PROGNOSTIC VALUES OF THYROID TUMOURS

Th yroid cancer accounts for approximately  of total cancer cases in developed countries. Th e aim of this study has been to analyze the histopathological variants of thyroid tumours with regard to gender and age. Despite their relative rarity in our material, they exhibit a wide range of morphological patterns and biological behaviour. During the period from -,  biopsy cases of thyroid tumours, which were fi xed in buff ered neutral formalin and embedded in paraffi n, have been reviewed. Tissue sections (μm thick) were cut and stained with hematoxylin and eosin (H&E). Follicular adenomas have been found in ,  of cases, thyroid carcinomas in , , whereas thyroid secondary carcinomas have been found in ,  of cases. As far as histological variants of thyroid carcinomas are concerned, most frequently found were papillary carcinomas in , of cases; followed by follicular carcinomas in , of cases; follicular variants of papillary carcinomas in , of cases; medullary carcinomas in , of cases, while anaplastic and Hurthle cell carcinomas have been found in , of cases each. All histological variants of thyroid tumours occurred more frequently in women than in men. Papillary carcinoma has been found in  of female cases. Th yroid tumours in our material mainly occurred in the third, the fourth and the fi fth decade of life. Our data indicate that apart from the fact that papillary carcinomas, well diff erentiated, and characterised by relatively good prognosis, were most frequent variants, certain morphological variants of it were associated with poor prognosis.


Introduction
Human thyroid neoplasia represents a variety of lesions ranging from well-diff erentiated benign tumours to anaplastic malignant tumours ().Th yroid tumours can be divided into two groups, nonmedullary and medullary thyroid cancer of hereditary or nonhereditary origin.Nonmedullary includes papillary carcinoma, follicular carcinoma; Hurthle variant of follicular cancer, insular cancer and anaplastic cancer ().Thyroid cancer represents  of all cancers.Women are affected  times more than men.Peak incidence is -s.It arises from the two cell types in the gland.Follicular cells cause papillary, follicular, and anaplastic tumours.C-cells produce medullary tumours.A higher proportion of follicular and anaplastic cancers is found in populations with low dietary iodine. female,  sporadically and  familial preponderance is reported.Familial cases are typically all over the gland, while sporadic frequently are not multifocal., -,  of all new cancer cases are reported in the United States. of patients who die of other causes have occult thyroid cancer and  have microscopic cancers. of thyroid gland at autopsy in some studies have papillary carcinomas (<, cm) (Overall, fewer than  of nodules are malignant (, , ).
Well-Diff erentiated Th yroid Carcinomas (WDTC)-Papillary, Follicular, and Hurthle cell Pathogenesis of these tumours is unknown.Papillary carcinoma (PTC) has been associated with the RET proto-oncogene; however no definitive link has been proven.Certain clinical factors increase the likelihood of developing thyroid cancer.Histological subtypes are: Follicular variant, tall cell, columnar cell, diffuse sclerosing and Encapsulated.Prognosis is  survival at  years.Females predominate.Mean age of  years (, ).Cytological features alone cannot predict patient outcome in PTC.This study indicates for the first time that loss of cellular polarity and the tumour growth pattern are useful parameters for identifying the so called low risk group in common type PTC and in predicting patient outcome in terms of tumour recurrence and cancer related death ().Microscopic vascular invasion is well recognized in thyroid cancer particularly in the follicular and poorly differentiated histological types.However massive invasion of tumour into the great veins or external compression of the superior vena cava is rare.Lymph node involvement is common.Major route of metastasis is lymphatic.- of patients have lymph node involvement.Clinically undetectable lymph node involvement does not worsen the prognosis.Papillary/follicular carcinoma must be considered a variant of papillary thyroid carcinoma (mixed form), and Hürthle cell carcinoma should be considered a variant of Follicular thyroid carcinoma (FTC).In the US about - of all thyroid cancers are follicular.Th yroid cancers are quite rare, accounting for only , of all cancers in adults and  in children.During the last few years, the frequency of FTC has appeared to increase; however, this increase is related to improvement in diagnostic techniques and a successful campaign of information about this carcinoma.Of all thyroid cancers, - is follicular.According to world epidemiologic data, follicular carcinoma is the second most common thyroid neoplasm; in some geographic areas, however, FTC is the most common thyroid tumour.Relative incidence of follicular carcinoma is higher in areas of endemic goitre.
In papillary carcinoma, it should be noted that histological vascular invasion may be considered as a sign of an increased tendency toward hematogenic invasion and consequent increase in the relative percentage of metastases; ultimately, this means a poorer prognosis.In the presence of risk factors indicating a possible increase in biologic aggressiveness adequate postoperative treatment and close follow up become essential ().Among  patients with diff erentiated thyroid cancer,  presented symptoms and signs of hyperthyroidism.Graves' disease was diagnosed in  cases, multinodular goitre in eight, whereas toxic adenoma was found in four cases.Diff erentiated thyroid cancer found incidentally at surgery for hyperthyroidism has a good prognosis ().Th e relative importance of prognostic factors in papillary and follicular thyroid cancer has been studied in  patients using Cox's proportional hazards model.Prognostic factors studied were: histology, tumour grade, extra thyroidal growth, nodal involvement, distant metastases at diagnosis, nuclear DNA content, age at diagnosis, and sex.The present study demonstrates that nuclear DNA content is a prognostic factor in those patients with papillary and follicular thyroid cancer without distant metastases at diagnosis ().The second most important factor was the histological (sub) type (well differentiated papillary carcinoma vs. moderately differentiated papillary carcinoma and follicular carcinoma) ().(, ).Th e aim of this research has been to analyze the histopathological variants of thyroid tumours with regard to their incidence and prognosis according to the histological type and subtype, gender and age.Despite their relative rarity in our material, they exhibit a wide range of morphological patterns and biological behaviour.

