A woman of 28, with absence of comorbidity, family history negative for thyroid disease, was in treatment at our out-patients surgery for Hashimoto's thyroiditis with levothyroxine. The sonographic followup in May 2011 revealed the presence of a suspicious lump. The patient underwent FNAB (type 5) with bilateral cervical-lymphadenopathy suspicious for disease. The patient underwent total thyroidectomy en bloc. Histological examination of frozen sections diagnosed papillary carcinoma. As per protocol was performed dissection of the sixth cervical level and laterocervical lymphadenectomy bilaterally. The definitive histological examination showed metastases in five of the ten nodes of the sixth level (pT1N1Mx) and latero-cervical lymph nodes free of disease. Later the patient was subjected to radioiodine therapy, and now she is free from disease. Her sister underwent echo-thyroid screening that showed multinodular goiter, with a suspicious lump of 2 cm in diameter, with a vascular pattern type IV and grade III FNA, located on the middle third of the right lobe, cervical-lymphadenopathy was absent, metastasis was suspected, and therefore was subjected to surgical treatment. During surgery, the piece was sent for histological examination of frozen sections of the suspected lump that diagnosed the presence of papillary thyroid carcinoma (pT1N0Mx) and for this reason we proceeded to the dissection of level VI laterocervical. Screening was extended to other family members and three thirddegree relatives were diagnosed with multinodular goiter. They met both major criteria and one minor was diagnosed with FNMTC.

A 54 year old man, a family history of benign thyroid diseases, was treated in our out-patients department for two years for thyroid nodule of 0.8 cm. The lump was hypoechoic, with type I vascular pattern, the patient had normal thyroid function, so he was subjected to therapy with levothyroxine and follow-up clinical, laboratory and ultrasound every six months. The last ultrasound showed the presence of a second suspicious lump of 1 cm echogenic upper pole of the left lobe with type III vascular pattern, was subjected to FNA (IIIB), so it signaled indication for surgery. During the surgery (thyrodectomy en bloc) the histological examination of frozen sections diagnosed of papillary thyroid cancer was performed. For that reason we continued with the dissection of level VI (pT1N1aM0). The sister 28 years old, treated for Hashimoto's thyroiditis during a routine ultrasound scan revealed the presence of a nodule of 1.2 cm at the inferior pole of the left lobe. The lump was echogenic, type III vascular pattern, FNA grade III, that the definitive histological examination after surgery diagnosed as papillary thyroid cancer. Also papillary thyroid microcarcinoma at the lower pole of the right lobe (pT (m) 1N0Mx) was diagnosed. Also in this case (presence of 1 major criterion and three minor) FNMTC, was diagnosed.

About 95% of non-medullary thyroid tumors arise from follicular cells and about 3.5 to 6.2% of this fall within the group of nonmedullary thyroid cancer families (Familial non-medullary thyroid cancer FNMTC). By FNMTC all thyroid tumors associated with other neoplastic syndromes (for example the S. Cowden, FAP) are excluded.

As for sporadic thyroid tumors, in FNMTC the histotype most frequent is the papillary tumor (> 90%) [1,2] and 36-57% cases of FNMTC occurs in a gland already affected by other pathological thyroid conditions (adenomatous goiter, Hashimoto's thyroiditis, hypothyroidism or hyperthyroidism) [1,2]. There are no microscopic differences that distinguish the FNMTC from sporadic tumors, even if the FNMTC may submit a trabecular structure with TCO cells (thyroid cell oxiphila). At the home of a suspected FNMTC is an autosomal dominant trait with incomplete penetrance, although it is not possible to exclude a polygenic trait [3]. Even up until today it has not been possible to determine, with certainty, which mutated genes can be correlated with FNMTC. There are many loci implicated: MNG1, TCO, fPTC / PRN and NMC1 [4], but in literature there isn't any corresponding data that identifies the association of mutation of this loci with FNMTC. The strong association between goitre and papillary thyroid cancer even in cases without familiarity, tends to assume that the multinodular goitre associated with papillary thyroid cancer is not only a familial syndrome. Probably in multinodular goiter there is a transformation of epithelial cell in thyroid cancer [3]. On the other hand it is equally common to see patients over the age of 60 diagnosed with a long history of nodular thyroid disease who do not develop thyroid cancer. This can be explained by incomplete penetrance of the autosomal dominant trait, hypothesis supported by genealogical analysis performed on different family groups [4]. Same factors have been identified for inclusion and exclusion FNMTC to identify families at risk of developing thyroid cancer (Table 1): Primary inclusion criteria are: 1) thyroid cancer in two or more first degree relatives, 2) multinodular goiter in three or more first or second degree relatives. Secondary inclusion criteria are: 1) early thyroid cancer, 2) multifocal and / or bilateral tumor, 3) tumor invasion of thyroid surrounding tissue, 4) benign thyroid disease in young patients of FNMTC family. There is hereditary predisposition to FNMTC if two primary criteria are satisfied or one primary criteria and three secondary criteria are satisfied.

Table 1: predictive criteria for identification of familial PTC/MNG families[3].

The main distinguishing characteristic of FNMTC in comparison to sporadic tumors is more aggressive [8]. The multicenter study conducted by Alsanea et al. [8] observed that 48 patients with FNMTC have a 44% incidence of relapse compared to 7% of sporadic tumors in the lowest disease-free survivor. Other distinctive features associated with the aggressiveness of the tumor are: 1) multifocality (71% -93% vs 19%) [9-11], 2) bilaterality (43% vs 8%) [9-11], 3) early lymph node invasion (57% vs 28%) [10,11], 4) early vascular invasion (43% vs 5%) [10,11].

With diagnosed FNMTC it woud be advised to put the patient's relatives in regular screening.

The early presentation and highly aggressive FNMTC justifies early screening, ten years earlier than the general population. In patients relatives with FNMTC who have diagnosed nodular thyroid disease Sipple et al. propose total thyroidectomy based on four factors: 1) the somatic mutation is present in all thyroid follicular cells, 2) the multifocality and bilaterality of cancer, 3) increased likelihood of metabolic treatment with I131 Radio, 4) allows the use of thyroglobulin in the follow-up post-operatively [14,15]. In FNMTC, regardless of the size, the strategy should be aggressive: total thyroidectomy with VI level-lymphadenectomy, followed by radioiodine therapy with I-131 and therapy with levothyroxine, maintaining TSH level at <0.1 mIU/l in patients at moderate risk, and TSH level at <0.05 in patients at high risk.

Currently the category of FNMTC is defined by very specific criteria that help to identify families whose members are exposed to the risk of developing FNMTC. All those who are susceptible to FNMTC should undergo clinical and ultrasound follow-up to detect early malignant lesions of the thyroid. In subjects at risk for FNMTC with suspicious nodules surgery is advised and in the case of pre-operative, intra-or postoperative diagnosis of PTC it is correct to adopt an aggressive treatment (total thyroidectomy + VI level lymphadenectomy followed by radioiodine therapy and hormone suppression therapy) in order to counter the aggressive behavior of FNMTC. Those small families with strong evidence for susceptibility to goitre / papillary thyroid cancer should also be included in FNMTC even though they don't fall within the criteria for inclusion in FNMTC.