Primary squamous cell carcinoma of the thyroid -case report of a rare disease

Primary squamous cell carcinoma of the thyroid -case report of a rare disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Primary squamous cell carcinoma of the thyroid -case report of a rare disease Bernadett Lévay, Alexandra Kiss, Ferenc Oberna, Erika Toth This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2654594/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction Primary squamous cell carcinoma (SCC) of the thyroid gland is a very rare entity. The prognosis is very poor with a short survival time. The aim of this article is to report a case of a SCC of the thyroid gland in a 68-year-old woman, emphasizing how complicate is the operation and the adequate treatment of this disease. Case report A 68-year -old woman presented with rapidly growing neck mass with hoarseness and compressive symptoms. Physical examination revealed a hard fixed tumor with right sided vocal cord palsy. Histopathological result confirmed the diagnosis of SCC of the thyroid. PET/CT scan excluded the possibility of other primary malignancies. A surgical intervention was performed, however the patient died in the middle of the palliative radiation therapy. Conclusion SCC of the thyroid gland is a great challenge for the surgeon and also for the multidisciplinary team to come up with the best treatment option which is suitable for the patient due to its unfavorable prognosis. squamous cell carcinoma thyroid gland Figures Figure 1 Figure 2 Figure 3 Introduction Primary squamous cell carcinoma (SCC) of the thyroid gland is a very rare entity less than 1% of all primary carcinomas of the thyroid gland. Only a few cases are reported in the literature. [1] This malignancy has a very aggressive behavior and a very poor prognosis, the median survival time is less than 6 months after the time of diagnosis.[2] The optimal treatment would be the surgical resection followed by adjuvant radiotherapy and chemotherapy. The aim of this article is to report the case of a SCC of the thyroid gland in a 68-year-old woman, emphasizing how complicate is the operation and the adequate treatment of this disease.[3] Case Report A 68-year-old female patient with a 35-year 2 months of history of a large mass on the anterior neck was admitted to the National Institute of Oncology due to progressive dyspnoe, hoarseness and swallowing problems. In her previous medical history hypertension, diabetes and GERD appeared. With physical examination a fixed hard neck mass was palpable in the thyroid gland mostly on the right side with right sided lymphadenopathy. Laryngoscopy showed a right sided vocal cord palsy. The neck and chest CT showed a huge solid mass in the thyroid region dislocating and compressing the trachea, which reached the superior mediastinal region . (Figure 1.) Thyroid ultrasound was performed revealing a mass of the right lobe measuring 8.3 × 5.8 × 5.0 cm with retrosternal extension, and with a 1.8x1.7cm calcified mass in the middle of the lobe. The ultrasound also showed the presence of enlarged metastatic lymph nodes in the right lateral neck regions. Fine needle aspiration (FNA) cytology was performed two times, which showed squamous cell carcinoma with metastatic lymph nodes in the lateral neck region. Core biopsy was taken with the result of squamous cell carcinoma showing CK5, p40 co-expression. Oesophagoscopy was unremarkable. The patient was prepared for operation. A paratracheal and modified lateral neck dissection on the right side of the neck were performed. Regarding the prominent extra capsular invasion, only an extended R1 resection could be done instead of total thyroidectomy. The tumor infiltrated the trachea, esophagus and the surrounding soft tissues. The larger part of the tumor was removed from the trachea with shaving technique, the recurrent nerves could not be identified on either side. The patient's hospitalization was uneventful and was discharged on the fourth postoperative day. Histology and molecular pathology analysis of the resection specimen.: Histological examination showed the presence of well differentiated invasive SCC with keratinization, infiltrating mainly the right lobe of the thyroid gland (Figure 2, Figure 3). The tumor showed typical immunophenotype, it was CK5 and p40 positive. Large areas of fibrosis with calcification and foci of necrosis were observed in the central area of the tumor. There were no sign of other component (e.g. papillary area) suggestive of primary thyroid cancer. Out of the 40 resected lymph nodes, 10 showed metastasis of the SCC. Extranodal extension of the tumor was present on multiple lymph node levels. Biomarker analysis showed prominent PD-L1 expression. PD-L1 expression was detected with DAKO 22C3 PharmDx kit according to the manufacturer instructions. 