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Quiz Case

Diagnostic difficulties in evaluation of primary malignant lesions of thyroid: A study of cytomorphology, histopathology, and immunohistochemistry

Department of Pathology, Maharishi Markandeshwar Institute of Medical Sciences and Research, Ambala, Haryana, India
Corresponding author: Kanwarpreet Kaur Cheema, Department of Pathology, Maharishi Markandeshwar Institute of Medical Sciences and Research, Ambala, Haryana, India.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Cheema KK, Singh P, Roy M, Khanna SP. Diagnostic difficulties in evaluation of primary malignant lesions of thyroid: A study of cytomorphology, histopathology, and immunohistochemistry. CytoJournal 2023;20:10.

18-year-old male presented with complaints of midline neck swellings since 1½ years associated with history of loss of weight. On examination, it was soft to firm in consistency. Contrast-enhanced computed tomography (CECT) neck was suggestive of neoplastic etiology. Cytopathological findings following ultrasound (USG)-guided fine-needle aspiration and cytology (FNAC) are shown in [Figure 1].

Figure 1:
(a-c) Smear showing atypical spindle cell arranged in dyscohesive clusters and swirls. The cells reveal hyperchromatic nuclei with moderate amount of cytoplasm (MGG, ×400); (d) Smear showing a biphasic lesion comprising of both epithelial component (arrow) forming acini and spindle cells (MGG, ×100).


Which of the following is the LEAST LIKELY diagnosis?

  1. Medullary Carcinoma Thyroid

  2. Primary Synovial Sarcoma (SS)

  3. Spindle Epithelial Tumor with Thymus-Like Differentiation (SETTLE)

  4. Papillary Carcinoma

  5. Undifferentiated (Anaplastic) Thyroid Carcinoma

  6. Immature Teratoma of thyroid

Answer: d. Papillary Carcinoma


Papillary carcinoma thyroid (PTC) cannot be the differential diagnosis in this case as cytologically PTC reveals syncytial cell aggregates and sheets with distinct anatomical borders. Papillary fragments with or without a fibrovascular core can also be seen. The cells typically show intranuclear inclusions and nuclear grooves.

However, medullary carcinoma, SETTLE, undifferentiated (anaplastic) carcinoma, immature teratoma of thyroid, and SS can all reveal spindle cell pattern. Although primary SS of thyroid is not a well-known entity and is very uncommon, the possibility cannot be ruled out.

The patient presented with a midline neck swelling [Figure 2] since a year and a half associated with loss of weight. His thyroid function tests were within normal limits. USG showed an oval hypoechoic lesion with central cystic area in the right lobe of thyroid [Figure 3]. This was followed by a radionuclide thyroid scan which showed a euthyroid gland with hypofunctioning nodule in the upper pole of the right lobe of thyroid gland [Figure 4]. CECT neck showed a well-defined heterogeneously enhancing solid cystic lesion in the right lobe with adjacent extensions and mass effect. Solid component showed significant post-contrast enhancement with mass attenuation suggestive of neoplastic etiology.

Figure 2:
Patient presented with a soft to firm midline neck swelling.
Figure 3:
Ultrasonography of thyroid showing an oval hypoechoic lesion with central cystic area in the right lobe of thyroid.
Figure 4:
Radionuclide thyroid scan showing a euthyroid gland with hypofunctioning nodule in the upper pole of the right lobe of thyroid gland.

On cytology, the smears were cellular and revealed a biphasic lesion consisting of spindle cell and epithelial components. The atypical spindle cells were arranged in dyscohesive clusters and forming whorled pattern. Individual cells revealed hyperchromatic nuclei with scant tapering cytoplasm. Interspersed in between were seen epithelial cells arranged in acinar pattern having round to oval nuclei with some showing prominent nucleoli [Figure 1]. Focal areas suggestive of amyloid were identified. However, they stained negative for Congo red [Figure 5]. Diagnosis of undifferentiated carcinoma (the Bethesda Category VI) was considered with the following possibilities:

  1. Primary SS – Biphasic

  2. Medullary Carcinoma Thyroid

Figure 5:
Smears showing negative congo red stain (Congo red, ×100).

