Thyroid sclerosing mucoepidermoid carcinoma with eosinophilia distinct from the salivary type

Abstract

We report three cases of thyroid sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE), which is an extremely rare variant of mucoepidermoid carcinoma (MEC). The aims of this report were to describe the clinicopathological findings, including results from immunohistochemical and fluorescence in situ hybridization analysis of thyroid SMECE, as well as to discuss the distinction between thyroid SMECE and its salivary counterpart. The cases included a 63-year-old female, a 44-year-old male, and a 66-year-old female, with all patients presenting with Hashimoto’s thyroiditis. Nodal metastasis was not found in any of the three cases. Neither regional recurrences nor distant metastases were found in any patient during the follow-up, which was 20 years, 3 years, and 18 months, respectively. Histologically, tumors were composed of epidermoid carcinoma cells, intermediate type carcinoma cells, and goblet cell-type mucus-secreting carcinoma cells, with all tumors displaying a sclerotic stroma with eosinophilic and lymphocytic infiltration. The formation of eosinophilic abscess in the tumor nests that might be a novel characteristic finding of SMECE was observed. Immunohistochemically, the carcinoma cells were positive for cytokeratin 34βE12, TTF-1, and PAX8, but negative for thyroglobulin. In two cases, increased IgG4-positive plasma cells were observed. Mastermind-like transcriptional coactivator 2 (MAML2), according to fluorescence in situ hybridization, was intact in all cases. In conclusion, thyroid SMECE has favorable outcomes and seems to be genetically different from salivary MEC. This is the first report to describe the presence of increased IgG4-positive plasma cells in the stroma of SMECE.

MUCOEPIDERMOID CARCINOMA (MEC) is composed of various combinations of epidermoid, intermediate, and mucous cells. These carcinomas mainly occur in the salivary glands [1], and have been rarely reported in other organs, such as the lung [2], esophagus [3], breast [4], pancreas [5], uterine cervix [6], and thyroid [7, 8]. Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is an extremely rare variant of MEC that displays a sclerotic stroma with eosinophilic and lymphocytic infiltration [9]. Interestingly, we more frequently encountered cases with a sclerotic variant in the thyroid, in the literature [10-19].

Thyroid SMECE invariably occurs in a background of Hashimoto’s thyroiditis [10] and may derive from squamous metaplasia or the ultimobranchial body [16]. The prognosis of this malignancy is favorable, although nodal metastases, extrathyroidal invasion, vascular invasion, and perineural invasion are common [12]. We encountered three patients with this rare sclerotic variant of MEC. The aims of this report were to describe the clinicopathological findings, including results from immunohistochemical and fluorescence in situ hybridization (FISH) analysis of thyroid SMECE, as well as to discuss the distinction between thyroid SMECE and its salivary counterpart.

Materials and Methods

The study protocol was reviewed and approved by the Institutional Review Board of Kuma Hospital (20170914-4). We reviewed 18,826 primary thyroid carcinoma cases resected in Kuma Hospital between 1993 and 2016, and subsequently found five cases (0.027%) with mucopidermoid carcinoma that included three cases (0.016%) with SMECE. SMECE was defined as malignant epithelial neoplasm showing epidermoid and glandular differentiation and displaying a sclerotic stroma with eosinophilic and lymphocytic infiltration. Histopathological features were assessed using hematoxylin eosin-stained sections from formalin-fixed, paraffin-embedded tissue. Representative tissue blocks were selected for immunohistochemical analysis. Immunohistochemical staining was performed using the automated Leica Bond-Max system and Bond Refine detection kit (Leica Microsystems, Wetzlar, Germany), according to the manufacturer’s recommendations. Primary antibodies used for the immunohistochemical staining are shown in Table 1. Ki-67 labeling index was estimated by counting at least 500 carcinoma cells. Clinical data were obtained from patient medical records at Kuma Hospital.