40% of tumor cells showed complete or partial PD-L1 expression, tumor proportion score (TPS) was 40%. Combined positive score (CPS) was 50. Detailed molecular analysis was also performed using Oncomine Focus Assay on IonTorrent S5 platform. The kit contains the following genes. Oncomine focus hotspot: AKT1, ALK, AR, BRAF, CDK4, CTNNB1, DDR2, EGFR, ERBB2, ERBB3, ERBB4, ESR1, FGFR2, FGFR3, GNA11, GNAQ, HRAS, IDH1, IDH2, JAK1, JAK2, JAK3, KIT, KRAS, MAP2K1, MAP2K2, MET, MTOR, NRAS, PDGFRA, PIK3CA, RAF1, RET, ROS1, SMO Oncomine focus copy number: AKT1, ALK, AR, BRAF, CCND1, CDK4, CDK6, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, FGFR4, KIT, KRAS, MET, MYC, MYCN, PDGFRA, PIK3CA Oncomine focus gene fusion: ABL1, AKT3, ALK, AXL, BRAF, EGFR, ERBB2, ERG, ETV1, ETV4, ETV5, FGFR1, FGFR2, FGFR3, MET, NTRK1, NTRK2, NTRK3, PDGFRA, PPARG, RAF1, RET, ROS1. Both DNA and RNA based sequencing were performed. After macro-dissection tumor cell content of the sample was 60%. We detected NRAS exon 3 mutation, p.Gln61Lys, c.181C>A, with 24,32% mutant allele ratio and amplification of EGFR gene with copy number 17,18. The patient was referred to multidisciplinary tumor board before further therapy. Regarding the PDL-1 positivity immunotherapy and radiotherapy was recommended. On the 34th postoperative day, urgent tracheotomy was needed due to heavy dyspnoe. PET/CT scan was recommended which showed a huge mass between the upper parajugular region down to the anterior mediastinum surrounding the trachea and infiltrating the vessels on both sides of the neck and reaches the hypopharynx and larynx as well and also ruled out the possibility of other primary malignancies. Lymphadenopathy was observed in the mediastinum and on both sides of the neck. FDG dense nodules were found in the lungs on both sides, as well as in the thoracal vertebrae, in the sacrum and in the pelvis. Lymphadenopathy was detected in the cervical, right hilar and right inguinal region. Multidisciplinary tumor board offered palliative radiotherapy with 10x3 Gray. Patient received 5x3 Gray radiation, when severe renal failure developed , which ended up with dialysis. She was admitted to the uro-oncology department . Due to her physical status, active oncotherapy could not be carried out. After 5x3 Gray palliative radiation the patient died. Discussion A primary SCC of the thyroid is rare, representing < 1% of all primary thyroid carcinomas. It is more common in females. Due to its rarity, only few cases are reported in the international literature. It is considered to be highly aggressive tumor with a poor prognosis.[ 4 ] SCC affects usually older patients between the fifth and sixth decade and is usually associated with a history of goiter. In the majority of cases, the patients present at the time of diagnosis with a rapidly enlarged neck mass, followed by symptoms of infiltration and compression of adjacent neck structures (dyspnea and hoarseness). Infiltration of cervical lymph nodes may or may not be present.[ 5 – 6 ] Clinically anaplastic thyroid carcinoma is the main differential diagnosis. In our case histologically very evident squamous cell differentiation was seen, we could not detect any other component after cut up the whole specimen. SCC is of unknown etiology, as the thyroid gland normally lacks squamous epithelium. Several theories have been suggested regarding its etiology. However, three theories have been popularized. First, the embryonic nest theory suggests that the squamous cells are derived from the remnants of thyroglossal duct or the epithelium of the thymus.[ 7 ] Secondly, the metaplasia theory suggests that these cells present as a result of Hashimoto's thyroiditis.[ 8 ] Thirdly, the de-differentiation theory suggests that existing papillary, follicular, medullary or anaplastic carcinoma dedifferentiate into SCC.[ 9 ] In everyday practice squamous differentiation is most frequent in papillary thyroid carcinoma but in these cases the papillary component can be detected. However we have not seen any papillary area in the tumor in our case and the results of molecular analysis were not suggestive of papillary thyroid cancer also. Molecular pathological analysis showed NRAS exon 3 mutation, p.Gln61Lys, c.181C > A which is most frequent in follicular thyroid tumors and very rare in squamous cell carcinomas of any region. However amplification of EGFR gene is frequently seen in head and neck squamous cell carcinomas, NRAS mutation is extremely rare, which can underline the real thyroid origin of our case.