The patient, then, underwent a total thyroidectomy and the specimen was sent for histopathological examination (HPE). On gross examination [Figure 6], we received a thyroidectomy specimen comprising two lobes measuring 3.5 × 2 × 0.5 cm and 3.2 × 1.8 × 1 cm, respectively, and isthmus measuring 1.5 × 1 × 0.4 cm. Attached skeletal muscle measured 4 × 3.5 × 1.5 cm. Cut section showed tumor mass in the right lobe measuring 2 × 1.5 cm with solid-cystic areas.

Figure 6:
Total thyroidectomy specimen with tumour mass showing solid-cystic areas.

Microscopy [Figure 7] showed a cellular neoplasm composed predominantly of spindle-shaped cells arranged in fascicles. The cells revealed ovoid to spindle-shaped nuclei with fine granular chromatin, inconspicuous nucleoli, and 3–4 mitoses per high-power fields. Scattered small tubules and papillae [Figures 8 and 9] lined by cuboidal epithelium having uniform ovoid nuclei were present imperceptibly admixed with the spindle-shaped cells. No extrathyroidal extension and invasion into extrathyroidal skeletal muscle were noted. The above-mentioned features further strengthened the suspicion of a spindle cell sarcoma, suggestive of SS.

Figure 7:
(a and c) Section showing spindle cells arranged in fascicles and whorls (H and E, ×100); (b and d) Higher magnification of the same (H and E, ×400); (e) Section showing epithelial cells arranged in papillae and tubules (H and E, ×100); (f) Higher magnification of the same (H and E, ×400).
Figure 8:
Section showing epithelial cells arranged in papillae and tubules (H and E, ×100).
Figure 9:
Higher magnification of the same (H and E, ×400).

IHC studies were done in a referral center. The tumor was immunoreactive for CK, CD99, and epithelial membrane antigen (EMA).

  1. CK – Immunoreactive score 4+ in lesional cells

  2. CD 99 – Immunoreactive score 3+ in lesional cells

  3. EMA – Immunoreactive score 3+ in lesional cells.

  4. Non-immunoreactive score 0 in lesional cells – CK7, Calretinin, Synaptophysin, TTF-1, and CK5/6.


Q2. Which of the following is the definitive diagnosis?

  1. Medullary Carcinoma Thyroid

  2. Primary SS


  4. Papillary Carcinoma

  5. Undifferentiated (Anaplastic) Thyroid Carcinoma

  6. Immature Teratoma of thyroid

Q3. Which of the following IHC markers is not specific for this entity?

  1. TLE1

  2. h-caldesmon

  3. EMA

  4. Cytokeratin (CK)

Q4. Which of the following molecular pathologies is diagnostic of this entity?

  1. Gain of function mutation in RET proto-oncogene

  2. TP53 mutations

  3. t(X;18)(p11.q11) translocation

  4. Point mutations

Answers to additional questions:

Answer 2: b. Primary SS

Answer 3: a. TLE1

Answer 4: c. t(X;18)(p11.q11) translocation


Answer 2

SETTLE versus Primary SS

SETTLE can be differentiated from SS on the basis of lower nuclear grade, glomeruloid glandular structures, stromal hyalinization, and diffuse expression of high molecular weight CK. The abovementioned features were absent in the present case.

Medullary carcinoma versus Primary SS

Cytological smears of medullary carcinomas are cellular and the cells may show variable patterns including plasmacytoid, small cells, or spindle cells. They may also variably exhibit amyloid or coarse red cytoplasmic granularity. In contrast to SS, these are positive for TTF-1 (weak to moderate), while the amyloid is positive for Congo red, both of which were negative in the present case.

Undifferentiated (anaplastic) carcinoma versus Primary SS

The patients with anaplastic carcinomas (AC) are usually women who present after 60 years of age. Cytological examination of AC shows the presence of necrotic background and highly pleomorphic malignant cells. The cells may range from spindle/squamoid cells to multinucleate and bizarre giant cells.

Immature teratoma of thyroid versus Primary SS

Although immature teratomas of thyroid can also be considered as a differential diagnosis, very few cases have been reported, with an average age of 43 years. Although in these cases also FNA reveals dominance of immature spindle cells since there was absence of immature neural tissue in the present case; thus, the possibility of being a malignant teratoma was excluded from the study. In addition to this, our patient was of 18 years of age and the FNA smears revealed a biphasic tumor comprising of both; spindle cell as well as epithelial cell component.

