Sclerosing mucoepidermoid carcinoma of the thyroid with eosinophilia: a case report and review of the literature

Abstract

Background

Sclerosing mucoepidermoid carcinoma of the thyroid with eosinophilia (SMECE) is a rare thyroid tumor. More and more reports have proposed that sclerosing mucoepidermoid carcinoma of the thyroid with eosinophilia is significantly invasive, but its origin and pathogenesis are currently controversial.

Case presentation

We presented a 42-year-old female of Han ethnicity. She had a 4-year history of thyroid nodules, and mild decrease in thyroid function was observed at the time of surgery. Subsequently, pathological examination revealed typical morphological characteristics of sclerosing mucoepidermoid carcinoma of the thyroid with eosinophilia. Compared with surrounding normal thyroid tissues, significant eosinophil infiltration was observed in the tumor stroma. Negative thyroglobulin immunohistochemical staining and uniquely positive expression of tumor protein p63 and cytokeratin 5/6 were detected in tumor cells. No genetic mutation was detected by next-generation sequencing. No extrathyroid invasion, lymph node metastasis, or distant metastasis was found. The patient was alive without evidence of disease after 24 months of follow-up.

Conclusions

The case presentation supported this point that sclerosing mucoepidermoid carcinoma of the thyroid with eosinophilia originated from solid cell nests, and eosinophils might play an important role in the tumorigenesis and development of sclerosing mucoepidermoid carcinoma of the thyroid with eosinophilia. In addition, a comprehensive analysis of the previously reported cases from reported literature revealed that age and distant metastasis might be the risk factors affecting prognosis.

Graphical Abstract

Background

Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is a rare thyroid tumor displaying epidermoid and glandular differentiation and a sclerotic stroma with eosinophilic and lymphocytic infiltration [1, 2]. SMECE tends to occur in adult females and has been often accompanied by Hashimoto’s thyroiditis (HT) [1, 2].

Currently, the following controversies exist in relevant reports about SMECE: First, the earliest literature reported that SMECE originated from the squamous differentiation of thyroid follicular epithelium [3]. However, the subsequent case reports suggested that this tumor originated from a solid cell nest [4, 5]. Shah et al. indicated that the lack of molecular changes in thyroid tumors indirectly provided further support for the solid cell nest phenotype of these tumors [2]. Second, some literature suggested that the tumor was of a low grade [3, 6], while others proposed that the tumor exhibited aggressive behavior [5, 7]. Third, Sukumar et al. demonstrated that V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations and the RAS–RAF–MAPK kinase (MEK)–extracellular signal-related kinase (ERK) signaling pathway were involved in the pathogenesis of SMECE in two cases [8], while others did not detect BRAF mutations in SMECE [9, 10]. However, the pathogenesis of SMECE is still unknown.

Here, we will fully demonstrate the molecular characteristics of a case of SMECE tested using existing technology. By summarizing previously reported cases, we have explored relevant clinicopathological and molecular parameters that might affect the prognosis of SMECE, and the possible pathogenesis of SMECE has been analyzed.

Case presentation

The patient was a 42-year-old female, who was of Han ethnicity, with a known history of thyroid nodules discovered during physical examination in 2018. During this period, she reported occasional hoarseness, hyperhidrosis, occasional palpitation, and difficulty swallowing. She also stated that she had no choking when drinking water, and did not complain of convulsions or breathing difficulties. Physical examination showed that the thyroid was bilaterally symmetrical, and no swelling, tenderness, tremor, or palpable nodules were found. In December 2022, the follow-up examination by ultrasound revealed that the echo of the thyroid parenchyma was uneven, and a weak echo nodule with a size of about 1.2 cm × 1.1 cm × 1.0 cm was observed in the lower left part of the thyroid, with unclear boundaries and irregular shape. The patient had undergone ultrasound-guided thyroid biopsy in her local hospital, and the results indicated papillary carcinoma in the left lobe of the thyroid.