Table 1 Primary antibodies used in immunostaining and antigen retrieval methods

Antibody	Clone	Vendor	Location	Antigen retrieval	Dilution
Cytokeratin, HMW	34βE12	Dako	Glostrup, Denmark	Proteinase K	Ready-to-use
CEA	COL-1	Histofine	Tokyo, Japan	(–)	Ready-to-use
Thyroglobulin	polyclonal	Histofine	Tokyo, Japan	(–)	Ready-to-use
TTF-1	8G7G3/1	Dako	Carpinteria, CA, USA	Heat (pH 6)	1:100
PAX8	EPR13510	Abcam	Cambridge, UK	Heat (pH 9)	1:250
p63	4A4	Histofine	Tokyo, Japan	Heat (pH 9)	Ready-to-use
p53	DO7	Dako	Glostrup, Denmark	Heat (pH 9)	1:1,000
HER2	SV2-61γ	Histofine	Tokyo, Japan	Proteinase K	1:150
Ki-67	MIB-1	Dako	Glostrup, Denmark	Heat (pH 6)	1:200
Immunoglobulin G	A57H	Histofine	Tokyo, Japan	Proteinase K	Ready-to-use
Immunoglobulin G4	HP6025	Histofine	Tokyo, Japan	Proteinase K	Ready-to-use

HMW, high molecular weight; CEA, carcinoembryonic antigen; TTF-1, thyroid transcription factor-1

FISH analysis for a mastermind-like transcriptional coactivator 2 (MAML2) (11q21) gene translocation was performed using a ZytoLight^® SPEC MAML2 Dual Color Break Apart Probe (ZytoVision GmbH, Bremerhaven, Germany), according to manufacturer’s instructions. The break-apart MAML2 probe consisted of a spectrum orange–labeled proximal (centromeric) probe and a spectrum green–labeled distal (telomeric) probe. Slides were counterstained with 40,6-diamidino-2-phenylindole (DAPI; Abbott Molecular, Des Plaines, IL, USA) for nuclei counterstaining. One-hundred randomly selected, non-overlapping carcinoma cell nuclei were examined for the presence of yellow (normal) or green and orange (chromosomal break point) fluorescent signals with an Olympus fluorescence microscope (Olympus Life Science, Center Valley, PA, USA). The demonstration of MAML2 rearrangement was considered when more than 20% of the analyzed cells showed split green and orange signals.

Case Presentation (Table 2)

Case 1

The patient was a 63-year-old Japanese female with a mass on the left side of the neck, measuring 4.3 cm. Serum-free thyroxine (FT4) was normal (1.29 ng/dL), but thyroid-stimulating hormone (TSH) was elevated (8.45 μIU/mL). Ultrasound showed a hypoechoic lesion, with lymphoma being suspected (Fig. 1a). Fine needle aspiration cytology (FNAC) determined the neck mass to be a benign lymphoid lesion (Fig. 2a), but the preoperative clinical impression was intrathyroid thymic carcinoma with cystic formation, due to the mass being located at the lower pole of the thyroid. The patient subsequently underwent a left lobectomy with central neck dissection (CND). The pathological diagnosis of the resected mass was mucoepidermoid carcinoma with Hashimoto’s thyroiditis. Subsequently, external radiation therapy (60 Gy) was performed. Neither regional recurrences, nor distant metastases, were found during the 20-year follow-up period.

Fig. 1

Ultrasound findings of thyroid sclerosing mucoepidermoid carcinoma with eosinophilia. The lesions are hypoechoic and occupy most of one lobe. The lesions of case 2 (b) and 3 (c) were lobulated. (a, case 1; b, case 2; c. case 3)

Fig. 2

Fine-needle aspiration cytology findings of thyroid sclerosing mucoepidermoid carcinoma with eosinophilia. Case 1 (a) exhibits lymphocytes, but no carcinoma cells. Cases 2 (b) and 3 (c) show carcinoma cells in the background of lymphocytes and eosinophils (arrows).

Case 2

The patient was a 44-year-old Japanese female with a neck mass. Serum thyroglobulin, FT4, free triiodothyronine (FT3), TSH, and thyroglobulin antibody (TgAb) were 1.1 ng/mL, 0.84 ng/dL, 2.26 pg/mL, 1.08 μIU/mL, and 138.1 IU/mL, respectively. On ultrasound, the lobulated, hypoechoic nodule, measuring 59 × 26 × 38 mm, was found to be located in the right lobe of the thyroid (Fig. 1b). FNAC of the nodule revealed carcinoma cells, lymphocytes, and eosinophils (Fig. 2b), with SMECE or Langerhans cell histiocytosis being suspected. The patient underwent total thyroidectomy with CND. The resulting pathological diagnosis was SMECE, papillary microcarcinoma, and Hashimoto’s thyroiditis. Nodal metastasis was not found. Subsequently, no recurrence or distant metastasis has been noticed during 3 years of follow-up.

