Wei WANG ,Manmei LONG ,Zhichao WANG

ABSTRACT Ectopic hamartomatous thymoma is a rare,generally benign neoplasm that mainly arises in the lower neck region and is yet to be completely understood.Herein,we describe a case with two separate and sequential growing neoplasms for the first time,distinguished from other reported solitary cases.A 58-year-old Chinese male presented with a 6-month history of two nontender,self-palpated masses in the suprasternal region of his neck.Physical examination revealed two masses with diameters of 5 cm and 2 cm.Ultrasound examination 2 years ago revealed a hyperechoic mass with a fat-derived possibility.These two neoplasms were clinically diagnosed as lipomas without other radiological examinations and were completely excised.Microscopically,they were well circumscribed and characterized by admixture with spindle cells,epithelial nests,and adipocytes in variable amounts,without atypia or mitotic activity.Immunohistochemical staining revealed that both neoplasms showed a biphasic pattern,with an epithelial nature with strong and diffuse positive expression of cytokeratin (CK) and myoepithelial differentiation with CK5/6 and p63 positivity in the spindle cells.There was no evidence of recurrence after a 28-month follow-up period.In this report,we present a unique case of ectopic hamartomatous thymoma to show the existence of multiple tumors in this rare disease.We hope to raise the awareness of the possibility of this disease when the tumor rises in typical lower neck regions,especially when mixed soft tissue or fat components are shown by imaging examination.

KEY WORDS Ectopic hamartomatous thymoma;Suprasternal neoplasm;Biphasic pattern

INTRODUCTION

Ectopic hamartomatous thymoma (EHT) is a rare,generally benign tumor.The majority of EHTs exist in the lower neck,such as the suprasternal,supraclavicular,and sternoclavicular areas.They have a remarkable predominance in middle-aged men[1],which may be linked to high androgen receptor reactivity and stimulate tumor growth[2].Since the first case reported in 1982[3],there have been over 80 cases reported in the English literature.Most of them were benign tumors,except for 6 cases with malignancy components[2-3].To date,all these reported cases have grown solitarily.Herein,we present a case with two separate and sequential growing EHTs for the first time,distinguished from other reported EHT cases.

CASE PRESENTATION

A 58-year-old man presented to our clinic with a 6-month history of two nontender,self-palpated,and slowly enlarging masses in the suprasternal region of his neck.The patient denied hoarseness,emotional changes,nausea,vomiting,fever,or weight loss.He had a history of diabetes mellitus for more than 10 years.His vital signs were normal.Physical examination revealed two masses,5 cm and 2 cm in diameter.They were oval,soft,and smooth,causing no pain or pressure pain,and did not adhere to the surrounding tissues.There were no palpable cervical lymph nodes or axillary lymphadenopathy.In his health check in our hospital 2 years ago,an ultrasound examination revealed one hyperechoic mass with fatderived possibility but corresponding images were lost due to a long time.Owing to their benign nature,these two neoplasms were clinically diagnosed as lipomas without additional radiological examination and were excised completely.Two well-encapsulated masses,measuring 5.8 cm × 4 cm × 3 cm and 1.8 cm × 1.7 cm × 1.5 cm,were removed from the suprasternal space.The cut surfaces were slightly solid and grayish-yellow.Histopathological examination showed a mixture of～60% spindle cells,～40% adipose tissue,and a few scattered epithelial nests(Fig.1).There was no evidence of atypia or mitotic activity.Immunohistochemical staining (Fig.2) showed spindle cells were positive for CK,CK5/6,p63,CD10,CD34,and calponin and partially positive for epithelial membrane antigen (EMA) and smooth muscle actin(SMA);CK7 and CK18 were found partially positive in epithelial cells;S100 was positive only in adipose tissue;all components were negative for MSA.No evidence of EHT recurrence was noted after a 28-month follow-up period.Unfortunately,this patient had undergone a major gastrectomy six months previously because of gastric cancer.

Fig.1 Histological results. Histological results of H&E staining show that the section contains a mixture of spindle cells,epithelial nests,and mature adipose tissue with different powers.A:100×;B:200×;C:400×.Scale bars:100 μm.

Fig.2 Immunohistochemistry results of the case. Immunohistochemistry results show the section is strongly positive for CK signal(A) and CD10 (B),weakly positive for CK5/6 (C) and calponin (D),and partially positive for EMA (E) and SMA (F) in the spindle cells.The glands show CK,CK5/6,EMA,and SMA positivity in the basal cells.Scale bars:100 μm.

