Ear, Nose & Throat Journal2023, Vol. 102(9) 584–589© The Author(s) 2022Article reuse guidelines:sagepub.com/journals-permissionsDOI: 10.1177/01455613221141225journals.sagepub.com/home/ear
Objective: Intrathyroidal thymic carcinoma (ITC) is a rare low-grade malignant thyroid tumor. There is neither sufficient understanding of this tumor nor its clinical treatment. This study is to explore the clinicopathological features, treatment, and prognosis of ITC and thereby provide a reference for the diagnosis and treatment of the disease. Methods: The clinical, pathological, therapeutic, and prognostic data of 13 patients with ITC were retrospectively analyzed. Results: The case series comprised 7 males and 6 females, with an average age of 51.9 ± 10.1 years. After surgical resection, all patients received postoperative neck radiotherapy at dosages of 60–66 Gy. Five patients with level VI lymph node metastasis additionally received 6 courses of cisplatin chemotherapy. All patients were followed-up for 21–132 months (median = 66 months), and all of them survived without recurrence or metastasis. Conclusions: The diagnosis of ITC depends mainly on pathological and immunohistochemical results, particularly CD5 positive staining. Surgical resection is the preferred primary treatment modality which can be supplemented with radiotherapy and chemotherapy to reduce the risk of recurrence and metastasis.
Keywordsintrathyroidal thymic carcinoma, CD5, surgery, radiotherapy, chemotherapy
Intrathyroidal thymic carcinoma (ITC), also known as thyroid carcinoma showing thymus-like differentiation, intrathyroidal epithelial thymoma (ITET) or primary thyroid thymoma, is a rare low-grade malignant thyroid tumor. It is part of the thymic carcinoma family and accounts for 0.083% to 0.15% of primary malignant thyroid tumors.1,2 Currently, there are less than 100 case reports on the disease. In 2004, the World Health Organization classified ITC as an independent pathological type of thyroid malignancy. ITC can be easily confused with primary thyroid squamous cell carcinoma, spindle cell tumor with thymus-like differentiation, or anaplastic thyroid carcinoma. Due to its rarity, there is neither sufficient understanding of the ITC tumor nor consensus on clinical treatment plans. In this study, the clinical, pathological, therapeutic, and prognostic data of 13 patients with ITC, admitted between January 2009 and December 2021, were retrospectively analyzed to improve the understanding of ITC and provide a reference for diagnosis and treatment of the disease.
A total of 13 Chinese ITC patients were treated in the Department of Otorhinolaryngology-Head & Neck Surgery, Hanzhong Central Hospital, Hanzhong, Shaanxi, China, between January 2009 and December 2021. All patients underwent surgical treatment and the surgical specimens were independently reviewed by 2 experienced pathologists to confirm the diagnosis using hematoxylin and eosin (H&E)-stained sections and immunohistochemical examinations. Clinical characteristics, imaging findings of B-mode ultrasound and computed tomography (CT), pathological features, treatment methods, and prognosis were analyzed. This retrospective study was approved by the ethics committee of Hanzhong Central Hospital. The patient informed consent was waived because this is a retrospective study.
Pathological specimens were fixed with 4% neutral formaldehyde, routinely dehydrated, embedded in paraffin, sectioned, stained with H&E, and observed by microscopy. Subsequently, immunohistochemistry was performed using the streptavidin-perosidase method, and the antibodies included leukocyte differentiation antigen 5 (CD5), CD117, and thyroid transcription factor-1 (TTF-1). All procedures were carried out strictly according to instructions (Fuzhou Maixin Biotechnology Development Co., Ltd, Fuzhou, China).
The surgical procedure was determined by the size of the tumor. Ipsilateral thyroid lobe and isthmus resection + ipsilateral VI lymph node dissection were performed for tumors with diameters ≤ 4 cm, while total thyroidectomy + bilateral VI lymph node dissection was performed for tumors with diameters > 4 cm.