Case 3

The patient was a 66-year-old Japanese female with hypertension and hyperlipidemia. On ultrasound, a solid, hypoechoic, and lobulated nodule with focal cystic area, measuring 65 × 28 × 48 mm, occupied the right lobe and the isthmus of the thyroid (Fig. 1c). Serum thyroglobulin, FT4, FT3, and TSH were 0.24 ng/mL, 0.93 ng/dL, 2.96 pg/mL, and 2.37 μIU/mL, respectively. TgAb and thyroid peroxidase antibody (TPOAb) were elevated (200.9 IU/mL and 407 IU/mL, respectively). The nodule was diagnosed as papillary thyroid carcinoma with a squamous cell carcinoma component, based on FNAC findings that showed carcinoma cells associated with lymphocytes and eosinophils (Fig. 2c). The patient underwent a total thyroidectomy with a right modified neck dissection. The resulting pathological diagnosis was SMECE with Hashimoto’s thyroiditis. Nodal metastasis was not identified. Subsequently, no recurrence or distant metastasis has been noticed during 18 months of follow-up.

Pathological Findings

The analyzed tumors showed infiltrating growth against the surrounding thyroid tissue, with invasion into the perithyroidal connective tissue in cases 2 and 3. On the cut surface, they were whitish-tan in color, and cases 1 and 3 displayed large cystic components (Fig. 3).

Fig. 3

Cut surface of the resected thyroid. Lobulated and infiltrative whitish tumor with cystic area (★) is observed in the right lobe (Rt.), with the left lobe (Lt.) showing Hashimoto’s thyroiditis (case 3).

Microscopic findings of the carcinoma cells seen in cases 1 and 3 were similar. The tumors were composed of small round carcinoma cells showing alveolar, trabecular (Fig. 4a), anastomosing cord-like, tubular, and cystic (Fig. 4b) patterns. Carcinoma cells with squamous differentiation (epidermoid carcinoma cells) (Fig. 4c), carcinoma cells with clear cytoplasm and distinct cell membrane (intermediate type carcinoma cells) (Fig. 4c), and carcinoma cells with abundant mucin (goblet cell type mucus-secreting carcinoma cells) (Fig. 4d), were mixed in the nests. The carcinoma cells in case 2 were mainly large polygonal atypical cells with keratinization (Fig. 4e). They formed large nests including scattered cystic spaces and a small number of mucous secreting cells. All tumors had abundant stromal components associated with dense lymphoplasmacytic infiltration and lymph follicles. A large number of eosinophils were also observed in the stroma; eosinophils infiltrated into the tumor nests and occasionally revealed eosinophilic abscess (Fig. 4f). The carcinoma of case 1 was limited to the thyroid. Cases 2 and 3 showed extrathyroidal invasion. Nodal metastasis was not detected in any of the three reported patients. All cases were associated with Hashimoto’s thyroiditis. Fibrosis with “storiform” pattern and obliterative phlebitis were not observed.

Fig. 4

Microscopic findings of thyroid sclerosing mucoepidermoid carcinoma with eosinophilia. Trabecular and reticular pattern (a); cystic spaces containing proteinaceous materials (b); epidermoid carcinoma cells (c, e); intermediate type carcinoma cells (c); goblet cell-type, mucus-secreting carcinoma cells (d); hyalinized collagen tissue with dense lymphoplasmacytic and eosinophilic infiltration (a, c, e); and eosinophilic abscess within carcinoma cell nest (f) are observed. (HE stain: a, case 1, 100×; b, case 3, 40×; c, case 1, 200×; d, case 1, 400×; e, case 2, 200×; f, case 3, 200×)

