|Year : 2019 | Volume
| Issue : 3 | Page : 128-136
A case-based approach to aggressive variants of papillary thyroid carcinoma with literature review
Joseph Antoine Flordelis Chatto1, Annette Laurente Salillas2
1 Department of Pathology, Governor Celestino Gallares Memorial Hospital, Tagbilaran City, Bohol, Philippines
2 Department of Pathology, Governor Celestino Gallares Memorial Hospital, Tagbilaran City, Bohol; Department of Pathology, MHAM College of Medicine, Cebu City, Philippines
|Date of Submission||10-Sep-2019|
|Date of Acceptance||23-Oct-2019|
|Date of Web Publication||18-Nov-2019|
Dr. Joseph Antoine Flordelis Chatto
Department of Pathology, Governor Celestino Gallares Memorial Hospital, Tagbilaran City, Bohol
Source of Support: None, Conflict of Interest: None
Papillary thyroid caarcinoma (PTC) is the most common thyroid and endocrine malignancy. Although considered to be indolent, aggressive variants have been identified, including the Tall Cell (TCV), Columnar Cell (CCV), Hobnail (HPTC) and Solid Variants (SVPTC). The objective of this study is to pre-operatively recognize the cytologic features of these variants. Four cases with final diagnoses of TCV, CCV, HPTC and SVPTC were reviewed and compared with Fine Needle Aspiration Biopsy (FNAB) smears. The first case is a 44-year-old female diagnosed with TCV pre-operatively through FNAB and was confirmed through tissue biopsy showing malignant glands in papillary formation with greater than 50% of tall cells. The second patient is a 54-year-old female with CCV showing stratified columnar cells with cytoplasmic supranuclear and subnuclear vacuoles. Third is a 57-year-old female with HPTC exhibiting eccentrically-located nuclei imparting a hobnail appearance with cellular dyscohesiveness. The fourth case is a 59-year-old female diagnosed with SVPTC showing predominantly solid sheets surrounded by thin, delicate fibrous stroma. They all have nuclear features of PTC. TCV, CCV, HPTC and SVPTC are related to extrathyroidal extension, angiolymphatic invasion, positive surgical margin and lymph node metastasis. FNAB is an important tool to recognize these variants preoperatively and plan for amore comprehensive management.
Keywords: Biologically aggressive papillary thyroid carcinoma, columnar cell variant, hobnail variant, papillary thyroid carcinoma, solid variant, tall cell variant
|How to cite this article:|
Chatto JA, Salillas AL. A case-based approach to aggressive variants of papillary thyroid carcinoma with literature review. Thyroid Res Pract 2019;16:128-36
|How to cite this URL:|
Chatto JA, Salillas AL. A case-based approach to aggressive variants of papillary thyroid carcinoma with literature review. Thyroid Res Pract [serial online] 2019 [cited 2020 Jul 14];16:128-36. Available from: http://www.thetrp.net/text.asp?2019/16/3/128/271156
| Introduction|| |
Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy accounting for 80%–90% of all thyroid malignancies. It is also the most common endocrine malignancy and makes up for 1% of all newly diagnosed cancers. Most cases occur in adults between 20 and 50 years, with a female-to-male ratio of 4:1. PTC is diagnosed primarily by its nuclear features, such as the ovoid, ground glass nuclei with nuclear grooves and pseudoinclusions. It usually has an indolent course with excellent prognosis and long-term survival rate. However, the World Health Organization Classification of Tumours has recognized biologically aggressive variants of PTC, which have less favorable prognosis. These variants include tall cell (TCV), columnar cell (CCV), solid (SVPTC), and diffuse sclerosing. Another PTC subtype is the hobnail variant (HPTC), which is newly recognized, also with an aggressive clinical behavior, and was first described in 2010 by Asioli et al. These tumors are rare, and patients are reported to have poor clinical outcomes. Because of their clinical implications, any foci of such changes should be documented. Here, we present cases of the tall cell, columnar cell, hobnail, and solid variants that were seen at the Governor Celestino Gallares Memorial Hospital in Bohol, Philippines. The aim of this study is to preoperatively recognize the cytologic features of these rare and aggressive PTC variants in order to plan for a more aggressive management.