[ 10 ] The optimal treatment of primary thyroid SCC is surgical excision with adjuvant radiotherapy and chemotherapy. However, many studies suggest that it is relatively radio-resistant and has poor response to chemotherapy, leaving complete surgical excision the only chance of prolonging survival of these patients. [ 11 , 12 ] Nowadays immune-oncological therapies, like anti-PD1 and anti-PD-L1 therapy, are a very successful therapeutic options for head and neck squamous cell carcinomas. Booya et al. reviewed 10 cases on SCC n the thyroid and discussed that p21, MIB-I, and p53 are overexpressed in primary squamous cell carcinoma of the thyroid and may have relevance to early diagnosis of SCC in the patient. [ 13 ] In our case PD-L1 expression was high both on tumor cells and on tumor infiltrating lymphocytes which predict good response to these drugs. Unfortunately the rapid progression of the disease prevented any further therapies. Patients with primary thyroid SCC have a very poor prognosis and the main cause of death is direct invasion or compression of the trachea. Cho et al. recently performed a systematic review and individual participant data meta-analysis regarding primary SCC of the thyroid gland. According to this meta-analysis (89 patients), the mean age of diagnosis was 63 years (range, 24–90), a female preponderance (M : F = 1:2) was noted and the commonest complaint was the anterior neck mass. It was noted that predictability of diagnosis with fine needle aspiration cytology was accurate in less than one-third of the patients and more than half of cases had been diagnosed as papillary thyroid carcinoma or were non-diagnostic. [ 14 ] Complete surgical resection (Ro) of the tumor would be the only significant prognostic factor on multivariate analysis, and the benefit of adjuvant treatment was not proved. Moreover, the prognosis of these patients was very poor (only 20% of 3 year survival rate). [ 15 , 16 ] Conclusion SCC of the thyroid gland is a very rare and aggressive tumor with poor prognosis. Complete surgical resection (Ro) of the tumor is the only significant prognostic factor, whereas efficacy of adjuvant treatment (chemo- and radiotherapy) remains controversial in the international literature. A fatal outcome is usually a result of its complications, due to loco-regional spread of the disease to adjacent organs and structures.[ 17 , 18 ] Declarations Patient signed the inform consent that her history might be used for scientific purposes.Ethics approval and consent to participate Authors gave permission for publication Funding- no fundings were given for this research Authors' contributions: LB-manuscript writing, surgeon KA-manuscript writing OF-manuscript revision TE- editing the pathological report References Sun BH, Yu ST, Ge JN, Lei ST. Primary squamous cell carcinoma (PSCC) of the thyroid: A case report and review of the literature. Gland Surg. 2020;9(2):474–7. Othman RT, Baizeed AMA, Mohammed AA. Squamous cell carcinoma of the thyroid gland in an elderly female presenting as a rapidly enlarging thyroid mass. Int J Surg Case Rep. 2020;70:119–22. Raggio B, Barr J, Ghandour Z, Friedlander P. “Primary squamous cell carcinoma of the thyroid,” Ochsner J. , vol. 19, no. 3, pp. 290–292, Sep. 2019. Yang S, et al. Primary Squamous Cell Carcinoma in the Thyroid Gland: A Population-Based Analysis Using the SEER Database. World J Surg. May 2019;43(5):1249–55. Kallel S, Kallel R, Ayadi S, Ghorbel A. Primary squamous cell carcinoma of the thyroid associated with papillary thyroid carcinoma and Hashimoto’s thyroiditis. Eur Ann Otorhinolaryngol Head Neck Dis. Aug. 2018;135(4):291–3. Ibrahim M-I-S, Jusoh Y-R, Adam N-N, Mohamad I. Primary Squamous Cell Carcinoma of the Thyroid Gland. ” Iran J Otorhinolaryngol. Jan. 2018;30(96):65–8. Wygoda A, Rutkowski T, Szcześniak-Kłusek B, Mrochem-Kwarciak J, Jędrzejewska M, Składowski K. Primary squamous-cell thyroid carcinoma - a successful treatment with five-year follow-up. ” Endokrynol Pol. 2017;68(5):592–6. Struller F, Senne M, Falch C, Kirschniak A, Konigsrainer A, Muller S. Primary squamous cell carcinoma of the thyroid: Case report and systematic review of the literature. Int J Surg Case Rep. 2017;37:36–40. Del Rosario M, Dasanu C, Tsai H, Johnson R. “Primary squamous cell carcinoma of the thyroid with complete response to radical radiotherapy and concurrent cisplatin-based chemotherapy,” BMJ Case Rep. , vol. 2017, 2017. Aaron Hobbs G, Der CJ. Rossman. RAS isoforms and mutations in cancer at a glance. J Cell Sci. 2016;129:1287–92. 