Primary Extra-Osseous Ewing Sarcoma of the Thyroid: A Case Report and Review of the Literature

Thyroid cancers encompass a wide range of tumors, from indolent cases with low mortality to extremely aggressive malignancies with short overall survival. Proper diagnostic work-up and classification are crucial to tailor patient treatment. Well-differentiated thyroid carcinoma such as papillary, follicular and Hürthle cell carcinoma account for more than 95% of all cases, while other subtypes are less frequently seen [1]. Mesenchymal thyroid neoplasms are exceedingly rare among which Ewing sarcoma (ES) represents only 2% [2]. ES is a member of the so-called “small round blue cell” tumors, most commonly arising in bone and most frequently found in children and adolescents. Extra-osseous Ewing sarcoma (EES) is less frequent and can occur at a wide variety of anatomic [3]. Several recent reports have described an adamantinoma-like Ewing sarcoma (ALES) arising in the thyroid gland, based on the identification of EWSR1 rearrangement in neoplasms showing the classic ES morphology with epithelial differentiation (keratin and p63 or p40 expression) [4‐8], and carcinoma of the thyroid with Ewing family tumor elements (CEFTEs) when associated with papillary thyroid carcinoma [9‐12]. Here we present the case of a patient diagnosed with EES located in the left thyroid lobe and a review of the current literature.

Primary ES family tumors tend to occur most commonly in bone, primarily in adolescents and young adults, and is characterized by chromosomal rearrangements involving the EWSR1 gene [3]. More recently EES termed ALES has been increasingly recognized in the head and neck region including salivary gland and thyroid [13], and also carcinoma of the thyroid with CEFTEs [9]. Although ES can express epithelial markers such as pankeratin [14], p63 and/or p40 were reported only in ALES [13]. In our case, the absence of p40 and p63 expression and the lack of papillary thyroid carcinoma foci associated with the tumor support the classification of EES over ALES or CEFTE.

The pre-operative FNA diagnosis remains challenging (Table 1). As reported by Kabata et al. [15], a correct FNA diagnosis was not achieved in any case. More recently one report [16] describes a successful interpretation by FNA. It is interesting to note that the few cases that were able to correctly diagnose the tumor were done in association with a core needle biopsy [15, 16] or excision biopsy [4] (Table 1).

As in our case, a potential pitfall in the interpretation of cytological specimens is the diffuse expression of keratin, which may lead to the misclassification of the cancer as PDTC. This is especially true when entrapped benign, TTF-1 positive thyrocytes are present in the FNA sample as encountered in our case, and similarly as described by Chikeka et al. [17], or when p40 or p63 are only expressed focally [6, 8], or are absent.

The differential diagnosis encompasses a broad range of neoplasms including metastatic basaloid squamous cell carcinoma, which expresses keratin, p63 and p40, and medullary thyroid carcinoma which can be confirmed by testing for calcitonin and CEA expression. In the setting of a calcitonin-negative tumor, other neuroendocrine entities of the thyroid gland including intrathyroidal paraganglioma should be considered. Intrathyroidal thymic carcinoma based on the immunohistochemical profile (positivity for keratin, EMA and CD117) should also be excluded.

Given the high-grade nature of the tumor and unusual immunoprofile and histomorphology, a thyroid gland metastasis should also be considered. In our case, a metastasis from the patient’s known breast cancer was excluded using immunohistochemical markers for GATA-3, mammaglobin, and BRST2. This clinical presentation of EES is reminiscent of the case reported by Maldi et al. [6].

ES is an aggressive disease with a 70% overall 5-year relative survival rate [3]. However, the difference in prognosis between EES and ES is still controversial. A report from the Children’s Oncology Group analyzing a cohort of two clinical trials including 213 extraskeletal ES and 826 skeletal ES showed that EES were associated with a slightly better event-free survival [18]. In contrast, Lynch et al. [19] did not find any impact on survival in the adult population. Most patients with thyroid involvement presented with angio-lymphatic invasion and a small subset with lymph node metastasis (Table 1). The majority of patients received adjuvant chemotherapy and all showed no evidence of disease in the clinical follow-up except for one patient [20]. However, it is important to emphasize that the clinical follow-up for most patients was limited, and therefore any conclusions about the long term patient prognosis is uncertain.

In conclusion, correct pre-operative diagnosis of extra-osseous ES remains challenging. Pathologists, including those specializing in cytopathology, should be aware that ES should be considered in the differential diagnosis of poorly differentiated tumors of the thyroid, including those with diffuse keratin expression and focal expression of p40/p63. For such cases, CD99 and NKX2.2 immunostaining or molecular analysis with NGS or FISH can be helpful to properly classify the tumor which is of crucial importance for proper patient management.