High Grade Myoepithelial Carcinoma of Maxillary Sinus with Extensive Rhabdoid Differentiation and INI-1 Loss: Expanding the Histopathological Spectrum of Sinonasal Carcinoma

Abstract

Myoepithelial carcinoma (MEC) of salivary gland is an uncommon tumor with no specific age or sex predilection. Most of the cases (~90%) arise in parotid and submandibular glands followed by palate. MEC of maxillary sinus is rare. We describe an extremely rare case of high grade MEC with rhabdoid differentiation and INI-1 loss involving maxillary sinus of an elderly male.

Introduction

Myoepithelial carcinoma (MEC) of salivary gland is an uncommon tumor with no specific predilection for age or sex. These tumors arise predominantly in major salivary glands, and involvement of nasal cavity or maxillary sinuses are rare [1–3]. MEC are infiltrative tumors with varied histological pattern comprising of spindle, plasmacytoid, epithelioid and clear cell morphology, and high grade MEC show propensity for distant metastasis [4, 5]. MEC of primary maxillary sinus origin is very rare. We describe an extremely rare case of high grade MEC of primary maxillary sinus with rhabdoid differentiation and INI-1 loss along with clinico-radiological, histological and immunohistochemistry (IHC) details.

Case Report

A 65-year-old male presented with history of persistent left nasal blockage, increased watering from left eye and swelling over left cheek/maxillary region for 3 months. On local examination a proliferative growth of 6 × 4 cm involving left upper alveolus was seen. Facial movement and vision was normal; although ptosis was present. Left level Ib lymph node was palpable. Routine biochemical and hematological investigations were unremarkable.

Computed Tomography (CT) scan of the paranasal sinuses (PNS) showed large soft tissue density mass in the left maxillary sinus causing expansion and erosion of bone, extending into and occluding the nasal cavity as well as ethmoidal air sinus. The soft tissue mass was also infiltrating the medial and inferior wall of the left orbit with erosion of the left side turbinate and nasal septum, with focal extension into pterygoid and infratemporal fossa. Erosion was also seen in the left pterygoid plate, hammulus and cribriform plate.

Biopsy from the mass showed partially ulcerated squamous mucosa devoid of dysplasia with underlying stroma extensively infiltrated by a poorly differentiated malignant tumor in biphasic pattern. Major population comprised of large neoplastic cells in sheets exhibiting eccentric nucleus, prominent nucleoli with abundant eosinophilic cytoplasm and hyaline inclusions; while the second population comprised of plump spindle cells in a myxoid background (Figure 1). Significant mitosis was evident along with focal necrosis.

Fig. 1.

Microimages showing a submucosal infiltrative tumor (a), comprising of rhabdoid and spindle cells in a myxoid background (b). Sheets of rhabdoid cells seen with eosinophilic cytoplasmic inclusion and mitotic activity (c, d). (Arrow points mitotic activity)

The morphological differentials considered include undifferentiated carcinoma, melanoma, rhabdomyosarcoma (RMS), high grade undifferentiated sarcoma and extra-renal rhaboid tumor. On IHC, the tumor cells were positive for Pancytokeratin (AE1/AE3), S100, Calponin and SMA, while negative for P40, desmin, NUT, SOX10, HMB45, and Melan-A. There was diffuse loss of INI-1 on further IHC (Fig. 2), and BRG-1 was retained.

Fig. 2.

On immunohistochemistry, the tumor cells show strong CK with cytoplasmic inclusions (a), SMA (b), and S-100 positivity (c). The tumor cells show diffuse loss of INI-1 immunoexpression (d) while expression is retained in stromal and endothelial cells (left half: arrow)

With above clinical, morphological and IHC findings, a final diagnosis of high grade MEC with INI-1 loss was rendered. The case was discussed in multi-specialty tumor board; in view of extensive wide spread infiltrative nature of tumor the case was inoperable and patient was planned for palliative chemotherapy and radiotherapy. The lymph node was clinically palpable and enlarged and thus was not addressed as it would not affect the plan of action (palliative CT/RT). However, patient was lost to follow up.

Discussion

MEC of salivary gland is an uncommon tumor (~1% of all salivary gland tumors) with no age or sex predilection. Most of the cases (~90%) arise in parotid and submandibular glands followed by palate [1, 2]. MEC are rarely seen in maxillary sinus, the first case being described by Graadt Van Roggen et al. [3]. A clinicopathological study of 51 cases of MEC of salivary gland by Kane et al. [5] has shown an incidence 6% involving maxillary sinus.

MEC is an infiltrative growth of neoplastic myoepithelial cells, displaying a mixture of spindle, plasmacytoid, epithelioid and clear cell morphology, and propensity for distant metastasis [2, 4]. Savera et al. [2] first described the rhabdoid features in their study of 25 cases of MEC of salivary glands; three (12%) of these cases of MEC showed hyaline/rhabdoid features. SMA and Calponin were positive in 50% and 75% of the cases respectively. However, INI-1 immunoexpression was not evaluated in their study. An overview of the cases reported in literature is presented in Table 1.

Table 1.