Answer 3

SSs show a moderate/strong nuclear expression for TLE1 which is a transcriptional corepressor. However, it is not specific for this entity alone. TLE 1 may also be seen in malignant nerve sheath tumor and solitary fibrous tumor. Other non-specific markers include bcl2 and CD99. Although a majority of SS show membranous positivity for these, they are not specific.

Answer 4

SSs are characterized by SYT-SSX1, SYT-SSX2, or SYT-SSX4 fusion gene. This is a result of t(X;18)(p11;q11) translocation which leads to the fusion of SS18 on chromosome 18 to one of the SSX genes- SSX1, SSX2, or SSX4.

Based on the above findings and discussion, a final diagnosis of the primary SS of thyroid was given.


SS is an exceedingly rare malignant mesenchymal neoplasm accounting for about 10% of soft-tissue sarcomas.[1] These are an extremely rare, malignant group of tumors characterized by chromosomal translocation t(X;18)(p11.2;q11.2) which results in the expression of SYT-SSX gene transcript.[2] SS is thought to arise from multipotent stem cells and not synovium.[3,4] Thus, they can occur at any site.[3,4] However, these usually arise in the deep soft tissue of the upper as well as lower extremities (70%), more often in the para-articular areas, followed by the trunk (15%) and the head and neck region (7%).[2] They are classified either as biphasic, composed of both spindle cell and epithelial cell component, or may be monophasic spindle cell type.[2,5]

The primary SS of thyroid is a rare, high grade, and aggressive tumor. To the best of our knowledge, only 13 cases have been reported in the literature so far.[1] It commonly presents in young adults and adolescents[1,6] and men are affected more than women with a 2:1 sex ratio.[1] The presenting symptoms usually include an asymptomatic rapidly growing neck mass.[1] The symptoms may also include hoarseness, dysphagia, dysphonia, and excessive salivation which may all be a result of compression effects by a rapidly growing tumor.[1] This unusual location makes the diagnosis of SS difficult.[6]

Radiological examination usually falls short in differentiating it from other thyroid malignancies. However, it can contribute in the assessment of location, size, vascularization, and local invasion.[1]

Pre-operative diagnosis based on FNAC is usually not supportive, although HPE may be contributory to some extent.[7] The conclusive diagnosis of this entity relies mainly on the diagnostic molecular studies such as fluorescence in situ hybridization.[5] However, immunohistochemistry may show positivity for EMA, CKs, and focal S100 expression (40% cases).[2] H-caldesmon is always negative.[2] Strong nuclear positivity is seen for TLE1 and membranous staining for BCl2 and CD99, but these markers are not specific.[2]


The primary SS of thyroid is an extremely uncommon entity; however, the possibility cannot be entirely ruled out. Cytological findings, in our case, were strongly in favor of the primary SS. Although the definitive diagnosis was possible only on IHC studies, however molecular profiling is mandatory for further evaluation.


The authors declare that they have no competing interests.


KKC designed and conducted the study and performed the literature search. PS drafted the manuscript and helped in critical analysis. SPK helped in writing and review of the manuscript. MR performed literature search and helped in microphotography.


This study was conducted with approval from the Institutional Review Board of the institution associated with this study. Authors take responsibility to maintain relevant documentation in this respect.

LIST OF ABBREVIATIONS (In alphabetic order)

CECT – Contrast-enhanced computed tomography

CK – Cytokeratins

EMA – Epithelial membrane antigen

FISH – Fluorescence in situ hybridization

FNAC – Fine-needle aspiration and cytology

HPE – Histopathological examination

IHC – Immunohistochemistry

PCT – Papillary carcinoma thyroid

SETTLE – Spindle epithelial tumor with thymus like differentiation

SFT – Solitary fibrous tumor

SS – Synovial sarcoma

TFTs – Thyroid function tests

USG – Ultrasound

WNL – Within normal limits


To ensure the integrity and highest quality of CytoJournal publications, the review process of this manuscript was conducted under a double-blind model (authors are blinded for reviewers and vice versa) through automatic online system.


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