Radiotherapy. Commencing on the third week after surgery, radiotherapy was administered to the thyroid and the bilateral cervical lymph node drainage area at a fractionation of 60 Gy/30 Fx.
Chemotherapy. Patients with central lymph node metastasis were given cisplatin (30 mg/day for three days) every two weeks for a total of 6 courses.
Drug Therapy. After surgery, patients were given 12.5–25μg/d of levothyroxine tablets orally on an empty stomach in the morning, with the dose adjusted according to the patient’s thyroid function.
Patients were undergone thyroid ultrasound examination and thyroid function review every 3 months, for a year after the surgery. Subsequently, the frequency of the follow-ups was reduced to once per year and included a thyroid ultrasound, a thyroid function review, and a chest CT.
The clinical characteristics of the patients are listed in Table 1. Of the 13 patients, 7 were men and 6 were women. The patients’ age ranged from 39 to 72 years with a mean (± SD) age of 51.9 ± 10.1 years. While most patients (12/13) presented with a slow-growing painless neck mass, only one patient presented with hoarseness since 20 days. None of the patients presented with dyspnea or dysphagia. Blood investigations revealed that thyroid hormones, thyrotropin, thyroid peroxidase antibodies, antithyroglobulin antibodies, and thyroglobulin were within normal limits in all the patients.
B-mode Ultrasound Results. The tumor manifested as a solid mass with blurred margins, low echoes, and an irregular shape. No calcification was observed, but blood flow signals were seen both in and around the tumor.
CT Results. Soft-tissue density masses with unclear margins and no calcification were consistently observed in all patients’ CT images. The images of the one patient with hoarseness showed a hypodense mass shadow on the right lobe of the thyroid, with unclear margins, causing surrounding structures to be compressed and displaced and the trachea to be compressed and flattened.
Gross Examination. The tumors showed a solid nodular or lobulated form, a gray-white section, a clear boundary with the surrounding area, and a hard texture.
Microscopic Results. Under low-magnification microscopy, the tumor appeared to have infiltrated the thyroid tissue in nodular or lobulated form (Figure 1A). The margins were smooth and partly resembled the lobulated structure of thymic carcinoma. In addition, the tumor tissue could be clearly distinguished from the surrounding normal thyroid tissue. Under highmagnification microscopy, the tumor cells were relatively large and had a polygonal shape (Figure 1B). The cytoplasm was mildly eosinophilic, the nucleus was vesicular and had an oval shape, and heteromorphism was not obvious.
Immunohistochemistry. All the specimens (13/13, 100%) expressed the CD5 marker and eleven (11/13, 84.6%) specimens expressed the CD117 marker (Figure 2). TTF-1 and Congo red staining results were negative.
Eleven patients, whose tumor diameters were ≤ 4 cm, underwent ipsilateral thyroid lobe and isthmus resection + ipsilateral VI lymph node dissection. The 2 patients whose tumor diameters were > 4 cm underwent total thyroidectomy + bilateral VI lymph node dissection. Radiotherapy was then administered in the third week, after surgery, at a dose of 60 Gy/30 Fx for the 8 patients without lymph node metastasis, and 66 Gy/33 Fx for the 5 patients with central lymph node metastasis. The 5 patients with lymph node metastasis were additionally treated with 6 courses of cisplatin chemotherapy. All 13 patients received orally administered levothyroxine tablets after surgery.
All patients were followed-up for 21–132 months with a median of 66 months (Table 1). During the follow-up period, the results of the patients’ thyroid ultrasound, thyroid function, and chest CT were within the normal range, and no patient developed recurrence or metastasis.