The patient was admitted to West China Hospital of Sichuan University for surgical treatment in January 2023. The patient’s clinical symptoms were the same as described above. Laboratory examinations showed that the patient had a slight increase in thyroid-stimulating hormone (TSH; 4.51 mIU/L), a slight decrease in serum free triiodothyronine (FT3; 3.56 pmol/L), an increase in anti-thyroid peroxidase antibodies (229 IU/ml), and normal anti-thyroglobulin antibodies. No increase in carcinoembryonic antigen (CEA) was observed. Left lobectomy and isthmus thyroidectomy were performed, and lymph node dissection was carried out during the operation.

Postoperative pathological examination revealed a clear boundary between the tumor tissue and the surrounding thyroid with a fibrous tissue-like capsule. Numerous lymphocytes, plasma cells, and eosinophils could be observed in the tumor tissue, with eosinophils being prominent. The tumor cells exhibited pronounced atypia, displaying distinct squamous epithelial-like differentiation, with keratinized beads formed in certain regions. Tumor stroma was hyperplastic and accompanied by obvious fibrosis, causing tumor cells to be distributed into nests, and mucus protein could be found. Ovoid nuclei of varying sizes could be observed, with vacuolar chromatin and obvious nucleoli, and occasionally, nuclear grooves could be found; the mitotic figures are 0–1/10 high-power field (HPF). The surrounding normal thyroid tissue showed obvious lymphocyte and plasma cell infiltration and the formation of lymphoid follicles, showing lymphocytic thyroiditis-like changes (Fig. 1). No tumor metastasis was found in the cervical lymph nodes.

Fig. 1

Histological features and immunohistochemical results of sclerosing mucoepidermoid carcinoma of the thyroid with eosinophilia tumor tissue, including TG, paired box 88, thyroid transcription factor-1, cytokeratin 7, p63, cytokeratin 5/6, were compared with those of the surrounding non-neoplastic thyroid tissue (the magnification under the low-power microscope is 5×, while that under the high-power microscope is 100×)

Immunohistochemical results showed that the tumor cells harbored negative expression of TG and partial expression for paired box 8 (PAX8), and positive staining results were observed in thyroid transcription factor-1 (TTF-1), cytokeratin 7 (CK7), tumor protein p63, and cytokeratin 5/6 (CK5/6). Meanwhile, peripheral thyroid tissues exhibited positive expression of TG and CK7 and partially positive expression of PAX8 and TTF-1, and negative immunostaining results were found in p63 and CK5/6 (Fig. 1). Fluorescence in situ hybridization detection of mastermind-like transcriptional co-activator 2 (MAML2) rearrangement showed negative results. Next-generation sequencing (NGS) showed negative results for MAML2 rearrangement, mesenchymal-to-epithelial transition factor (MET) amplification, BRAF V600E mutation, NUT midline carcinoma family member 1 (NUTM1) rearrangement, and neurotrophic receptor tyrosine kinase 1 (NTRK1) or neurotrophic receptor tyrosine kinase 3 (NTRK3) mutation (Fig. 2; Supplemental Fig. 1; Supplemental Table 1; the full name of the abbreviations are shown in Supplemental Table 2).

Fig. 2

Molecular features of the sclerosing mucoepidermoid carcinoma of the thyroid with eosinophilia. The mastermind-like transcriptional co-activator 2 fluorescence in situ hybridization test indicated a negative result (a). Next-generation sequencing showed the negative results of mastermind-like transcriptional co-activator 2 rearrangement (MAML2) (b), mesenchymal-to-epithelial transition factor (MET) amplification (c), V-Raf murine sarcoma viral oncogene homolog B1 V600E (BRAF V600E) mutation (d), and NUT midline carcinoma family member 1 (NUTM1) rearrangement (e)

The patient received no other treatment after surgery, and no recurrence or metastasis was observed after 24 months of follow-up.

