant of papillary thyroid carcinoma is commonly encountered in children and adolescents. It involves the whole thyroid diffusely and also shows sclerosis, squamous metaplasia, tumour-associated lymphocytic infiltrate, abundant psammoma bodies, and marked lymphatic invasion. All patients affected by these tumour show nodal disease and up to 25% also have lung metastases. Because of its clinical presentation some authors classify this tumour as an aggressive form of papillary thyroid carcinoma, whereas, other believe that it behaves like the usual papillary thyroid carcinoma [8.52].

Hurthle cell carcinoma is a variant of follicular carcinoma, which is predominantly or solely composed of oncocytic cells (at least 75%). These, tumours are frequently associated with extrathyroidal extension and with both distant and nodal metastases. Several studies have shown that Hurthle cell carcinoma is a more aggressive tumour and follows a less favourable clinical course than follicular carcinoma [8.53-8.57].

In encapsulated carcinoma, up to 14% of papillary carcinoma can be encapsulated [8.1, 8.13].

These tumours consist of either pure papillary, follicular, or a mixture of both growth patterns.

Usually the tumour capsule is thick, can show dystrophic calcifications and there is no evidence of capsular and/or vascular invasion [8.1, 8.13]. The nuclear features make the diagnosis of papillary carcinoma possible. It is generally believed that these tumours follow an indolent clinical course [8.1, 8.2, 8.3, 8.13, 8.8, 8.59]. These tumours can be associated

with lymph node metastases, however, local recurrence and metastatic spread is uncommon