Material and Methods
During the period from -,  biopsy cases of thyroid tumours, which were classifi ed according to the WHO histological classifi cation as well as pTNM system, have been reviewed.() Th yroid tumour tissues were fi xed in  buff ered neutral formalin from Bio-Optica (Italy) and embedded in paraffi n (Sigma-Aldrich, Germany).Tissue sections (μm thick) were cut and stained with hematoxylin-eosion (Merck, Darmstadt, Germany).

Anamnesis:
Anamnestic clinical data were collected from the University Clinical Centre of Kosovo (UCCK) register, as well as follow-up clinic visits of patients referred to the UCC of Kosovo.Specimens from  biopsy cases diagnosed at the Institute of Pathology, UCCK, during the period from  to  were reviewed retrospectively.Information regarding gross feature were collected from the protocols.

Analysis in detail:
Th e data on patients' gender and age; blood tests, thyroid scan, ultrasound and fi ne needle aspiration cytology results as well as extent of disease, pathomorphological characteristics, therapy, locoregional control, diseasefree survival and disease-specifi c survival, were collected.

Diagnosis:
Th e  cases included in our study had tumours larger than cm in diameter.
Histopathological examination, determining the histologic type of the tumour, grading, and staging, as well as other characteristics, such as the vascular extension, infiltration into the adjacent parenchyma or in the thyroid capsule, was performed.The major attributes of the staging system pTNM system () were included: age as the most important prognostic factor, below and above the age of ; T tumours were considered to be those below  cm; T tumours included minor extrathyroidal extension invading the strap muscles; T tumours included Ta and Tb, Ta being operable tumours; all anaplastic cancers were T, although operable anaplastic thyroid cancers were considered to be Ta.