Discussion and conclusions

In summary, SMECE is a rare thyroid tumor that mostly occurs in females, and patients often harbor HT. We have summarized previously reported SMECE cases, and 73 SMECE cases have been reported. Of these cases, 89% (65/73) were in female patients, with a mean age of 55.6 years (range 26–89 years). The tumor size ranged from 0.5 cm to 13 cm (mean 4.3 cm). The tumor has a tendency to occur in the right lobe of the thyroid gland (33/61, 54.1%). The development of SMECE is often accompanied by the appearance of HT (52/55, 94.5%), and a small number of cases (7/55, 12.7%) are complicated with papillary thyroid cancer (Supplemental Table 3). SMECE was generally typical in morphology, presenting as squamous/epidermal-like cell nests, mucous secreting cells forming glandular or tubular structures, and infiltration of eosinophils, lymphocytes, and plasma cells. Dense fibrous stroma divided the tumor cell nests into string-like or tubular structures. The tumor would not express TG, but positive expression of p63 and CK5/6 could often be detected. The long-term survival of the patients with SMECE was usually optimistic. In terms of prognosis, the previous literature were all case reports.

The influence of clinicopathological and molecular factors on patient’s prognosis were analyzed on the basis of logistic and Cox regression analysis (Tables 1, 2; Supplemental methods). The results showed that larger tumor size (odds ratio [OR], 1.499; 95% confidence interval [CI] 1.082–2.077; p = 0.015), right/entire thyroid lobe location (OR, 3.806; 95% CI 1.194–12.129; p = 0.024), extrathyroid invasion of the tumor (OR, 14.295; 95% CI 3.426–59.643; p < 0.001) and positive TTF-1 immunostaining (OR, 16.530; 95% CI 1.019–268.179; p = 0.048) were risk factors for lymph node metastasis, after adjusting for baseline parameters of age and sex. And larger tumor size (OR, 1.639; 95% CI 1.092–2.460; p = 0.017) was associated with distant metastasis. Older age (hazard ratio [HR], 1.072; 95% CI 1.014–1.134; p = 0.015), larger tumor size (HR, 1.858; 95% CI 1.160–2.976; p = 0.010), lymph node metastasis (HR, 12.022; 95% CI 1.402–103.116; p = 0.023), and distant metastasis (HR, 9.749; 95% CI 1.627–58.410; p = 0.013) could predict a poor prognosis. Overall, we emphasized that older age, larger tumor size, extrathyroid extension, lymph node metastasis, and distant metastasis might be the risk factors that affect prognosis, and positive TTF-1 immunohistochemical staining was associated with lymph node metastasis. But few cases with detailed prognostic information have been reported so far; thus, more in-depth studies are expected to illustrate the association between TTF-1 expression and prognosis in SMECE.

Table 1 Logistic proportional hazard models analysis of the clinical and molecular parameters on lymph node invasion and distant metastasis

Table 2 Cox analysis of the clinical and molecular parameters on patients’ prognosis

Regarding the origin of SMECE tumor, we compared the tumor tissue with the surrounding normal thyroid with immunohistochemical staining in this case analysis. The results showed that SMECE tumor tissue exhibited negative TG expression, and prominently positive staining of p63 and CK5/6. Previous cases showed consistent results in that most cases exhibited negative TG immunostaining (61/63, 96.8%), but almost all patients harbored positive p63 expression (32/33, 97%), and all patients exhibited positive cytokeratin staining (42/42, 100%) (Supplemental Table 3). Negative TG expression indicated that the mucus protein in the tumor cell nest did not belong to follicular epithelial-differentiated thyroglobulin, and positive p63 and CK5/6 expression suggested that this tumor originated from an epithelial-derived tumor with a solid cell nest [2].

