A Cytopathological Study of Malignant Thyroid Lesions and Its Implications in A Referral Center

Background: Fine needle aspiration [FNA] is the well-established diagnostic modality. It has a positive predictive value of 99% in diagnosing malignant thyroid lesions. The incidence of various thyroid malignancies in our department was evaluated using FNA and they were compared to those available in the literature. Methods: During our study period, cases those were referred to our lab for FNAC thyroid were retrieved from the records. From that, malignant cases reported during our study period were enumerated and reexamined. The prevalence of malignant cases, its age and sex incidence was calculated. Increase in the incidence of undifferentiated thyroid carcinoma cases in our setup was recognized and our experience was compared with those available in the literatures. Result: During our study period, 339 thyroid cases were reported. The incidence of papillary carcinoma was 26.3% and anaplastic carcinoma was 58% in our study. Peak age incidence was around 50-60 years. Female predominance was noted in all age groups except in the 50-60 year category where male predominated. When the tumor was staged based on TNM classification, anaplastic carcinoma presented with a higher stage. Conclusion: Thyroid FNAC has a high predictive value in the diagnosis of malignancies. The incidence of undifferentiated carcinoma was higher in our setup. The reason for the increase in the incidence needs further evaluation.


Introduction
Benign thyroid nodules are commonly encountered in a fine needle aspiration [FNA] clinic. The incidence of malignant thyroid nodule is 5% [1] . The positive predictive value of FNA in diagnosing malignant thyroid lesion is 99% [2] . Among the malignant tumors of the thyroid papillary carcinoma of thyroid [PTC] is the most common constituting around 80% of all the thyroid malignancy [3] . Poorly differentiated thyroid carcinomas [PDTC] accounts for 4% to 7% of thyroid carcinomas, undifferentiated (or anaplastic) carcinoma of the thyroid [UTC] represents less than 5% of malignant thyroid tumors, medullary thyroid carcinoma [MTC] accounts for 5% to 10% of all thyroid carcinomas, squamous cell carcinoma [SQC] of the thyroid accounts for 1% or less of thyroid cancers and metastatic tumors to the thyroid are constitute 0.1% to 0.3% of thyroid aspirates [4,5] . Our study was done to calculate the incidence of various malignant tumor in our setup and to compare it with the literature reports.

Materials and Methods
During our study period for seven months FNA cases that were referred to us for thyroid lesions were retrieved from the records. As both FNA procedure and the interpretation were carried out by the pathologist the accuracy of our diagnosis was more [6] . Age, sex, clinical details including thyroid profile, duration of the lesion, family history of thyroid cancer, previous head and neck irradiation, rapid growth, hardness or adherence of the lump to surrounding structures and the presence of associated lymphadenopathy and clinical examination of the thyroid including size were retrieved from the records. Age and sex incidence were calculated. The size [based on ultrasound findings] based split of malignant lesions was done to evaluate the stage at which each thyroid carcinoma presented in our study. The slides were reexamined by three cytopathologists as recommended by Bethesda reporting of thyroid cytology [TBSRTC] and lesions were categorized according to Bethesda recommendations. Malignant lesions were categorized into type based on the morphology. Because malignancy in follicular neoplasm cannot be made on cytology, these lesions were not included in our study. The incidence of various thyroid malignancies was calculated. These findings were compared with the available literature reports. As our study used fine needle aspiration as a single diagnostic modality as it do have a higher sensitivity and specificity, neither histopathological correlation nor follow up was done.  Table 2].
When sex incidence was calculated, in the age group 50-60 years male predominance was noted [M: F: 2.5:1]. In all other age groups female predominance was noted [ Table 2]. When stage of the tumor was compared with the type of tumor, higher stage was noticed in anaplastic carcinoma [ Table 1].  T1 T2 T3 T4 T1 T2 T3 T4 T1 T2 T3 T4  339  1  2