| Case Reports|| |
The first patient is a 44-year-old female who presented with a 10-year history of a right anterior neck mass. On physical examination, a large goiter was noted in the right with no lymphadenopathies. FT4 was decreased while the FT3 and thyroid-stimulating hormone (TSH) were normal. Fine-needle aspiration biopsy (FNAB) was done, which revealed PTC, TCV. The smears showed neoplastic follicular cells in fragments, crowded groups, and rosettes with others scattered as single cells. Most of the tumor cells appeared tall and columnar with ovoid, pale nuclei and were arranged in a palisading pattern. Thick colloid lakes were also noted [Figure 1].
|Figure 1: (a) Clusters and crowded groups of thyroid follicular cells with a papillary formation, ×10. (b) Tumor cells appear elongated with large, overlapping nuclei and nuclear grooves with abundant eosinophilic cytoplasm. (c) Tumor cells with elongated cytoplasm with nuclear overlapping and nuclear grooves, ×40|
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The second case is that of a 57-year-old female who presented with an 11-year history of a left thyroid neck mass with no other associated symptoms. Physical examination showed a large left thyroid mass. Thyroid function tests showed normal values. FNAB showed findings consistent with colloid goiter with hyperplastic change and cystic degeneration with papillary carcinoma not ruled out. The smears were reviewed and showed several irregular clusters of thyroid follicular cells with elongated cytoplasm and pleomorphic nuclei exhibiting pseudostratification [Figure 2]a and [Figure 2]b. Several cells show nuclear grooves and vague inclusions [Figure 2]c. Despite the rare nuclear features of PTC seen, the presence of the pseudostratified elongated cells with pleomorphic nuclei made us favor the diagnosis of PTC CCV.
|Figure 2: Fine-needle aspiration biopsy showing (a and b) nuclear pseudostratification of thyroid follicular cells with eosinophilic cytoplasm, ×10. (c) Ovoid irregular nuclei with pseudostratification and occasional nuclear grooves, ×40|
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The third patient is a 54-year-old female presenting with a 10-year history of a left anterior neck mass with normal TSH. Sonography was done, which showed enlargement of the left thyroid with a hypoechoic solid mass. FNAB showed a follicular neoplasm in a background of a colloid goiter. A review of smears revealed medium-sized thyroid follicular cells arranged in branching cell groups. Some formed micropapillary and microfollicular structures while others were dispersed single cells with distinct “teardrop” cytoplasm, apically placed nuclei producing a surface bulge leading to a “comet cell” appearance [Figure 3]a, [Figure 3]b, [Figure 3]c. On higher magnification, the nuclei showed variable degrees of atypia with nuclear grooves and inclusions seen [Figure 3]d [Figure 3]e. Other areas showed single cells with abundant cytoplasm and sharp borders, which were aggregated in tile-like manner [Figure 3]f.
|Figure 3: Fine-needle aspiration smears (a-c) the comet-like cell is shown with “teardrop” cytoplasm, ×10, ×40, ×100. (d and e) Soap bubble-like nuclear inclusions are recognizable, ×40, ×100. (f) Single cells with abundant cytoplasm and sharp borders aggregated in a tile-like manner, ×40|
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The fourth case is that of a 59-year-old euthyroid female who presented with a 3-year history of a left anterior neck mass. Ultrasound showed a 3.30 cm × 2.76 cm × 2.65 cm mass with architectural distortion. The mass was hypervascular to color flow with tributaries transecting in the enlarged mass. Smears were minimally cellular composed of benign thyrocytes admixed with atypical cells having ovoid, pale, and enlarged nuclei with few nuclear grooves and one indistinct intranuclear pseudoinclusion seen in a bloody background [Figure 4]a and [Figure 4]b.
|Figure 4: Fine-needle aspiration smears (a) benign thyrocytes admixed with atypical cells showing ovoid, pale, and enlarged nuclei with few nuclear grooves. (b) One indistinct intranuclear pseudoinclusion seen in a bloody background|
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Right subtotal thyroidectomy was subsequently performed on patient 1. The right subtotal thyroidectomy specimen weighed 150 g and was tan gray, rubbery, and smooth measuring 8 cm × 8 cm × 6 cm. On cut section, a solid, tan cream mass measuring 7 cm × 7 cm is seen [Figure 5].