DISCUSSION

A summary of English literature reports on the clinicopathological features of EHTs is provided in Table 1,based on the review article of Sato et al.[1]and all other published cases.There are eight new updated cases[4-8],including the current case.Compared to the former review,similar results suggest a predominance in middleaged (mean,46.38) males (77.01%),with the supraclavicular (41.38%),suprasternal (25.29%),and sternoclavicular areas (20.69%) as the most common sites.The average tumor size was 4.66 cm,and the malignant rate was approximately 6.82%.

Table 1 Clinical and pathological summary of all the EHTs cases

NA:Not available.

Due to its rarity,controversy always exists regarding the origin and designation of EHT.In 1982,it was first described in the literature by Smith and McClure.They pointed out its histological composition and speculated it to be a type of thymolipoma[3].Rosai et al.assumed its origin to be from the abnormal development of the third branchial arch,which failed to migrate to the mediastinum.Because of its characterized predilection site and mixed components,they first designated it as“ectopic hamartomatous thymoma”[9].The name“EHT”is still used,although not accurately.New terminology for this neoplasm is under discussion,including branchial anlage mixed tumor[10],thymic anlage tumor[11],or biphenotypic branchioma[1].Biphenotypic branchioma,the term involved in the origin and histological features of this tumor,shows its advantages in nomenclature and deserves more promotion.

Histologically,sections are characterized by a mixture of spindle cells,epithelial nests,and mature adipocytes in different proportions determining the hardness of the tumor.Morphological changes have been reported,such as a large area of dilated duct-like or Hassall corpusclelike structures lined by squamous epithelium[11].Androgen receptors were stained in the nucleus of both the spindle cells and the epithelial components of the tumor,which may be related to the occurrence of EHT and explain the male predominance[2].Immunohistochemically,the tumor reveals an epithelial nature with strong and diffuse positive CK expression.The spindle cells also display myoepithelial differentiation with CK5/6,p63 positivity,and negative S100[1].Therefore,the tumor shows a biphasic pattern.Malignant components in EHT are extremely rare,and 5/6 of them are diagnosed as adenocarcinoma in six reported cases[1,4-5].HER2 overexpression can be a potential marker for the pathogenesis of malignant transformation[5].They can be excised completely without recurrence.

Diagnosis depends on both clinical and histological examinations.In our case,the long developmental period,no positive signs on physical examination,and ultrasound report — the well-defined oval hyperechoic mass in the anterior neck region,all gave a hypothesis of lipoma.This incorrect initial diagnosis was also described in other cases[7-8].The key to the correct diagnosis,in this case,was a histological examination.Microscopically,the typical histological composition of the tumor opposed the diagnosis of lipoma.The absence of expression of PAX8 in EHT can exclude the possibility of thymus-related neoplasms that share similar locations.In addition to tumors that occur in similar regions,mesenchymal tumors with biphasic patterns such as synovial sarcoma,which encompasses a high proportion of spindle cells,can also be mistaken for EHT.There would be more confusion when infiltrating the surrounding adipose tissue.However,features of synovial sarcoma,distinct atypia,mitotic figures,negative expression of CK5/6 in the spindle cells,and adenoid spaces formed by epithelial cells are all different from EHT.Pleomorphic adenomas should be considered when typical mixed components are observed.They have similar growth sites and gender predominance.The presentation of chondromyxoid matrix and cartilaginous tissue with PLAG1 rearrangement can help identify this disease[12].Dendritic fibromyxolipoma also shows mixed elements that can be distinct from EHT based on differences in immunohistochemical staining with strong immunoreactivity for CD34 and BCL2.

EHT is a benign tumor.Local mass resection is the recommended treatment method.There is no recurrence or metastasis after complete resection,even in malignant cases.However,follow-up should be closely performed.Two cases of EHT recurrence were reported due to incomplete resection,although no further tumor growth was observed after complete re-exclusion.

CONCLUSION

In conclusion,we have presented a special case of EHT,which is more reasonable to designate as biphenotypic branchioma.Although it is difficult to diagnose clinically due to its rarity and complexity,we hope to raise general surgeons’ awareness about the possibility of this disease when tumors arise in typical lower neck regions,especially when mixed soft tissue density is shown by imaging examination.

ETHICS DECLARATIONS

Ethics Approval and Consent to Participate

The need for ethics approval was waived as it is a case report.Written informed consent was obtained from the patient before enrollment in the study.

Consent for Publication

All the authors have consented to the publication of this article.

Competing Interests

The authors declare no conflicts of interest.The authors state that the views expressed in the article are their own and not the official position of the institution or funder.

AUTHOR’S CONTRIBUTIONS

W W was responsible for the clinical data and literature search and wrote the manuscript.MM L performed H&E staining and immunohistochemistry.ZC W contributed to the pathological diagnosis and revised the manuscript.All authors have read and approved the final version of the manuscript.