10.1242/jcs.182873 . Shenoy VS, Rao RA, Kamath PM, Prasad V, Haseena S. Primary Squamous Cell Carcinoma of Thyroid – A Rare Malignant Goitre. Indian J Surg Oncol. Dec. 2016;7(4):467–9. Lichiardopol C, Şurlin V, Foarfă MC, Ghiluşi MC, Bondari S. “Primary squamous cell carcinoma of the thyroid: a case report.,” Rom. J. Morphol. Embryol. = Rev. Roum. Morphol. Embryol. , vol. 57, no. 2 Suppl, pp. 831–836, 2016. Booya A, Sebo F, Kasperbauer TJ, Fatourechi JL. Primary squamous cell carcinoma of the thyroid: report of ten cases. Thyroid. 2006 Jan;16(1):89–93. Cho JK, Woo S, Park J, Kim M, Jeong H. Primary squamous cell carcinomas in the thyroid gland: an individual participant data meta-analysis. Cancer Med. Oct. 2014;3(5):1396–403. 10.1002/cam4.287 . Chavan RN, Chikkala B, Biswas C, Biswas S, Sarkar DK. “Primary Squamous Cell Carcinoma of Thyroid: A Rare Entity,” Case Rep. Pathol. , vol. 2015, pp. 1–3, 2015. Sapalidis K et al. “Primary squamous cell carcinoma of the thyroid gland,” J. Surg. Case Reports , vol. 2014, no. 12, pp. rju133–rju133, Dec. 2014. Zhao J, Wang J, Wu D, Xiong J. “[Primary squamous cell carcinoma of thyroid: a case report].,” Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese J. Otorhinolaryngol. head neck Surg. , vol. 49, no. 1, pp. 69–70, Jan. 2014. Kleinhans H, Schmid KW, Verse T.“[Primary squamous cell carcinoma of the thyroid gland]., ” HNO , vol. 61, no. 7, pp. 661–663, Jul. 2013. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2654594","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":181856453,"identity":"8e232a7a-d050-4422-9ab8-b60e16507bc4","order_by":0,"name":"Bernadett Lévay","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYDCCA8wNICqBXwLMlZAhQgsjRIvkDAYQS4KHeC0GN8BaGAhr4bt9sPExT83hPOPbzccf3aix4GFgP3x0Az4tkucSm415jh0uNrtzLLE55xjQYTxpaTfwaTE4w9gmOYPtcOK2GzmGzTlsQC0SPGaEtLT/nPHvcOLmGSAt/4jT0sbwse1w4gYJoJbcNiK0SJ5hbJb42JdeLHEjLXF2bp8EDxshv/CdYT74IeGbdR7/jOQDn3O+1cnxsx8+hlcLFDQjmGxEKAeBOiLVjYJRMApGwYgEAAUsThiAUhrEAAAAAElFTkSuQmCC","orcid":"","institution":"National Institute of Oncology","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Bernadett","middleName":"","lastName":"Lévay","suffix":""},{"id":181856455,"identity":"f69a0f4d-35c5-4ac5-b03f-178b08a67623","order_by":1,"name":"Alexandra Kiss","email":"","orcid":"","institution":"National Institute of Oncology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alexandra","middleName":"","lastName":"Kiss","suffix":""},{"id":181856457,"identity":"f2c3090d-2ae1-400c-9c7e-a3bc5750ef00","order_by":2,"name":"Ferenc Oberna","email":"","orcid":"","institution":"National Institute of Oncology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ferenc","middleName":"","lastName":"Oberna","suffix":""},{"id":181856459,"identity":"3cb8719a-2fbe-45ba-b07f-bd1ad405b7da","order_by":3,"name":"Erika Toth","email":"","orcid":"","institution":"National Institute of Oncology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Erika","middleName":"","lastName":"Toth","suffix":""}],"badges":[],"createdAt":"2023-03-04 10:59:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2654594/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2654594/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":34232844,"identity":"e8ce2960-6f48-4d18-ab56-37dd956e472b","added_by":"auto","created_at":"2023-03-14 14:20:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":4175882,"visible":true,"origin":"","legend":"\u003cp\u003eNeck CT scan shows a large mass dislocating and compressing the trachea\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-2654594/v1/e3905d3169e6a157a84642ed.png"},{"id":34232843,"identity":"2a005fe3-26f6-4ca9-babd-4478e05d4611","added_by":"auto","created_at":"2023-03-14 14:20:13","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1318297,"visible":true,"origin":"","legend":"\u003cp\u003eConventional squamous cell carcinoma infiltrating the thyroid gland.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2654594/v1/32dd68da83774601b4e652b2.jpeg"},{"id":34232845,"identity":"19de19b5-ecf7-4b60-9c7a-ed8654d0b06b","added_by":"auto","created_at":"2023-03-14 14:20:14","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":934489,"visible":true,"origin":"","legend":"\u003cp\u003eHigh power photo of the squamous cell carcinoma. Focal keratinization can be seen.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2654594/v1/fb40c0d2133fd299e92bb596.jpeg"},{"id":34482082,"identity":"857fe844-e9ec-4583-81f7-267cf07f8f00","added_by":"auto","created_at":"2023-03-19 22:59:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2065403,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2654594/v1/682bd109-fb0e-44ce-8d5d-7c4dc9ae34fd.