Th erapy:
Th erapeutic choices were: . total thyroidectomy in the treatment of the apparently benign pathology when spread bilaterally (the fi nal histological examination of a cancer should lead to considering the operation adequate); . lobo-isthmectomy in the treatment of unilateral benign pathology or suspected FNAB for follicular neoplasm (the histological examination of a cancer led to consider this operation adequate only in presence of favourable prognostic parameters.However, in presence of even one unfavourable variable, we considered the totalisation necessary); . total thyroidectomy in presence of a strongly suspected preoperative diagnosis of cancer.The first management stage for those with tumour diameters > cm included total thyroidectomy with central node dissection and postoperative I ablation (Sigma-Aldrich, Germany.Most patients have undergone fi ne-needle aspiration cytology for diagnosis and for planning of treatment.Clinical, imaging and biological postoperative monitoring as well as suppress and substitution hormone therapy were mandatory.

Statistical analysis:
Statistically significant differences were analyzed using the χ  test.Statistical correlation between possible prognostic factors and the duration of disease-free interval was analyzed by univariate and Cox's multivariate survival analysis.

Results
During our study, out of  cases with thyroid tumours, benign tumours (follicular adenomas) have been found in , of cases, whereas thyroid carcinomas in , of cases.(Table. & Figure .)From the overall number of cases with thyroid tumours (), papillary carcinomas have been most frequently found (Table a).
Great statistical significance between histopathological variants of thyroid tumours (χ  -test = , , p<,) has been found.Th e tumours with highest frequency of occurrence were papillary carcinoma -pure variant (, ) followed by follicular adenoma (, ).
The graphic shows thyroid tumour incidence according to histological variants.The highest blue and red columns represent the percentage of follicular adenoma and papillary carcinoma (Figure a).
Out of  cases of thyroid carcinomas (Table b.), ,  papillary carcinomas in total have been found (, pure papillary carcinoma + , follicular variant of papillary carcinomas), being the most frequent histological variant, while follicular carcinomas were found to be increasing ,.Our results have shown approximately similar percentage in correlation with the published data.
Figure b illustrates the percentage of histological variants of thyroid cancer, representing the highest incidence of papillary carcinoma -blue column.
Thyroid tumours in general were more frequent in women than in men (Table ), ,  vs. , (≈).The difference was of great statistical significance (χ  -test = , , p<, ).However, histological variants of thyroid tumours were analyzed regarding the gender predominance and it was found that they were all more frequent in women than in men.Th e most important statistical signifi cance was detected in cases of papillary carcinoma (χ  -test = , , p<, ), as well as in follicular adenoma (χ  Five year age-standardised survival rates for thyroid cancer by sex in Kosovo have shown increased incidence and survival rates during the years especially in females (Figure).
It is important to note that our study has shown that age represents the major factor when determining prognosis for differentiated thyroid cancer.Young people rarely died of this disease regardless of whether the surrounding lymph nodes were affected, tumour was left behind, or the tumour extended into the veins or outside the tissue that encapsulated it.Nevertheless, in older patients all of these factors played a signifi cant role in long term disease-free survival (Figure ).