Discussion
Thyroid malignancy is commonest among endocrine tumors. Annual incidence ranges from 1.0 to 2.9 cases per 100,000 men and 3.4 to 9.1 cases per 100,000 women [7] . Thyroid FNA is a rapid, safe, cost-effective modality to diagnose thyroid lesions [8] . Cytology has a sensitivity and specificity of up to 94% and 98% respectively for the diagnosis of malignant lesions [9]. TBSRTC recommends six diagnostic categories which includes -Non diagnostic, benign, atypia of undetermined significance or follicular lesion of undetermined significance, follicular neoplasm or suspicious for a follicular neoplasm, suspicious for malignancy and malignant. Malignancy is more common in solitary nodule and the prevalence of malignancy in solitary cold nodules ranges from 10% to 44.7% [10] . Malignant thyroid tumors are broadly divided into well differentiated-PTC and follicular carcinoma, poorly differentiated-insular carcinoma and undifferentiatedanaplastic carcinoma.
Papillary carcinoma is the most common malignancy among the thyroid carcinoma. It arises secondary to head and neck radiation and it is associated with BRAF, RAS mutation and RET/PTC rearrangements [11] .There is a female preponderance with female to male ratio 4:1 and seen in all ages [12] . In our study female: male was 3:1 in concordance with Schlumberger M's study [12]. The incidence of PTC peaks around 43+_ 12 years [13] . In contrast, the peak age group in our study was 16 years.
Pediatric PTCs and PTCs that occur in young adults have some unique features. They are usually larger in size, metastasize early and often present with cervical metastasis [14] . These tumors show high expression of sodium-iodide transporter [NIS]. This NIS expression results in increased response to radio iodine therapy resulting in better prognosis [15] . The incidence of papillary carcinoma in Sinna E.A and Ezzat N's study was 72.4%, whereas in our study the incidence of PTC was 26.3% [16] .
Grossly, the tumor is solid grey white and cystic changes are seen in 10% of the cases. Multicentricity and occult tumors less than one centimeter in size are also common in PTC. Histologically, PTC is identified by its nuclear features including, enlarged oval irregular nucleus, overlapping and crowding of the nucleus, grooves, intracytoplasmic inclusions and Orphan Annie nucleus. Nuclear cytoskeletal abnormality leads on deformable nucleus hence the irregular contour, grooves and pseudo inclusions seen in the nucleus [17] . Cytologically, PTC shows all the nuclear features except nuclear clearing. Instead the nucleus show dispersed chromatin pattern. Anatomical bordering, nuclear grooves, nuclear overlapping and crowding, intranuclear inclusion and dispersed chromatin are diagnostic of PTC in the cytological smears. All the features should be there for PTC includes HBME-1 membranous positivity, cytoplasmic CK19 positivity, CD44, p63 and galectin 3.
to diagnose a PTC [Fig 1]. IHC markers that are specific www.pacificejournals.com/apalm eISSN: 2349-6983; pISSN: 2394-6466 Insular carcinoma is seen in elderly age group with a female predominance. Grossly, tumors are necrotic and have an invasive margin. Histologically, the tumor cells are small arranged in an insular pattern with foci of necrosis. Cytologically, the cells are smaller, with dispersed chromatin, convoluted nuclei, increased mitotic figures [more than 3/10 hpf] in a necrotic background [18] . Immunohistochemical markers that are positive include TTF-1, thyroglobulin and synaptophysin. Insular carcinoma was not encountered by us during our study period.

Undifferentiated carcinoma [anaplastic carcinoma] [UTC]
constitutes around 17.2% of all the thyroid malignancies [14] . In all other studies the incidence were <5% of all the thyroid malignancies [19,20] . In contrast, in our study group the incidence was 58% which was higher than all the study groups seen in the literatures. It is a tumor of elderly females secondary to nodular goiter, FA [Follicular adenoma], FTC [Follicular carcinoma thyroid] and PTC [21] . In our study male: female was 1.2:1 in contrast to LiVolsi V A, et al's study [19]. Two cases in our study presented with features of UTC secondary to PTC. It was invasive at presentation and it was associated with both local and distal metastasis. Extra thyroidal extension in UTC tumors was seen in 91% of our cases [ Table 3]. Histologically, this tumor shows both malignant epithelial and spindle cell morphology. Medullary carcinoma thyroid constitutes around 5-10% of all the thyroid neoplasm [16,22] . Likewise in our study too the incidence of MTC was 5.3%. It is associated with RET and RAS mutations.  [23] . Cytologically, polygonal or spindle shaped cells are arranged individually or form loose monolayer sheets [Fig 4]. Amyloid is also seen. Tumor cells are positive for CK, chromogranin, CEA, calcitonin and TTF-1.
Thyroid malignancies contribute about 1.5-3% of all carcinomas in children and adolescent group [24] . In our study group, PTC was seen predominantly in younger age groups less than twenty years of age constituting 10.5% of all the thyroid malignancies. Family history of thyroid malignancies and irradiation are considered to be the risk factors associated with thyroid malignancies in young adults. The increased incidence of PTC in young adults in our study group needs further evaluation.
The incidence of UTC was much higher than all the study groups. The reason for increased incidence of UTC in our study group may be because of the following reasons: UTC might have developed from undiagnosed PTC which was seen predominantly in younger age groups in our study. May be more studies related to the genetic instability associated with PTC might give us a clue.
UTC might have arisen in the background of some unknown gene mutations prevalent in our area which needs further evaluation.

Conclusion
FNAC is the cheapest available diagnostic tool in classifying a thyroid nodule. There was a female predominance in our study group. The incidence of UTC is 58% in our study group which needs further analysis.