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Primary squamous cell carcinoma of the thyroid -case report of a rare disease","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePrimary squamous cell carcinoma (SCC) of the thyroid gland is a very rare entity less than 1% of all primary carcinomas of the thyroid gland. Only a few cases are reported in the \u0026nbsp;literature. [1] This malignancy has a very aggressive behavior and a very poor prognosis, \u0026nbsp;the \u0026nbsp;median survival time is less than 6 months after the time of diagnosis.[2] The optimal treatment would be the surgical resection followed by adjuvant radiotherapy and chemotherapy. The aim of this article \u0026nbsp;is to report the case of a SCC of the thyroid gland in a 68-year-old woman, emphasizing how complicate is the operation and the adequate treatment of this disease.[3]\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003eA 68-year-old female patient with a 35-year 2 months of history of a large mass on the anterior neck \u0026nbsp;was admitted to the National Institute of Oncology \u0026nbsp; due to progressive \u0026nbsp; dyspnoe, hoarseness and swallowing problems. In her previous medical history \u0026nbsp; hypertension, diabetes and GERD appeared. With physical examination \u0026nbsp;a fixed hard neck mass was palpable in the thyroid gland mostly on the right side with right sided lymphadenopathy. Laryngoscopy showed a right sided vocal cord \u0026nbsp; palsy. The neck and chest CT showed \u0026nbsp; a huge solid mass in the thyroid region dislocating and compressing the trachea, which reached the superior mediastinal region . (Figure 1.) Thyroid ultrasound was performed revealing a mass of the right lobe measuring 8.3 \u0026times; 5.8 \u0026times; 5.0 cm with retrosternal extension, and with a 1.8x1.7cm \u0026nbsp;calcified mass in the middle of the lobe. \u0026nbsp;The ultrasound also showed the presence of enlarged metastatic lymph nodes in the right lateral neck\u0026nbsp;regions. Fine needle aspiration (FNA) cytology was performed two times, which showed squamous cell carcinoma with \u0026nbsp;metastatic lymph nodes in the lateral neck region. Core biopsy was taken with the result of squamous cell carcinoma \u0026nbsp;showing CK5, p40 co-expression.\u0026nbsp;Oesophagoscopy\u0026nbsp;was unremarkable. The patient was prepared for operation. A paratracheal and modified lateral neck dissection on the right side of the neck were performed. Regarding the prominent extra capsular invasion, only an extended R1 resection could be done instead of total thyroidectomy. The tumor infiltrated the trachea, esophagus and the surrounding soft tissues. The larger part of the tumor was removed from the trachea with shaving technique, the recurrent nerves could not be identified \u0026nbsp;on either side. The patient\u0026apos;s hospitalization was uneventful and was discharged on the fourth \u0026nbsp; postoperative day.\u003c/p\u003e\n\u003cp\u003eHistology and molecular pathology analysis of the resection specimen.:\u003c/p\u003e\n\u003cp\u003eHistological examination showed the presence of well differentiated invasive \u0026nbsp;SCC with keratinization, infiltrating mainly the right \u0026nbsp;lobe of the thyroid gland (Figure 2, Figure 3). The tumor showed typical immunophenotype, it was CK5 and p40 positive. Large areas of fibrosis with \u0026nbsp; calcification \u0026nbsp;and foci of necrosis were observed in the central area of the tumor. There were no sign of other component (e.g. papillary area) suggestive of \u0026nbsp;primary thyroid cancer. Out of the 40 resected lymph nodes, 10 showed metastasis of the SCC. Extranodal extension of the tumor was present on multiple lymph node levels.\u003c/p\u003e\n\u003cp\u003eBiomarker analysis showed prominent PD-L1 expression. PD-L1 expression was detected with DAKO 22C3 PharmDx kit according to the manufacturer instructions. 40% of tumor cells showed complete or partial PD-L1 expression, tumor proportion score (TPS) was 40%. Combined positive score (CPS) was 50. Detailed molecular analysis was also performed using Oncomine Focus Assay on IonTorrent S5 platform. The kit contains the following genes. Oncomine focus hotspot: AKT1, ALK, AR, BRAF, CDK4, CTNNB1, DDR2, EGFR, ERBB2, ERBB3, ERBB4, ESR1, FGFR2, FGFR3, GNA11, GNAQ, HRAS, IDH1, IDH2, JAK1, JAK2, JAK3, KIT, KRAS, MAP2K1, MAP2K2, MET, MTOR, NRAS, PDGFRA, PIK3CA, RAF1, RET, ROS1, SMO Oncomine focus copy number: AKT1, ALK, AR, BRAF, CCND1, CDK4, CDK6, EGFR, ERBB2, FGFR1, FGFR2, FGFR3, FGFR4, KIT, KRAS, MET, MYC, MYCN, PDGFRA, PIK3CA Oncomine focus gene fusion: ABL1, AKT3, ALK, AXL, BRAF, EGFR, ERBB2, ERG, ETV1, ETV4, ETV5, FGFR1, FGFR2, FGFR3, MET, NTRK1, NTRK2, NTRK3, PDGFRA, PPARG, RAF1, RET, ROS1. Both DNA and RNA based sequencing were performed. After macro-dissection tumor cell content of the sample was 60%. We detected\u0026nbsp;NRAS exon 3 mutation, p.Gln61Lys, c.181C\u0026gt;A, with 24,32% mutant allele ratio and amplification of EGFR gene with copy number 17,18.