Histochemical and Immunohistochemical Findings

Histochemical and immunohistochemical results were similar among the three cases. In Alcian blue stain, the cytoplasm of the goblet cell type carcinoma cells showed strong staining (Fig. 5a). Proteinaceous materials present in the cystic spaces were slightly positive or negative for the staining. Mucous secreting cells scattered within epidermoid nests were enhanced by the staining, especially in case 2. Immunohistochemically, the epidermoid and intermediate carcinoma cells were strongly positive for high molecular weight cytokeratin (34βE12) (Fig. 5b) and p63 (Fig. 5c). The reactivities were demonstrated particularly in the epidermoid cells located at the periphery of the tumor cell nests. The epidermoid and intermediate carcinoma cells were slightly or moderately positive for TTF-1 (Fig. 5d) and PAX8 (Fig. 5e). The mucus-secreting carcinoma cells were positive for PAX8 and negative for high molecular weight (HMW) cytokeratin, p63, and TTF-1. The mucous secreting carcinoma cells in cases 1 and 3, as well as the epidermoid carcinoma cells in cases 2 and 3, were focally positive for carcinoembryonic antigen (CEA) (Fig. 5f). Neither the epidermoid carcinoma cells nor mucous secreting carcinoma cells reacted with thyroglobulin. The epidermoid carcinoma cells were positive for p53, but mucous-secreting carcinoma cells were negative. In the stroma, the numbers of IgG4-positive plasma cells per high power field (HPF) were 245 in case 1, 28 in case 3, and two in case 3. However, in the areas of the non-neoplastic Hashimoto’s thyroiditis, the numbers of IgG4-positive plasma cells per HPF were 34, 1, and 5, respectively. No cases with IgG4/IgG ratio of more than 40% were found throughout the specimens.

Fig. 5

Histochemical and immunohistochemical findings. The goblet cell type carcinoma cells show Alcian blue-positive mucin (a). The epidermoid carcinoma cells are strongly positive for high molecular weight (HMW) cytokeratin (b) and p63 (c), and moderately positive for thyroid transcription factor-1 (TTF-1) (d) and PAX8 (e). Carcinoembryonic antigen (CEA) reacts to both the epidermoid carcinoma cells and mucus-secreting carcinoma cells (f). (a, case 1, Alcian blue stain, 200×; b, case 1, immunostain for HMW cytokeratin, 200×; c, case 3, immunostain for p63, 200×; d, case 1, immunostain for TTF-1, 200×; e, case 3, immunostain for PAX8, 200×; f, case 3, immunostain for CEA, 200×)

FISH analysis

The criteria for a positive MAML2 gene rearrangement included: at least 20% of the cells counted to harbor signals of translocation, separation of the green and orange signals by at least two signal diameters, and at least 50 cells counted randomly [25]. All samples were successfully examined using MAML2 FISH, with all cases being found negative for the MAML2 gene rearrangement. FISH analysis did not detect the split signal in the MAML2 gene, whereas green deletion signal in the MAML2 gene was found with a rate of 8%, 5%, and 8% of the counted nuclei in the tumor cells in cases 1, 2, and 3, respectively (Fig. 6).

Fig. 6

Fluorescence in situ hybridization analysis of MAML2 gene translocation. The yellow arrow and red arrowhead show normal and deletion signal patterns, respectively. The deletion signal pattern in the MAML2 gene was presented in 8% of the counted nuclei in the tumor cells (case 3). A green and orange chromosomal break point signal pattern was not observed.

Discussion

According to the review by Shah et al. [17], thyroid SMECE has female predilection and typically occurs in the sixth decade. Almost all cases were associated with Hashimoto’s thyroiditis. Extrathyroidal extension and nodal metastasis were noted at the time of presentation in 47% and 36% of patients, respectively. Local recurrence and distant metastasis appeared in 33% and 29% of patients, respectively. However, patient outcome was favorable and 62% of cases were alive with no evidence of disease during follow-up (mean follow-up was 4 years). All of the cases in our study showed no nodal metastasis at presentation, and outcome was indolent. No recurrence or distant metastasis was detected during the follow-up period (20 years in case 1, 3 years in case 2, and 18 months in case 3). Shah et al. concluded that the overall and recurrence-free survival of SMECE may be lower than those for other well-differentiated thyroid cancers [17], but we believe that outcomes are favorable when diagnosis is made at an early stage, such as in our cases.

Ultrasound and FNAC of SMECE have not been well documented. According to our experience, SMECE appeared as a hypoechoic, lobulated mass on ultrasound examination. The findings may be confused with lymphoma or intrathyroid thymic carcinoma. On FNAC, all of the 3 reported patients had lymphocytes. In 2 of these patients, eosinophils were observed and SMECE was suspected. We believe that SMECE is the first candidate for a differential diagnosis of carcinoma cells associated with lymphocytes and eosinophils.