Reported cases of Myoepithelial carcinoma arising from Maxillary Sinus

Author	Total cases	Age (years)	Sex	Histopathologic features	Grade	INI-1 immunoexpression	Treatment	Follow-up
Graadt van Roggen [3]	1	67	Male	Solid sheets of round to spindle cells	High	Not done	Radical maxillectomy	Not provided
Silveira et al. [1]	1	44	Male	Rhabdoid	High	Intact	Maxillectomy	Progressive deterioration in health and LFU
Savera et al. [2]	1 (of 25 cases of salivary gland tumors)	38	Male	Clear	Low	Not done	Maxillectomy, CT	REC, DOD Scalp metastasis, DOD at 72 mths
Kane et al. [5]	3 (of 51 cases of salivary gland tumors) (6%)	36	Female	Not provided for individual cases	Not provided	Not done	Maxillectomy	120 mths, REC, AWD
		70	Female	Not provided for individual cases	Not provided	Not done	Excisional biopsy	4 mths, LFU
		24	Female	Not provided for individual cases	Not provided	Not done	Excisional biopsy	1 mth, LFU
Zhou [6]	1	41	Female	Round/oval cells	High	Not done	Maxillectomy, RT & CT	Recurrence and metastasis, DOD (13 mths after surgery)
Hata [7]	1	47	Female	Clear	High	Not done	Partial maxillectomy, Radiotherapy	REC, complete response AWD 30 mths after RT
Present case	1	65	Male	Rhabdoid (predominant) and spindle morphology	High	Lost	Diagnostic biopsy done	LFU

DOD died of disease, REC recurrence, LFU lost to follow-up, AWD alive with disease, CT chemotherapy, RT radiotherapy

In the presented case, in view of extensive rhabdoid differentiation on histomorphology and in germane with the clinical presentation, the differential diagnosis considered were squamous cell carcinoma with rhabdoid phenotype, sinonasal undifferentiated carcinoma (SNUC), malignant melanoma, RMS and SWI/SNF complex-deficient sinonasal carcinoma.

Subsequently on IHC, Pan-CK positivity and desmin negativity ruled out melanoma and RMS. INI-1 loss and P40 negativity also largely ruled out squamous cell carcinoma with rhabdoid phenotype and SNUC. Positivity for SMA, S100 and Calponin provided a tangible evidence to render a final diagnosis of high grade MEC with rhabdoid differentiation with INI-1 loss. A similar case of MEC with rhabdoid features in maxillary sinus has been reported by Silveira et al. [1], however, with intact INI-1 immunoexpression.

SMARCB1 (INI 1) is a tumor suppressor gene located at 22q11.2, and is involved in chromatin remodeling [8, 9]. The SMARCB1 gene product is ubiquitously expressed in nuclei of all normal tissue. Diffuse loss of INI-1 immunoexpression is seen in Atypical teratoid/rhabdoid tumor of CNS, malignant rhabdoid tumor of kidney, epithelioid sarcoma, epithelioid MPNST, myoepithelial carcinoma of soft tissue, and renal medullary carcinoma. IHC has emerged as an impressive and practically useful diagnostic tool to identify SMARCB1 altered malignant tumors in surgical pathology practice [8–10].

In view of INI-1 loss, SMARCB-1 deficient sinonasal carcinoma (SDSNC) was another close differential in our case which is a recently described distinct histopathological entity [8, 10]. Agaimy et al. [8] described the largest series of 39 cases of SDSNC. The most common (59% cases) histological pattern was that of an undifferentiated basaloid or “blue cell” tumor reminiscent of SNUC or non-keratinising squamous cell carcinoma, followed by second most common pattern (36% cases) comprising of pink cell tumor with “plasmacytoid/rhabdoid” cells. Remaining 5% (2 cases) showed spindle cell differentiation. However, the immunoexpression of S100, Calponin and SMA have not been evaluated. SWI/SNF complex-deficient sinonasal carcinoma was ruled out with retained SMARCA4 (BRG-1) IHC.

The presented case showed biphasic plasmacytoid/rhabdoid and spindle cell pattern in a myxoid background with high grade histological features, and expressed specific IHC markers of myoepithelial lineage, i.e. SMA, Calponin and S-100.

EWSR1 gene rearrangement has been described in a small subset of MEC and has been correlated with aggressive features [4]. However, in the presented case the EWSR-1gene rearrangement was not identified by break apart-FISH.

Hallani SE et al. [11] in their molecular study of 39 cases of epithelial-myoepithelial carcinoma (EMC) of salivary glands, have found single case of SMARCB-1 deficient high grade-MEC on NGS which they found corroborated by INI-1 IHC and FISH findings. The authors concluded that most EMC (80%) arose as ex-Pleomorphic adenoma (PA) and the genetic profile of EMC varies with the absence or presence of pre-existing PA. A progression to higher grade EMC with intact PLAG1 and HMGA2 correlates with the presence of TP53, FBXW7 mutations, or SMARCB1 deletion.

Regarding management of MEC, surgery is the mainstay of treatment if the tumor is resectable with or without radiation therapy. Efficacy of chemotherapy has not been established. The diagnosis of MEC requires pertinent morphology along with co-expression of Pan-CK espoused with at least one myoepithelial marker (S100, Calponin, SMA, GFAP and P63/P40). These markers are variably expressed from case to case as in the presented case P40 was absent, although S100, Calponin and SMA were positive. [4]

To conclude, high grade MEC with rhabdoid differentiation should be a differential when dealing with epithelioid tumor with rhabdoid features in head and neck region. Performing molecular studies like INI-1 evaluation and EWSR-1 gene rearrangement will help to identify a distinct subtype, which can further be explored pertaining to their prognostic and therapeutic implication.

Author Contributions

SP, MK, AJ, MA: Substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data. SP, GG, AS, GD: Drafting the article and revising it critically for important intellectual content. SP, MK, AM: Final approval of the version to be published.

Funding

The authors declare that they have no financial disclosures.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Informed Consent

A general informed consent was taken from the patient regarding sharing of clinical data for research purpose. All the patients’ information in the manuscript is anonymised and only de-identified data is used.