Intrathyroidal thymic carcinoma is a rare type of thyroid tumor. First reported by Miyauchi and colleagues in 1985, it was initially described as intrathyroidal epithelial thymoma to distinguish it from primary squamous cell carcinoma of the thyroid.3 In 1991, Chan et al. named the tumor as thyroid carcinoma showing thymus-like differentiation.4 Since both the thyroid gland and the thymus originate from the branchial sac, most scholars believe that ITC may originate from an ectopic thymus or remnant tissues of the branchial sac that have retained the potential to differentiate into thymic tissue.4
Intrathyroidal thymic carcinoma usually occurs in middleaged adults, with an average age of onset of 48 years and a male to female ratio of 1:1.3.5 The average age of the patients in our study was 51.9 years, at the time of diagnosis. The number of male and female patients was almost equal. No significant sex difference was observed in this study because of the small sample size.
Intrathyroidal thymic carcinoma occurs predominantly in the lower lobe of the thyroid,6 manifesting as a painless, slowgrowing neck mass in most patients, although some patients may also experience hoarseness, mainly due to recurrent laryngeal nerve palsy.7,8 Most patients with ITC present with normal thyroid function as the thyroid gland is not affected by the disease.9 Of the 13 patients in our study, the tumor was located in the lower lobe of the thyroid gland in 8 cases. 12 patients were asymptomatic, and all the patients had normal thyroid function, which is consistent with the literature.
Intrathyroidal thymic carcinoma lacks typical clinical manifestations. B-mode ultrasound often shows a hypoechoic, non-calcified solid mass with moderate blood flow distribution. Plain CT scans often show an ill-defined soft-tissue density shadow without calcification. Since the diagnostic efficacy of pre-operative fine needle aspiration biopsy is limited.10 It is difficult to diagnose ITC before surgery. Therefore, pathological evidence, particularly immunohistochemistry, is essential to confirm the diagnosis and differentiation of the disease. ITC can express CD5, CD117, carcinoembryonic antigen (CEA), high molecular weight cytokeratin (CK), epithelial membrane antigen, and p63, but not TTF-1 nor thyroglobulin. Reimann et al. believed that the expression of CK, CEA, and p63 in ITC was evidence of its thymic origin.11 Ito et al. found that the sensitivity and specificity of CD5 in the diagnosis of ITC were 82% and 100%, respectively.12 In addition, CD5 positivity is a key feature that distinguishes ITC from anaplastic thyroid carcinoma, medullary carcinoma, primary thyroid squamous cell carcinoma, and other thyroid carcinomas.13 However, it should be noted that ITC cannot be completely ruled out by a negative CD5 result and the final diagnosis should integrate all the pathological results. In this study, the CD5 positivity rate of the 13 patients was 100%, which, when combined with pathological changes, confirmed the diagnosis of ITC.
Studies on ITC with large sample sizes to derive a definitive treatment modality remain limited. Currently, surgical resection is the preferred treatment method.14 Therefore, all 13 patients in this study underwent surgery. Patients whose tumor diameters were ≤ 4cmunderwent ipsilateral thyroid lobe and isthmus resection + ipsilateral VI lymph node dissection, while patients with tumor diameters > 4 cm underwent total thyroidectomy + bilateral VI lymph node dissection.
Intrathyroidal thymic carcinoma frequently invades adjacent tissues and regional lymph nodes. Ito et al. reported that the risk of the tumor spreading to adjacent tissues and the metastasis rate of regional lymph nodes were 60% and 50%, respectively, and there was the risk of distant metastasis and death in some patients.12 The tumor invaded the recurrent laryngeal nerve in 7.7% (1/13) of the patients, and 38.5% (5/13) of the patients had central lymph node metastasis, in the present study. Most scholars believe that post-operative radiotherapy has an obvious effect on patients with local lymph node metastasis and can reduce the risk of recurrence.7 Ito et al. reported that the 10 ITC patients (including 9 patients with extrathyroidal invasion) who received post-operative radiotherapy did not experience recurrence. In contrast, cancer recurred in 3 of the 12 patients who did not receive radiotherapy, in another study.12 However, in their review of the data of 82 ITC patients, Ge et al. suggested that postoperative radiotherapy failed to reduce the risk of local recurrence.5 Contrastingly, our study showed that all the patients who received post-operative radiotherapy (with a total dose of at least 60 Gy), had no recurrence of cancer for 11 years. This result infers that an adequate dose of radiotherapy may help prevent ITC recurrence.