\u003c/p\u003e\n\u003cp\u003eThe patient was referred to multidisciplinary tumor board before further therapy. Regarding the PDL-1 positivity \u0026nbsp;immunotherapy and radiotherapy was recommended. On the 34th postoperative day, urgent tracheotomy was needed due to heavy dyspnoe. PET/CT scan was recommended \u0026nbsp; which showed a huge mass between the upper parajugular region down to the anterior mediastinum surrounding the trachea and infiltrating the vessels on both sides of the neck and reaches the hypopharynx and larynx as well and also \u0026nbsp;ruled out the possibility of other primary malignancies. Lymphadenopathy was observed in the mediastinum and on both sides of the neck. FDG dense nodules were found in the lungs \u0026nbsp;on both sides, as well as in the thoracal vertebrae, in the sacrum and in the pelvis. Lymphadenopathy was detected in the cervical, right \u0026nbsp;hilar and \u0026nbsp;right inguinal region. Multidisciplinary tumor board offered palliative radiotherapy with 10x3 Gray. Patient received 5x3 Gray radiation, when severe renal failure developed , which ended up with dialysis. \u0026nbsp;She was admitted to the uro-oncology department . Due to her physical status, active oncotherapy could not be carried out. After 5x3 Gray palliative radiation the patient died.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eA primary SCC of the thyroid is rare, representing\u0026thinsp;\u0026lt;\u0026thinsp;1% of all primary thyroid carcinomas. It is more common in females. Due to its rarity, only few cases are reported in the international literature. It is considered to be highly aggressive tumor with a poor prognosis.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] SCC affects usually older patients between the fifth and sixth decade and is usually associated with a history of goiter. In the majority of cases, the patients present at the time of diagnosis with a rapidly enlarged neck mass, followed by symptoms of infiltration and compression of adjacent neck structures (dyspnea and hoarseness). Infiltration of cervical lymph nodes may or may not be present.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eClinically anaplastic thyroid carcinoma is the main differential diagnosis. In our case histologically very evident squamous cell differentiation was seen, we could not detect any other component after cut up the whole specimen. SCC is of unknown etiology, as the thyroid gland normally lacks squamous epithelium. Several theories have been suggested regarding its etiology. However, three theories have been popularized. First, the embryonic nest theory suggests that the squamous cells are derived from the remnants of thyroglossal duct or the epithelium of the thymus.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Secondly, the metaplasia theory suggests that these cells present as a result of Hashimoto's thyroiditis.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] Thirdly, the de-differentiation theory suggests that existing papillary, follicular, medullary or anaplastic carcinoma dedifferentiate into SCC.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] In everyday practice squamous differentiation is most frequent in papillary thyroid carcinoma but in these cases the papillary component can be detected. However we have not seen any papillary area in the tumor in our case and the results of molecular analysis were not suggestive of papillary thyroid cancer also. Molecular pathological analysis showed NRAS exon 3 mutation, p.Gln61Lys, c.181C\u0026thinsp;\u0026gt;\u0026thinsp;A which is most frequent in follicular thyroid tumors and very rare in squamous cell carcinomas of any region. However amplification of EGFR gene is frequently seen in head and neck squamous cell carcinomas, NRAS mutation is extremely rare, which can underline the real thyroid origin of our case.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe optimal treatment of primary thyroid SCC is surgical excision with adjuvant radiotherapy and chemotherapy. However, many studies suggest that it is relatively radio-resistant and has poor response to chemotherapy, leaving complete surgical excision the only chance of prolonging survival of these patients. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] Nowadays immune-oncological therapies, like anti-PD1 and anti-PD-L1 therapy, are a very successful therapeutic options for head and neck squamous cell carcinomas. Booya et al. reviewed 10 cases on SCC n the thyroid and discussed that p21, MIB-I, and p53 are overexpressed in primary squamous cell carcinoma of the thyroid and may have relevance to early diagnosis of SCC in the patient. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] In our case PD-L1 expression was high both on tumor cells and on tumor infiltrating lymphocytes which predict good response to these drugs. Unfortunately the rapid progression of the disease prevented any further therapies. Patients with primary thyroid SCC have a very poor prognosis and the main cause of death is direct invasion or compression of the trachea. Cho et al. recently performed a systematic review and individual participant data meta-analysis regarding primary SCC of the thyroid gland. According to this meta-analysis (89 patients), the mean age of diagnosis was 63 years (range, 24\u0026ndash;90), a female preponderance (M : F\u0026thinsp;=\u0026thinsp;1:2) was noted and the commonest complaint was the anterior neck mass. It was noted that predictability of diagnosis with fine needle aspiration cytology was accurate in less than one-third of the patients and more than half of cases had been diagnosed as papillary thyroid carcinoma or were non-diagnostic. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] Complete surgical resection (Ro) of the tumor would be the only significant prognostic factor on multivariate analysis, and the benefit of adjuvant treatment was not proved. Moreover, the prognosis of these patients was very poor (only 20% of 3 year survival rate). [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSCC of the thyroid gland is a very rare and aggressive tumor with poor prognosis. Complete surgical resection (Ro) of the tumor is the only significant prognostic factor, whereas efficacy of adjuvant treatment (chemo- and radiotherapy) remains controversial in the international literature. A fatal outcome is usually a result of its complications, due to loco-regional spread of the disease to adjacent organs and structures.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003ePatient signed the inform consent that her history might be used for scientific purposes.Ethics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eAuthors gave permission\u0026nbsp; for publication\u003c/p\u003e\n\u003cp\u003eFunding- no fundings were given for this research\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions:\u003c/p\u003e\n\u003cp\u003eLB-manuscript writing, surgeon\u003c/p\u003e\n\u003cp\u003eKA-manuscript writing\u003c/p\u003e\n\u003cp\u003eOF-manuscript revision\u003c/p\u003e\n\u003cp\u003eTE- editing the pathological report\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSun BH, Yu ST, Ge JN, Lei ST. Primary squamous cell carcinoma (PSCC) of the thyroid: A case report and review of the literature. Gland Surg. 2020;9(2):474\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOthman RT, Baizeed AMA, Mohammed AA. Squamous cell carcinoma of the thyroid gland in an elderly female presenting as a rapidly enlarging thyroid mass. Int J Surg Case Rep. 2020;70:119\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaggio B, Barr J, Ghandour Z, Friedlander P. \u0026ldquo;Primary squamous cell carcinoma of the thyroid,\u0026rdquo; \u003cem\u003eOchsner J.\u003c/em\u003e, vol.\u0026nbsp;19, no. 3, pp.\u0026nbsp;290\u0026ndash;292, Sep. 2019.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang S, et al. Primary Squamous Cell Carcinoma in the Thyroid Gland: A Population-Based Analysis Using the SEER Database. World J Surg. May 2019;43(5):1249\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKallel S, Kallel R, Ayadi S, Ghorbel A. Primary squamous cell carcinoma of the thyroid associated with papillary thyroid carcinoma and Hashimoto\u0026rsquo;s thyroiditis. Eur Ann Otorhinolaryngol Head Neck Dis. Aug. 2018;135(4):291\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIbrahim M-I-S, Jusoh Y-R, Adam N-N, Mohamad I. Primary Squamous Cell Carcinoma of the Thyroid Gland. \u0026rdquo; Iran J Otorhinolaryngol. Jan. 2018;30(96):65\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWygoda A, Rutkowski T, Szcześniak-Kłusek B, Mrochem-Kwarciak J, Jędrzejewska M, Składowski K. Primary squamous-cell thyroid carcinoma - a successful treatment with five-year follow-up. \u0026rdquo; Endokrynol Pol. 2017;68(5):592\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStruller F, Senne M, Falch C, Kirschniak A, Konigsrainer A, Muller S. Primary squamous cell carcinoma of the thyroid: Case report and systematic review of the literature. Int J Surg Case Rep. 2017;37:36\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDel Rosario M, Dasanu C, Tsai H, Johnson R. \u0026ldquo;Primary squamous cell carcinoma of the thyroid with complete response to radical radiotherapy and concurrent cisplatin-based chemotherapy,\u0026rdquo; \u003cem\u003eBMJ Case Rep.