The second patient underwent left thyroid lobectomy, and the specimen was sent to our laboratory for biopsy. The left thyroid lobe was tan gray, ovoid, and smooth measuring 5.5 cm × 4 cm × 3 cm [Figure 6]a. A well-defined, solid tan brown mass was seen on cut section measuring 3 cm × 2 cm [Figure 6]b.
|Figure 6: (a and b) Left thyroid lobe. (b) Well-defined, solid tan brown mass was seen on cut section measuring 3 cm × 2 cm|
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Total thyroidectomy was performed on the third patient. The specimen weighed 60 g. The left lobe was enlarged to 8.5 cm × 4 cm × 2.7 cm, and the section showed a well-delineated, white tan solid mass with the greatest dimension of 3.7 cm [Figure 7]. The right thyroid measured 3.7 cm × 3.2 × 0.7 cm. Cut section revealed brown areas with one focal cream tan, solid mass measuring 0.3 cm in the widest dimension.
The fourth patient underwent left thyroid lobectomy with isthmusectomy. The left lobe was tan brown, ovoid, and firm measuring 7 cm × 5 cm × 3 cm. Cut section showed a solitary cream, well-defined mass measuring 7 cm in the greatest dimension [Figure 8].
Microscopic examination of case 1 showed malignant glands in papillary formation predominantly (>50%) lined by a single layer of tall cells with abundant eosinophilic cytoplasm. The heights of these cells are at least three times their width. On higher magnification, the nuclei were enlarged and elongated, crowded, and overlapping with multiple nuclear grooves [Figure 9].
|Figure 9: Right thyroid mass. (a and b) Malignant glands in papillary formation lined by a single layer of tall cells with eosinophilic cytoplasm, ×10. (c and d) The nuclei are enlarged and elongated, crowded, and overlapping with multiple nuclear grooves, ×40|
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Case 2 revealed a malignant thyroid neoplasm in papillary formation lined by stratified columnar cells, predominantly with clear cytoplasm. Supranuclear and subnuclear vacuoles are also seen in the cytoplasm [Figure 10]a and [Figure 10]b. Higher magnification showed nuclear crowding and overlapping with occasional nuclear grooves and pseudoinclusions noted in some of the tumor cells [Figure 10]c and [Figure 10]d.
|Figure 10: Left thyroid mass. (a) Malignant glands with a combination of tall columnar cells with pseudostratified nuclei as well as cell with follicular architecture, ×4. (b) Pseudostratified columnar cells with supranuclear and subnuclear cytoplasmic vacuoles, ×40. (c and d) Pseudostratified columnar cells with hyperchromatic nuclei, ×10 and × 40|
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On microscopic examination of the third case, the left thyroid mass showed a tumor with a papillary growth pattern and variably sized follicles [Figure 11]a. Some of the tumor cell nuclei were eccentrically located showing a bulging of the nuclei at the tip of the cell imparting a hobnail appearance [Figure 11]b. Loss of cellular cohesiveness was evidently leading to cell detachment [Figure 11]c. On higher magnification, both the papillae and neoplastic follicles were mostly lined by cuboidal-to-elongated cells with abundant, well-defined cytoplasmic borders. There are few nuclei showing multiple “soap bubble” intranuclear inclusions. Greater than 30% of the malignant cells with hobnail features form micropapillary structures without fibrovascular cores. Concomitant tall cells/oncocytic cells were also identified [Figure 11]d. A diagnosis hobnail variant of PTC was given. The right thyroid mass revealed a micropapillary thyroid carcinoma [Figure 12].
|Figure 11: Left thyroid mass. (a) Thin arborizing papillae with prominent hobnail cells, ×10. (b) Hobnail cells, ×40. (c) Loss of cellular cohesiveness resulting in tufts of detaching cells, ×10. (d) Tall and oncocytic cells lining micropapillae without fibrovascular core, ×40|
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Histosection of the fourth case showed a malignant tumor composed of solid sheets of neoplastic follicular cells surrounded by thin, delicate fibrous stroma [Figure 13]a. Higher magnification revealed mild-to-moderate nuclear pleomorphism with scanty cytoplasm. Nuclear grooves and pseudoinclusions are also noted [Figure 13]b. Some areas are arranged in trabeculae, while others have tall cell and microfollicular patterns. Necrosis is absent [Figure 13]c and d].