Microscopically, thyroid SMECE is characterized by a combination of nested epidermoid carcinoma cells, intermediate carcinoma cells, and mucous-secreting carcinoma cells, fibrohyaline stroma, and prominent eosinophilic and lymphoplasmacytic infiltrates [10-19]. All of our cases showed these features. In addition, we observed the infiltration of eosinophils within the tumor cell nests and even the formation of eosinophilic abscess in all three cases. The eosinophilic infiltration may be seen in the stroma of invasive squamous cell carcinoma. The phenomenon is termed tumor associated tissue eosinophilia, and has been used as an indicator of favorable prognosis [20, 21]. The findings of eosinophilic abscess have not been described, except for Langerhans cell histiocytosis [22]. We believe that the formation of eosinophilic abscess in the tumor nests could be a novel characteristic finding of SMECE.

According to previously reported cases, the immunohistochemical positive rates of thyroglobulin, p63, TTF-1, and PAX8 were 9%, 100%, 65%, and 11% in cases of SMECE, respectively [17]. The results probably show the reactivity of the epidermoid carcinoma cells, and do not include that of the mucus-secreting cells. We independently observed the reactivity of the epidermoid carcinoma cells and mucus-secreting carcinoma cells. In this study, we demonstrated that the epidermoid carcinoma cells were invariably positive for p63, TTF-1, and PAX8 in all three cases. The findings confirm that SMECE originated from the follicular cells, because TTF-1 and PAX8 are reliable markers [23]. As the mucus-secreting carcinoma cells were also positive for PAX8, it is thought that they were derived from the epidermoid cells or follicular cells.

MAML2 rearrangement is observed in more than half of salivary MEC cases, is specific for salivary MEC, and predicts a favorable prognosis [24-27]. However, MAML2 by FISH was intact in all three of our cases. Shah et al. reported the same results in 9 SMECE cases [17]. These findings suggest that salivary MEC and thyroid SMECE are pathogenetically different entities. In addition, thyroid MEC seems to differ from SMECE since the former is frequently associated with papillary thyroid carcinoma, can transform to an anaplastic carcinoma or display a poorly differentiated pattern of growth, and may have MAML2 rearrangements [28]. These findings are not observed in SMECE.

In cases 1 and 2, IgG4-positive plasma cells were elevated in the stroma of both the SMECE and non-neoplastic Hashimoto’s thyroiditis components. The pathological diagnosis of IgG4-related diseases requires an IgG4-positive plasma cells/IgG positive plasma cells ratio of >40%, fibrosis with a characteristic “storiform” pattern, and obliterative phlebitis [29, 30]. Therefore, Hashimoto’s thyroiditis seen in our cases did not satisfy the diagnostic criteria of IgG4-related disease. Interestingly, IgG4-positive plasma cells were increased in the stroma of thyroid SMECE. In 2012, Tian et al. first demonstrated increased IgG4-positive plasma cells in sclerosing MEC of the salivary gland, and suggested a role of IgG4-positive plasma cells in fibrogenesis [31]. Tasaki et al. reported a case of salivary SMECE, in which many IgG4-positive plasma cells appeared in the fibrosclerotic areas and non-neoplastic salivary gland tissue, with an IgG4/IgG ratio of 62% [9]. In nine cases of thyroid SMECE reported by Shah et al., increased IgG4-posive plasma cells were not demonstrated [17]. Here, we report the first two cases in which IgG4-positive plasma cells existed in the stroma of SMECE. The presence of these cells may be related to sclerosis, as Tian et al. suggested [31].

In conclusion, we reported three cases of SMECE with histological, immunohistochemical, and molecular pathological examinations. The formation of eosinophilic abscess in the tumor cell nests could be a novel finding of SMECE. The positivity for TTF-1 and PAX8 confirmed that SMECE originated from the follicular cells. As MAML2 by FISH was intact in all cases, thyroid SMECE seems to be pathogenetically different from salivary MEC. The prognosis of thyroid SMECE was found to be favorable. In addition, we first describe the presence of increased IgG4-positive plasma cells in the stroma of SMECE.

Disclosure

The authors have no conflicts of interest to declare regarding grant support or financial relationships.

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