\u003c/em\u003e, vol. 2017, 2017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAaron Hobbs G, Der CJ. Rossman. RAS isoforms and mutations in cancer at a glance. J Cell Sci. 2016;129:1287\u0026ndash;92. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1242/jcs.182873\u003c/span\u003e\u003cspan address=\"10.1242/jcs.182873\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShenoy VS, Rao RA, Kamath PM, Prasad V, Haseena S. Primary Squamous Cell Carcinoma of Thyroid \u0026ndash; A Rare Malignant Goitre. Indian J Surg Oncol. Dec. 2016;7(4):467\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLichiardopol C, Şurlin V, Foarfă MC, Ghiluşi MC, Bondari S. \u0026ldquo;Primary squamous cell carcinoma of the thyroid: a case report.,\u0026rdquo; \u003cem\u003eRom. J. Morphol. Embryol. = Rev. Roum. Morphol. Embryol.\u003c/em\u003e, vol.\u0026nbsp;57, no. 2 Suppl, pp.\u0026nbsp;831\u0026ndash;836, 2016.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBooya A, Sebo F, Kasperbauer TJ, Fatourechi JL. Primary squamous cell carcinoma of the thyroid: report of ten cases. Thyroid. 2006 Jan;16(1):89\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCho JK, Woo S, Park J, Kim M, Jeong H. Primary squamous cell carcinomas in the thyroid gland: an individual participant data meta-analysis. Cancer Med. Oct. 2014;3(5):1396\u0026ndash;403. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/cam4.287\u003c/span\u003e\u003cspan address=\"10.1002/cam4.287\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChavan RN, Chikkala B, Biswas C, Biswas S, Sarkar DK. \u0026ldquo;Primary Squamous Cell Carcinoma of Thyroid: A Rare Entity,\u0026rdquo; \u003cem\u003eCase Rep. Pathol.\u003c/em\u003e, vol. 2015, pp.\u0026nbsp;1\u0026ndash;3, 2015.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSapalidis K et al. \u0026ldquo;Primary squamous cell carcinoma of the thyroid gland,\u0026rdquo; \u003cem\u003eJ. Surg. Case Reports\u003c/em\u003e, vol. 2014, no. 12, pp. rju133\u0026ndash;rju133, Dec. 2014.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao J, Wang J, Wu D, Xiong J. \u0026ldquo;[Primary squamous cell carcinoma of thyroid: a case report].,\u0026rdquo; \u003cem\u003eZhonghua er bi yan hou tou jing wai ke za zhi = Chinese J. Otorhinolaryngol. head neck Surg.\u003c/em\u003e, vol.\u0026nbsp;49, no. 1, pp.\u0026nbsp;69\u0026ndash;70, Jan. 2014.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKleinhans H, Schmid KW, Verse T.\u0026ldquo;[Primary squamous cell carcinoma of the\u003c/span\u003e \u003cspan\u003ethyroid gland]., \u0026rdquo; \u003cem\u003eHNO\u003c/em\u003e, vol.\u0026nbsp;61, no. 7, pp.\u0026nbsp;661\u0026ndash;663, Jul. 2013.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"squamous cell carcinoma, thyroid gland","lastPublishedDoi":"10.21203/rs.3.rs-2654594/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2654594/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIntroduction\u003c/p\u003e\n\u003cp\u003ePrimary squamous cell carcinoma (SCC) of the thyroid gland is a very rare entity. The prognosis is very poor with a short survival time. The aim of this article is to report a case of a SCC of the thyroid gland in a 68-year-old woman, emphasizing how complicate is the operation and the adequate treatment of this disease.\u003c/p\u003e\n\u003cp\u003eCase report\u003c/p\u003e\n\u003cp\u003eA 68-year -old woman presented with rapidly growing neck mass with hoarseness and compressive symptoms. Physical examination revealed a hard fixed tumor with right sided vocal cord palsy. Histopathological result confirmed the diagnosis of SCC of the thyroid. PET/CT scan excluded the possibility of other primary malignancies. A surgical intervention was performed, however the patient died in the middle of the palliative radiation therapy.\u003c/p\u003e\n\u003cp\u003eConclusion\u003c/p\u003e\n\u003cp\u003eSCC of the thyroid gland is a great challenge for the surgeon and also for the multidisciplinary team to come up with the best treatment option which is suitable for the patient due to its unfavorable prognosis.\u003c/p\u003e","manuscriptTitle":"Primary squamous cell carcinoma of the thyroid -case report of a rare disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-03-14 14:20:09","doi":"10.21203/rs.3.rs-2654594/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"acffc16b-0300-488c-9a0b-7367d5bea69c","owner":[],"postedDate":"March 14th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-03-19T22:59:18+00:00","versionOfRecord":[],"versionCreatedAt":"2023-03-14 14:20:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2654594","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2654594","identity":"rs-2654594","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}