|Figure 13: (a) Malignant tumor composed of solid sheets of neoplastic follicular cells surrounded by thin, delicate fibrous stroma (b) Higher magnification showing mild-to-moderate nuclear pleomorphism with scanty cytoplasm (c) Tumor cells with tall cell and (d) microfollicular patterns|
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A final diagnosis of PTC, TCV is made for case 1. The patient complains of tumor recurrence at the right lobe 1 year after the surgery. PTC, CCV was the final diagnosis for the second case. There is no recurrence 1 year after the surgery. The third patient was diagnosed with PTC, hobnail variant and is lost to follow-up. The final diagnosis of the fourth case was PTC, solid variant. The patient is still due for follow-up.
| Discussion|| |
We presented four of the so-called biologically aggressive and rare variants of PTC. The TCV of PTC, first described by Hawk and Hazard in 1976, is uncommon and occurs in 1%–12% of all PTC but is notably increasing in incidence worldwide.,,,,, The CCV comprises about 0.2% of all PTC cases and was first described by Evans in 1986 who initially described two cases of clinically aggressive cases that commonly occur in men. He also described four cases of encapsulated variants, which occurred in women. The HPTC is newly recognized and was first described by Asioli et al. in 2010.,, Furthermore, the solid variant accounts for approximately 3% of PTC cases. Greater than 30% of which are survivors of the Chernobyl incident.,,,,
Clinically, patients with TCV tend to be older than those with classic PTC (cPTC), with an age range of 41–66 (mean of 50.1).,, The study conducted by Wang et al. indicates that females are predominantly affected, with a female-to-male ratio of 2.9–1. However, male patients tend to have more advanced disease when diagnosed at an older age. TCV is also found to be more prevalent in patients with Graves' disease. The same is true for CCV and HPTC which occur mostly in females and in older individuals.,, HPTC commonly occurs in women, with an average age ranging from 28 to 78 years, and patients usually present with neck mass and cervical lymphadenopathy. In stark contrast to the other variants, SVPTC tends to occur in children with no sex predilection.,, Although rare, it may still occur in adults, as seen in our case. Our four patients are 44-, 54-, 57-, and 59-year-old females. The mean tumor diameters of the four variants are comparable to the tumor size in the classic variant (3 cm).,, The largest tumor size in our cases is that of TCV (7 cm) and SVPTC (7 cm) followed by HPTC (3.7 cm) and CCV (3 cm). In a study by Michels in 2007 on 674 PTC cases, TCV cases were significantly bigger, more often bilateral and/or multifocal, and more widely invasive with more frequent extrathyroidal extension and a higher grade. Ultrasound findings of these variants mostly show hypoechoic nodules with or without extrathyroidal extension., The solid variant may also exhibit intranodular vascularity.
On cytology, the tumor cells of TCV appear elongated (three times as high than wide) with ample eosinophilic cytoplasm. Cytoplasmic membranes are sharp, which distinctly delineate one cell from the other. The nuclei are variably sized with striking features of PTC and abundant intranuclear pseudoinclusions. Characteristic soap bubble-like inclusions have been reported. Squamous metaplasia may also be appreciated.,,, The diagnosis of CCV based on FNA remains to be challenging because the typical nuclear features of PTC, such as the ground glass nuclei, nuclear grooves, and intranuclear pseudoinclusions, are not consistently present. Nuclear pseudostratification may be seen and its presence should alert the cytopathologist. Recently, the cytological features of HPTC have been reported as comet-like cells, representing the cytological counterpart of the histological hobnailing. The cytologic features of 18 cases of SVPTC were analyzed by Higuchi et al., and majority of them showed solid clusters as well as small papillary clusters in conjunction with a clean background. Giorgadze et al. reported three cytomorphologic patterns from a study of 13 cases, namely cohesive, syncytial-type tissue fragments; microfollicles/trabeculae; and dyshesive single cells. The limitation, in this case, is the bloody aspirate due to the hypervascular nature of the tumor.
