Biological factors

The diagnosis of follicular carcinoma is dependent on the presence of capsular and/or vascular invasion [8.1]. Some authors believe that the follicular carcinoma diagnosis should only be made in the presence of vascular invasion only [8.60]. Khan and Perzin [8.61], in their study of follicular tumours found that capsular invasion without vascular invasion was associated with metastatic disease. Evans [8.62] has reported similar findings. Therefore, follicular tumours showing only capsular invasion should be diagnosed as ‘minimally invasive follicular carcinoma’ and tumours with vascular invasion are termed as ‘angio-invasive follicular carcinoma’. The angio-invasive tumours lead to haematogenous metastasis to bone and lungs, causing death in 50% of patients at 10-year follow-up. In contrast, minimally invasive tumours have a minimal chance of metastasising. In general, compared to widely invasive follicular carcinoma that diffusely infiltrates the affected lobe or entire thyroid, the 10-year survival rates for encapsulated tumours range from 70% to 100% and for widely invasive type are 25% to 45% [8.1, 8.13, 8.62].

8.2.12. Autoimmune thyroid disease

Approximately one-third of cases of papillary cancer can arise in the background of lymphocytic thyroiditis or show a tumour associated lymphocytic infiltrate. Some studies have suggested that these associations can lead to favourable outcome. In addition, positive antithyroid antibodies can also be detected in up to 50% of cases of papillary cancer associated with a lymphocytic infiltrate and in 23% of patients with DTC. After treatment disappearance of these antibodies suggests a successful initial treatment, whereas, their persistence is indicative of persistent or recurrent disease [8.63, 8.64]. Some studies have shown that tumours arising on a background of Graves' disease have an aggressive clinical course. These are often multifocal, show invasion and have nodal, and distant metastases [8.65].

8.2.13. DNA ploidy

DNA aneuploidy indicates an adverse prognosis in papillary thyroid carcinoma. However, multivariate analysis has failed to substantiate its role as an independent prognostic indicator [8.66-8.68]. Some studies have shown that death and tumour recurrences are more common in patients with aneuploid Hurthle cell carcinomas [8.53, 8.66].

8.3. Biological factors 8.3.1. Oncogenes and DTC

Among various oncogenes studied in thyroid tumours, RET/PTC oncogenes are uniquely restricted to papillary carcinoma. RET/PTC was first extracted from a metastatic papillary cancer as a mutated proto-oncogene, which could transform NIH 3t3 cells [8.69, 8.70]. Its prevalence ranges from 3-35% in spontaneous papillary thyroid carcinoma depending upon geographic location, however, it is expressed in up to 70% of radiation induced papillary cancers [8.71, 8.72].

The RET/PTC oncogenes are rearranged forms of the RET proto-oncogene (RET); to date, eight fusion proteins, RET/PTC 1-8, have been described, each of these functions by causing transposition of a cellular gene adjacent to tyrosine kinase domain of RET (RET TK). All of

these have been implicated in the early stages of PTC. Three different activating genes, H4 (D10S170 locus), RIα, and ele1 have been shown to rearrange with RET to form RET/PTC1, RET/PTC2, and RET/PTC3 respectively [8.69, 8.73-8.79]. The sporadic papillary cancers most commonly express RET/PTC1 followed by RET/PTC2 and RET/PTC4 [8.9, 8.78, 8.79].

RET/PTC3 is more commonly expressed (up to 80%) in solid papillary tumours, especially the radiation-induced tumours seen in the Chernobyl reactor accident [8.71]. In addition, RET/PTC5 is also expressed in radiation-induced tumours [8.71]. Several investigators have suggested that RET/PTC leads to the development of papillary carcinoma. Cho, et al. [8.80]

have shown that targeted expression of RET/PTC1 in the thyroid gland of transgenic mice causes thyroid carcinoma, which are morphologically similar to human papillary thyroid carcinoma. Tissue culture studies have shown that on induction of RET/PTC retroviral constructs into thyroid epithelial cells can lead to development of nuclear features of papillary thyroid carcinoma as compared to control cells or cells infected with H-ras gene [8.81]. In addition, thyroid glands from patients with Hashimoto's thyroiditis strongly express (up to 95%) RET/PTC1 and PTC3 without histopathological evidence of papillary thyroid carcinoma, indicating a possible risk of papillary cancer in these patients [8.82]. All these studies suggest that RET/PTC rearrangements represent an early event in the papillary cancer tumourigenesis but further studies are needed to define RET/PTC role in tumour progression and prognosis. There is a list of other genes, which have been studied in both follicular and papillary thyroid carcinoma, however, none of these have been found to be specific as RET/PTC. RAS-mutations have been noted in follicular adenoma and carcinoma [8.83, 8.84].

TABLE 8.1. STAGING OF THYROID CANCERS USING AMERICAN JOINT COMMISION TNM CLASSIFICATION 2002 [8.87] (cont.)

Primary Tumour (T)

TX Primary tumour cannot be assessed T0 No evidence of primary tumour

T1 Tumour 2 cm or less in greatest dimension, limited to the thyroid

T2 Tumour more than 2 cm but not more than 4 cm in greatest dimension, limited to the thyroid T3 Tumour more than 4 cm in greatest dimension, limited to the thyroid or any tumour with

minimal extrathyroidal extension (e.g., extension to sternothyroid muscle or perithyroid soft tissues)

T4a Tumour of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, oesophagus, or recurrent laryngeal nerve

T4b Tumour invades prevertebral fascia or encases carotid artery or mediastinal vessels All anaplastic carcinomas are considered T4 tumours

T4a Intrathyroidal — surgically resectable

T4b Extrathyroidal extension — surgically unresectable

--- Regional Lymph Nodes (N)

Regional Lymph Nodes are the central compartment, lateral cervical, and upper mediastinal lymph nodes

NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis

N1a Metastasis to central compartment lymph node(s) or Level VI nodes

N1b Metastasis to unilateral, bilateral, or contralateral cervical or superior mediastinal lymph node(s)

--- Distant Metastasis (M)

MX Presence of distant metastasis cannot be assessed M0 No distant metastasis

M1 Distant metastasis

--- Stage Grouping

Papillary or Follicular

Under 45 Years 45 Years and Older Stage I Any T, Any N, M0 T1, N0, M0

Stage II Any T, Any N, M1 T2, N0, M0

Stage III T3, N0, M0

T1-3, N1a, M0

Stage IVA T4a, any N, M0

T1-3, N1b, M0

Stage IVB T4b, any N, M0

Stage IVC Any T, any N, M1

--- Medullary

Stage I T1, N0, M0 Stage II T2, N0, M0 Stage III T3, N0, M0

T1-3, N1a, M0 Stage IVA T4a, any N, M0

T1-3, N1b, M0 Stage IVB T4b, any N, M0 Stage IVC Any T, any N, M1

--- All anaplastic carcinomas are considered as Stage IV

Stage IVA — T4a, any N, M0 Stage IVB — T4b, any N, M0 Stage IVC — Any T, any N, M1

Activating mutations of thyrotropin receptor and a subunit of stimulatory G (Gs) protein gene has been found in some follicular adenomas and follicular carcinomas [8.85]. Inactivating

point mutations of the p53 gene are more commonly seen in poorly differentiated and anaplastic carcinomas [8.86].