Discussion
PTC and FTC are well differentiated slow growing, and have unique characteristics.Factors associated with a less favourable outcome are male sex, family history of papillary cancer, age > years, tumour diameter > cm, invasive or poorly differentiated tumour and lymph node or distant metastases.PTC is the most frequent endocrine cancer which amount up to - (, , ,  ).
Our data refers to a percentage - of PTCs.
There are numerous classification systems to determine predictive factors such as: AGES (age, grade, extent, size) classification using Cox model; AMES (age, metastasis and extent, size).All of these classifications showed to be helpful for predicting low and high risk tumours during our study.The age of patient and the size of the tumour can be determined preoperatively, while cytology and biopsy will determine the grade and extent after surgery.() It was suggested that the extent of surgery should be based on prognostic parameters, such as gender and lateral neck node metastasis, in patients with PTC.() Some investigators have reported that histopathologic characteristics such as the vascular extension, infiltration into the adjacent parenchyma or in the thyroid capsule are all indicative of a poor prognosis.() Others have found that longer disease-free interval was found in the patients with a tumour diameter < or = mm and without lymph-node metastases.() Previous studies have documented that PTC is usually indolent and the prognosis is favourable, with a  year survival generally reported to exceed .() According to literature, follicular variant of PTC is more aggressive than pure PTC.Other authors support another opinion assuming that the number of patients who are diagnosed as pure PTC may be higher when associated with Hashimoto's thyroiditis.() Our study supports the first opinion.
It is certainly understandable why in WDTC patients, in addition to traditional risk factors, prognostic factors, such as vascular invasion and capsular invasion, need to be evaluated; not only for achieving an adequate therapeutic approach, but also for avoiding over treatment of low-risk patients.
In another study, it was reported that PTCs are associated with metastases and decreased survival in a small group of patients.() The incidence of FTC is increasing in Kosovo (, ).In the US the increase of the incidence of the FTC has also been observed recently.Of all Our patients with MTC have been stage IV.Although the early diagnosis and the extensive surgical treatment of these patients might have influenced the outcome of the MTC, this is not always an indicator of the definitive cure of the disease, due to the capsular infiltration which is a bad prognostic factor.

Conclusion
Our data indicate that besides the fact that PTC were most frequent variants, well diff erentiated, and characterized by relatively good prognosis, certain morphological variants of this disease were associated with poor prognosis.PTC was presented more frequently in younger patients alongside with lymph node involvement in some cases.Furthermore we have found that the incidence of follicular carcinoma is increasing, which could be related to improvement in diagnostic techniques.Th ey were presented with higher age and more frequent distant metastasis.Laboratory and clinical techniques could help predict whether a particular tumour will behave in an aggressive or benign manner.Combined therapy seems to results in fewer recurrences and better survival than less aggressive initial therapy.

TABLE 1a .
Histopathological variants of Th yroid tumours

TABLE 3 .
Th yroid tumours with regard to decades N, M; stage II, any T, N, M; while follicular cancer has aff ected age group of  years and above stage III, T, N,M.Medullary thyroid cancer was presented with stage IVA, Ta, N, M.Anaplastic thyroid cancer was present in one case, stage IV (Table).

TABLE 4 .
Th e fi ve year survival rates of thyroid cancer according to histopathological variants Gender is an important prognostic factor(, , , ,  .).According to some authors gender does not play a signifi cant role both in recurrence and survival.()Ageatpresentationisawell-establishedstrongprognosticfactorforWDTC.(,,,,).In the paediatric population, PTC is a more aggressive disease.stageI,stageIIandstageIIIforFTC; while  of cases for MTC and ATC.Distant metastases at presentation were an independent prognostic factor only for FTC, but not for PTC().This was the case in our study, too.Tumour extension beyond the thyroid capsule (pT) is one of the strongest prognostic factors(,).The increased primary tumour size is a prevalent and accepted factor for poorer prognosis (, , , , , .).The  cases included in our study had tumours larger than cm in diameter.Th e overall survival rate has been investigated within a five-year period, and it has been found to be , whereas the metastasis-free survival rate was .An older age at the time of diagnosis and a larger tumour size were associated with an increased risk of distant metastases and of cancer-related death.()InKosovofiveyear-agestandardisedsurvival rates increased during the years.High risk patients with thyroid cancer stage pT/M and pT were over  years of age.Patients < or = years of age presenting with pulmonary metastasis from well-differentiated thyroid cancer had an excellent prognosis.Older patients have a poor survival outcome.Postoperative I- therapy is recommended in all patients.()PrognosisforPTCisnot worse in younger patients.Patients with confined intra thyroid lesion (<or=T, N, M) may be regarded "low risk" PTC patients.()Lowriskpatients with thyroid cancer stage pT and pT in Kosovo were under  years of age.Tumour size >  cm, distant metastasis, and non-radical tumour resection are the independent predictors of patients survival.Early diagnosis and early therapy can improve significantly the prognosis of MTC.(, )