The typical pathological feature of this case was that, unlike the surrounding non-tumor thyroid tissue, the tumor stroma was enriched in eosinophil infiltration. Previous reports had shown that eosinophil infiltration could regulate tumor progression by directly interacting with tumor cells or indirectly forming a tumor microenvironment. On the one hand, the signal transducer and activator of transcription (STAT) signaling pathways in eosinophils were reported to be involved in tumorigenesis [11]. Some studies had shown that eosinophil-derived IL-12 and IL-10 could reduce the metastasis and migration of tumor cells by enhancing the expression of E-cadherin on tumor cells and its adhesion [12]. Eosinophils indirectly promoted antitumor immunity by releasing IFNγ [13]. On the other hand, some studies had shown that eosinophil-derived C-C motif chemokine ligand 22 (CCL22) promoted the migration of immunosuppressive regulatory T cells (Treg) into the tumor microenvironment [14]. Eosinophils could synthesize and release a large number of other growth factors, such as epidermal growth factor (EGF) and transforming growth factor β1 (TGFβ1), which induced tumor cell growth and epithelial-interstitial transformation, respectively [15]. In addition, eosinophils could induce matrix remodeling by secreting matrix metalloproteinases, including matrix metallopeptidase 2 (MMP2) and matrix metallopeptidase 9 (MMP9), which also contributed to metastasis implantation [14]. One study by Li et al. showed that eosinophils had increased in malignant pleural effusions in cancer patients with thoracic metastases. Mechanically speaking, eosinophils could promote tumor cell migration and metastasis by secreting the C–C motif chemokine ligand 6 (CCL6) [16]. No specific gene mutations were found in the tissues of either this case or previous SMECE cases, indicating that genetic pathway might not be the promoting factor for SMECE tumorigenesis. The prominent infiltration of eosinophils suggested that immune induction might be one of the important causes for the occurrence of SMECE.

SMECE often occurs with HT. Silva et al. found that the incidence of thyroid cancer in the HT group was significantly higher than that in the non-HT group in 9851 patients [17]. Likewise, a clinical study by Paparodis et al. found that HT increased the risk of differentiated thyroid cancer only in subjects with normal and partially reduced thyroid function, but did not increase the risk of thyroid cancer in HT with complete hypothyroidism [18]. Apart from this, one meta-analysis by Xu et al. emphasized that HT was a “double-edged sword” in patients with thyroid cancer, manifested in that HT was a risk factor for thyroid tumors (OR = 1.71; 95% CI 1.57–1.80; p < 0.00001), but the prevalence of extrathyroid extension, metastasis, BRAF V600E mutation, and recurrence in patients with papillary thyroid cancer and HT was significantly lower [19]. Of course, further research is needed to explore the correlation between HT and thyroid tumors and its possible mechanisms.

SMECE should be differentiated from the following diseases. Firstly, the morphology of SMECE is similar to well-differentiated mucoepidermoid carcinoma (MEC) and MEC could also express CK and p63, but most MECs will have chromosomal translocations to form MAML2 gene-related fusions [1, 10]. Second, diffuse sclerosing papillary thyroid carcinoma often shows a solid tumor nest or papillary structure, accompanied by squamous metaplasia, and extensive lymphocyte infiltration. The tumor can appear as diffuse and dense sclerosis, but this tumor often has a large number of gravel bodies, combined with anaplastic lymphoma kinase (ALK) or rearranged during transfection (RET) rearrangement, and BRAF mutation [1, 20]. Third, SMECE needs to be differentiated from squamous-cell carcinoma, but squamous-cell carcinoma would not express TTF-1 [1]. Fourth, undifferentiated carcinoma (squamous-cell-like, epithelial type) also requires differential diagnosis. This tumor was of follicular cell origin, could express PAX8 and TTF-1, and had a squamous cell morphology, but most of this tumor should have BRAF V600E mutation [21, 22].

This case report and the review of previous cases supported that SMECE originated from solid cell nests of epithelial cells, and that the presence of HT and eosinophil infiltration was closely related to the occurrence and development of SMECE. Of course, more evidence is desired about the pathogenesis of this tumor. Older age and distant metastasis might be the risk factors affecting prognosis.