Histologically, TCV shows papillary growth, but a trabecular low-power appearance may be appreciated. It consists of cells that have a height of two to three times the width with eosinophilic cytoplasm, basally oriented nuclei, and the classic features of PTC.,,, Necrosis and mitosis are more common due to the larger size. This variant is still poorly defined because of the variability of the height of these tumor cells depending on the plane of section, presence of tall cells in other PTC variants, and different diagnostic criteria., Our patient's tumor is composed of >50% tall cells with basally oriented nuclei and with features of PTC. Currently, there is no standard definition concerning the proportion of tall cells required to allow a diagnosis of TC PTC.,,, The 2004 World Health Organization classification defines this variant as composed predominantly of cells whose heights are at least three times their widths. Nonetheless, there is still a debate as to the percentage of tall cells necessary to make a diagnosis with multiple recommendations ranging from 30% to 70%. Several studies have demonstrated previously diagnosed cases of cPTC reclassified as TCV after being reviewed by endocrine pathologists. In the study by Beninato et al. on 34 cases of TCV or PTC with tall cell features (TCFs) in 2013, the incidence of extrathyroidal extension, angiolymphatic invasion, positive surgical margin, and lymph node metastases was already increased in tumors with at least 10% tall cells. The demographic and clinicopathologic characteristics of PTC with TCFs (10%–50% tall cells) and TCV of PTC (>50% tall cells) were compared by Oh et al. and were noted to be the same. However, these tumors were significantly more aggressive than cPTC.
CCV is composed of pseudostratified columnar cells, which may contain supranuclear and subnuclear cytoplasmic vacuoles that are reminiscent of early secretory endometrium, which are seen in our patient.,, Overall morphology may resemble adenocarcinoma of the endometrium or gastrointestinal tract. The nuclei are hyperchromatic with the characteristic large clear nuclei of the classic papillary carcinoma only focally present. The cytoplasm is eosinophilic and tapering. Papillary, follicular, trabecular, and solid growth patterns are seen as well.,, As observed by Wenig et al. from 16 cases, multiple growth patterns can occur in one tumor, but the defining histologic criterion of CCV is the presence of nuclear stratification. The WHO Classification of Tumours did not specify the percentage of columnar cells required to make the diagnosis of CCV. Ferreiro et al. state that at least 50% columnar cells should be present, whereas Wenig et al. adopted 70% based on their study of 16 cases., Ito et al. did a study in 2008 subclassifying 1521 PTC s into the various histological variants and found that CCV comprised 0.4% of these cases. HPTC is composed of variably sized complex papillary structures without fibrovascular core and are lined by cells with increased nucleocytoplasmic ratios and apically placed nuclei producing a surface bulge (hobnail appearance). According to Bellevicine et al., typical features of HPTC include the presence of hobnail and papillary or micropapillary cytoarchitectural patterns, single teardrop cells similar to comet-like cells, high nucleocytoplasmic ratio, and severe crowding, all of which were seen in our case.
The criteria for the diagnosis of SVPTC include predominantly (>70%) solid growth pattern of the primary tumor, retention of nuclear features of PTC, and absence of necrosis., In the review of 20 patients by Nikiforov, all tumors had between 70% and 100% solid growth with nests of tumor surrounded by thin rim of fibrotic stroma in 11 cases and by broad fibrotic bands with extensive fibrosis in nine cases. All cases showed an abundant cytoplasm with nuclear features of classical PTC. This morphologic architecture is similar to our case with 80% solid pattern surrounded by thin fibrotic stroma in the absence of necrosis.
The immunohistochemical features of TCV are similar to cPTC. The tumor cells are positive for HBME, cytokeratin-19, galectin-3, CD15, and EMA. They may also be positive for p53, C-Met, MUC1, and type IV collagenase overexpression., For CCV, CDX2 is selectively expressed and can be used to distinguish from other variants.,, There are no specific immunohistochemical stains in HPTC. However, thyroglobulin, TTF-1, HBME-1, and p53 are positive in all cases, and there is a membrane staining for β-catenin and E-cadherin., Because one of the primary differential diagnoses for SVPTC is medullary carcinoma, thyroglobulin, TTF-1, and calcitonin should be performed, wherein SVPTC is positive for the former two and negative for the latter.
Although also seen in cPTC, the frequency of BRAF mutation is higher in TCV, CCV, and HPTC, which is a molecular marker related to aggressive tumor behavior.,,,,, Contrary to the other aggressive variant, SVPTC is most frequently associated with RET/PTC3 rearrangements., Molecular and immunohistochemical studies were not done on our patients due to the unavailability of these tests in our institution.
