Follicular carcinoma represents 5– 15% of thyroid cancer. It is more frequent in women and extremely rare in children and more common in areas with iodine deficiency.
Most follicular carcinomas are sporadic. The most important factors implicated in the aetiology of follicular cancer are iodine deficiency and exposure to ionizing radiations. A proof is that the increment of iodine with diet substantially decrements the incidence of follicular carcinoma. This is probably due to the increment of TSH (thyroid stimulating hormone), stimulated by iodine deficiency and involved in thyroid cancer development.
Moreover, exposure to ionizing radiations results in the development of follicular cancer, although less than papillary carcinoma.
Another important risk factor is the pre- existence of a benign neoplasia, which may represent a definite risk factor in about 15% of follicular carcinomas. The presence of follicular adenoma could be the precursor of follicular cancer, possibly resulting from RAS gene family mutations. On the other hand, the development of follicular cancer in the multinodular goitre could be due to prolonged stimulation of TSH .
Follicular carcinoma is a well- differentiated cancer originating from follicular epithelium and characterized by an exclusive follicular growth pattern.
The cells of follicular carcinoma do not show any nuclear features of papillary carcinoma.
Clinically, the follicular carcinoma presents itself as a solitary cold nodule with very slow growth but with high metastatic power. It usually metastasizes by vascular invasion, while lymphatic invasion is extremely rare. Metastases to lung and bone are the most frequent and they sometimes represent the early onset of the disease.
We can subdivide follicular carcinoma into a minimally invasive form and in a widely invasive form. The minimally invasive form is an encapsulated tumour, very similar to an adenoma, with histological evidence of tumour capsular and/ or vascular infiltration (see Figure 1). The second form of follicular carcinoma is widely invasive, presenting wide infiltrative aspects of vascular, peritumoral, and sometimes perithyroidal tissues. These types differ for their clinical and biological behaviour. In the former type the 10- year survival rate is about 90%, while in the latter form it de creases to 35%.
Fig1. Minimally invasive follicular thyroid carcinoma: histological evidence of tumour capsular infiltration with the typical mushroom- like appearance.
The Hürthle (oncocytic or oxyphilic) tumour was considered the most important ‘variant’ of follicular carcinoma.
As previously described, the most important genetic alterations involved in follicular cancer are the point mutations of the RAS gene family. These mutations affect codons 12, 13, and 61 of the H, K, and N- Ras genes. RAS gene mutations are present in more than 50% of follicular carcinomas, while the oncocytic or oxyphilic carcinomas present a lower percentage of RAS gene mutations. Another important genetic alteration is the PAX8/ PPARgamma (peroxisome proliferator- activated receptor gamma) rearrangement, which in volves about one- third of follicular carcinomas and about 5% of oncocytic or oxyphilic carcinomas.
Morphology
On gross examination follicular carcinoma, usually no larger than just a few centimetres in dimension, appears as an encapsulated, generally oval, solid nodule. A thick fibrous capsule generally sur rounds the lesion and foci of invasion can rarely be detected in the tumour capsule; for this reason, extensive sampling of the tumour capsule is essential for a correct diagnosis of follicular carcinoma. In the widely invasive form of follicular carcinoma, thyroid tissue or sometimes extrathyroidal tissue invasion can be macroscopically evident. Vascular emboli are rarely observed, especially in the large vein of the neck.
On light microscopy follicular carcinoma presents a typical follicular architecture (microfollicular, macrofollicular, normofollicular, or mixed), sometimes associated with insular, or solid, or trabecular areas. In these cases, it is fundamental to distinguish the follicular carcinoma from the poorly differentiated thyroid carcinoma, which presents the same growth pattern but worse prognosis. Follicular carcinoma cells are cubic, small, and round, with an even chromatin pat tern and small nuclei with small nucleoli. These nucleoli are more frequent and evident in oxyphilic follicular carcinoma, where they ac quire a cherry colour. The cells of the follicular carcinoma obviously lack the nuclear features of papillary carcinoma.
The morphology of the cells and the presence of a thick fibrous capsule make it difficult to differentially diagnose between follicular adenoma and follicular carcinoma. The only fundamental diagnostic features are infiltration of the tumoural capsule and vascular invasion (Figure 1). To date, there is no real consensus about the invasion of the tumour capsule. Most authors require that neo plastic cells penetrate the entire thickness of the fibrous capsule for a diagnosis of follicular carcinoma. Capsule ruptures caused by surgical lacerations or changes due to precedent biopsy or FNAs are considered pseudo- invasions, insufficient for a diagnosis of follicular carcinoma. The typical appearance of infiltration of the tumour capsule is similar to that of a mushroom (Figure 1). Vascular invasion is referred to the invasion of tumour cells into the veins, and such cells must be adherent to the endothelium or take place in the context of a thrombus. Vascular invasion, whose extent has prognostic importance, should be localized in or beyond the capsule. Limited invasion (less than four vessels) has a good prognosis, while extensive invasion (more than four vessels) is associated with a worse outcome. Widely invasive follicular carcinomas show intrathyroidal or extrathyroidal tissue infiltration. They might also show wide vascular infiltration which, alone, is insufficient to be classified as widely invasive. Widely invasive follicular carcinomas are often large tumours with solid or insular or trabecular growth patterns, and they must be distinguished from poorly differentiated thyroid carcinomas or from solid or trabecular variants of papillary carcinomas (see Table1 for classification scheme modified from WHO 2017).
Table1. Classification of follicular thyroid carcinoma
Hürthle (oncocytic or oxyphilic) cell carcinoma
The Hürthle (oncocytic or oxyphilic) cell carcinoma is a common tumour representing about 20% of follicular carcinomas. It is formed by Hürthle or oncocytic or oxyphilic cells, which are large cells with voluminous granular cytoplasm, and large centrally located nuclei with prominent nucleoli. Most authors re quire that Hürthle cells should be most of the tumour (more than 75%) for a diagnosis of Hürthle cell carcinoma. Hürthle cell carcinomas present solid, trabecular, and follicular growth patterns with fibrous bands between clusters of cells. The tumours have little stroma and for this reason may show a pseudopapillary pattern. Hürthle cell carcinoma can metastasize through the bloodstream, invading in particular the liver, lungs, and bone. Hürthle cell carcinoma can also metastasize lymphatically and spread to cervical lymph nodes. Tumours with large dimension (more than 4 cm), necrosis, high mitotic rate, presence of atypical mitoses, and foci of small cells have been recently classified as poorly differentiated Hürthle cell carcinoma.