Ito et al. reported that the 5-year and 10-year survival rates of ITC patients were 100% for patients without lymph node metastasis, 76% and 57% with lymph node metastasis, and 92% and 79% with peripheral tissue infiltration, respectively.12 This indicated that the lymph node metastasis and surrounding tissue involvement were prognostic factors. In this study, 5 patients had lymph node metastasis and received chemotherapy in addition to surgery and radiotherapy. This is because ITC is a chemosensitive tumor and has been reported to respond better to chemotherapeutic drugs such as cisplatin, doxorubicin, vincristine, and cyclophosphamide, carboplatin, and paclitaxel.15 Based on the patient’s condition, treatment compliance, and drug side effects, the 5 patients with central lymph node metastasis underwent additional cisplatin chemotherapy in our study. After chemotherapy, these 5 patients were followed-up for 132, 84, 66, 61, and 38 months, respectively, during which no patient developed recurrence or metastasis. These findings suggest that chemoradiotherapy may help improve the survival rate, although further confirmation with a larger sample size is needed.
Our study revealed that the surgical resection of the tumor followed by and chemotherapy and/or radiotherapy provided a better prognosis in patients with thyroid ITC. However, this study was limited by a small sample size, attributable to the rarity of ITC, and the divided opinions on chemotherapy and chemotherapy drugs. Thus, our findings should be considered with caution, and further research on this topic is needed.
In conclusion, the clinical and imaging manifestations of ITC lack specificity. Therefore, diagnosis of the disease relies mainly on pathological examination, particularly CD5 positive staining in immunohistochemistry. Once confirmed, surgery is the preferred treatment option, while post-operative adjuvant radiotherapy and chemotherapy can effectively prevent recurrence and metastasis.
We are indebted to Dr. Yan Yan and Dr. Zeng Rong from the Chinese Academy of Medical Sciences–Peking Union Medical College for their advice for this study.
Jinhui Liang: Investigation, data curation, formal analysis, and original draft writing. Mei Huang: Investigation, methodology, and data curation. Helang Huang: Investigation, data curation, and formal analysis. Li Li: Investigation and data curation. Hailin Luo: Investigation and data curation. Weidong Mao: Investigation and data curation. Shan Gao: Conceptualization, investigation, draft editing, and supervision. Haoxiang Xu: Conceptualization, draft editing, and project administration.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the research program of geriatric health of Jiangsu Province (number LK2021024).
This study was approved by the ethics committee of Hanzhong Central Hospital, Hanzhong, Shaanxi Province, China.
Because this is a retrospective study the informed consent was not applicable.
The authors confirm that the data supporting the findings of this study are available within the article.
Haoxiang Xu https://orcid.org/0000-0002-5047-5341
1 Department of Otorhinolaryngology and Head & Neck Surgery, Hanzhong Central Hospital, Hanzhong, China
2 Department of Pathology, Hanzhong Central Hospital, Hanzhong, China
3 Department of Radiotherapy, Hanzhong Central Hospital, Hanzhong, China
4 Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
5 Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, China
Received: October 4, 2022; revised: October 31, 2022; accepted: November 7, 2022
Corresponding Authors:Shan Gao, Department of Radiotherapy, Hanzhong Central Hospital, No. 557 St. Lao-Dong-Xi-Lu, Hantai district, Hanzhong 723000, Shaanxi, China.Email: 249402842@qq.com
Haoxiang Xu, Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, China; Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Chinese Academy of Medical Science & Peking Union Medical College, No. 12 Jiangwangmiao Street, Xuanwu District, Nanjing 210042, Jiangsu, China.Email: xbpipi@163.com