Most cases of PTC are managed by standard total thyroidectomy. However, in some variants with more aggressive behaviors, the correct recognition on preoperative FNA is useful for suggesting a more intensive neck surgery. Because of local invasion, neck dissection and irradiation tended to be more frequently performed in TCV patients. Studies recommend total thyroidectomy with routine prophylactic central lymph node dissection. Moreover, Wang et al. recommend radioactive iodine therapy for all patients regardless of the tumor size as well as a more aggressive postoperative thyrotropin suppression therapy. If newly diagnosed patients with TCV has undergone partial thyroidectomy, they should return for a completion thyroidectomy and central neck dissection followed by radioactive iodine ablation of residual tissue, as recommended by Jalisi et al. If total thyroidectomy was already performed initially, then the patients should return for radioactive iodine ablation. Subtotal thyroidectomy was performed on our first case despite the preoperative FNAB diagnosis of TCV. A more aggressive surgical management may have prevented the patient's present recurrence of tumor. Similarly, total thyroidectomy with central compartment neck dissection, lymphadenectomy, and/or resection of invaded surrounding structures followed by postoperative radioactive iodine is also recommended for CCV. Because SVPTC is considered to be more aggressive than cPTC, total thyroidectomy with appropriate lymph node dissection is recommended. Another literature states that tumors limited to the thyroid can be managed conservatively, whereas tumors extending outside the boundaries of the thyroid need a more aggressive therapy. Some studies also suggest the use of 18-fluoro-2-deoxyglucose positron emission tomography/computed tomography for staging and surveillance of patients with aggressive subtypes of thyroid cancer. For the second, third, and fourth cases, the aggressive variants (CCV, HPTC, and SVPTC) were not diagnosed on preoperative FNAB. Had they been recognized earlier, the patients would have benefited from a more appropriate surgical approach.
| Summary|| |
PTC is the most common thyroid and endocrine malignancy. We presented four of the so-called aggressive variants of PTC. TCV has a 4.5 times greater risk of recurrence compared to cPTC., It is associated with extrathyroidal extension, angiolymphatic invasion, positive surgical margin, lymph node metastasis, multifocality, distant metastasis, higher TNM stage, and higher mortality.,,,,,,, Similarly, CCV cases show advanced local growth and extrathyroidal extension and tend to show a more aggressive clinical behavior., It was suggested that the variant be divided into circumscribed and widely invasive subtypes, corresponding to indolent and aggressive clinical behavior, respectively.,,, The patient with columnar cell tumor variant has not recurred 1 year after the surgery compared to our patient with TCV. This could be attributed to the fact that the mass was encapsulated, which would mean a better prognosis. To the present time, only a few cases of PTC with prominent hobnail features have been described and most of them had aggressive behaviors.,, Concomitant TCFs and others with small foci of undifferentiated (anaplastic) thyroid carcinomas were seen in some reported cases. Comparably, our patient exhibited coexisting tall/oncocytic cells along with >30% hobnail features forming micropapillary structures. SVPTC is also associated with a slightly higher frequency of distant metastasis and less favorable prognosis compared to the cPTC. However, it has a better prognosis than poorly differentiated thyroid carcinoma.,, In a review of 200 patients who underwent surgery for PTC by Sebastian et al., the variants showing the worst prognosis were TCV and SVPTC and poorly differentiated.
The rare and aggressive variants of PTC pose a greater potential for invasion with poor clinical outcome. Thus, preoperative recognition of its features by FNAB is important in order to plan for a more appropriate management. These patients should also be closely monitored for recurrence.
| Conclusion|| |
It is essential to identify the aggressive variants of PTC because they frequently present with a more unfavorable clinical outcome than the cPTC. FNAB is an important tool to recognize these variants preoperatively and plan for a more comprehensive management. For these cases, various literature recommend total thyroidectomy with central neck dissection followed by radioactive iodine ablation of residual tissue.
In our setting, molecular testing is rarely done and the diagnosis as well as management is mostly based on the histomorphologic features of the tumor. In the advent of targeted therapy, we should aspire to make molecular profiling a part of the work-up for PTC to assure that the appropriate treatment modality is given.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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