Sinonasal SMARCB1 (INI1) Deficient Carcinoma with Yolk Sac Tumor Differentiation: A Case Report and Treatment Options

Abstract

SMARCB1 (INI1) deficient carcinoma (SDC) is a newly-described, aggressive, high-grade malignancy of the adult population. Rarely, these tumors demonstrate yolk sac differentiation. Treatment protocols are not defined due to the rarity of this entity. A 55 year-old-male presented with a tumor originating in the maxillary sinus. He was treated with neoadjuvant therapy followed by radical surgery and adjuvant treatment. We review the literature and discuss the course of disease and treatments of sinonasal SDC with yolk sac tumor differentiation. To our knowledge, this is the sixth reported case of sinonasal SDC with yolk sac tumor differentiation. This is the first publication describing the clinical course and efficacy of therapeutic interventions.

Introduction

Sinonasal tumors comprise a wide histologic spectrum. The 4th edition of the World Health Organization (WHO) classification of tumors of the head and neck (2017) describes new sinonasal malignancies based on advances in immunohistochemical studies [1]. SMARCB1 (INI1) deficient carcinoma (SDC) was defined in 2014 and pathologically characterized by case series [2–4]. The first case including yolk sac differentiation foci was published in 2018 [5].

SMARCB1 is a tumor suppressor gene that is expressed in all human tissues [2]. Its product is a member of SWI/SNF chromatin-remodeling complex [2]. SMARCB1 (INI1) deficiency is regarded as an important step in carcinogenesis, and SDC is a rapidly progressing, aggressive, high-grade malignancy. Chemotherapeutic agents have been investigated; however, treatment protocols are not defined. It is unknown whether yolk sac differentiation impacts the clinical course of SDC [5–7]. This is the first paper describing the clinical course and efficacy of various interventions.

Case Presentation

Initial Management

A 55-year-old male was referred to our clinic for swelling of the left cheek. On magnetic resonance imaging (MRI), a neoplastic process originating in the maxillary sinus was identified. It invaded the anterior wall of the sinus and extended to the subcutaneous tissues of the cheek and left orbit. Histopathologic examination of endoscopic biopsy specimens from the left lateral nasal wall revealed SMARCB1 deficient carcinoma (SDC) with yolk sac differentiation. Positron emission tomography—computed tomography (PET-CT) showed no regional or systemic dissemination. The tumor was staged as cT4aN0M0 [American Joint Committee on Cancer (AJCC) Staging Manual, TNM classification, 8th ed]. The patient was treated with four cycles of neoadjuvant chemotherapy (NACT) (docetaxel 75 mg/m2, cisplatin 75 mg/m², 5-fluorouracil 750 mg/m²); however, there was no response and the tumor progressed (Fig. 1). Post-therapy clinical classification TNM stage remained ycT4aN0M0.

Fig. 1.

 A PET-CT scan findings before neoadjuvant chemotherapy. B PET-CT scan findings after neoadjuvant chemotherapy

After neoadjuvant chemotherapy failure, the patient underwent orbital exenteration, subtotal maxillectomy, radical parotidectomy, and selective neck dissection (level I-III). The defect was reconstructed with an anterolateral thigh free flap (Fig. 2). The postoperative course was uneventful.

Fig. 2.

Surgical steps and reconstruction

Pathologic Examination of the Surgical Specimen

Intraoperatively, the tumor had irregular borders and required resection of the left middle concha, inferior concha, and posteriolateral nasal wall. No cervical metastases were identified. The post-therapy pathologic stage was ypT4aN0M0.

On histologic examination, the tumor was completely resected with clear margins that did not infiltrate the skin. Histologically, the tumor comprised squamoid/basaloid cell nests separated by thick, fibrous bands in a myxoid stroma. Areas with a nesting pattern demonstrated cells with scant, pale to eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli. Oxyphilic cells with glandular differentiation were also present. Areas with glandular differentiation often had a myxoid background and reticular/microcystic architecture reminiscent of a yolk sac tumor. Occasional cribriform spaces, pointing to possible glandular differentiation, and rare plasmacytoid cells were observed in areas of more solid architecture. Approximately 20% of the tumor showed glandular differentiation and less than 5% showed hyalinization, possibly secondary to neoadjuvant chemotherapy. Immunohistochemistry (IHC) revealed two different staining patterns: AFP, SALL4, glypican3, MOC31, CDX2, and vimentin were positive in yolk sac areas, and cells in nests were positive for keratin 5/6, keratin 7, and EMA. Both components showed complete loss of SMARCB1/INI-1 expression (Figs. 3 and 4).

Fig. 3.

Histologic findings. A Solid tumor nests with edematous and fibrinous stroma (100x, H&E). B Higher magnification of a solid area, comprising cells with vesicular nuclei, prominent nucleoli, and pale to eosinophilic cytoplasm. Occasional tumor cells show oxyphilic or plasmacytoid morphology. C Tumor area showing a microcystic pattern, reminiscent of a yolk sac tumor. D Some gland-like structures in an otherwise solid tumor area. E Extensive hyalinization near a residual tumor nest, a possible chemotherapy effect

Fig. 4.

Immunohistochemistry (IHC) studies. A SALL-4 staining demonstrates diffuse nuclear positivity in a yolk sac tumor-like area. B Glypican-3 is diffusely expressed in a yolk sac tumor-like area. C Keratin 5/6 staining shows membranous positivity in a solid area of tumor. D Keratin 7 staining shows focal membranous positivity in a solid area of the tumor. E Loss of nuclear expression of SMARCB1/INI1 is observed in both a solid tumor area and F a yolk sac tumor-like area

Later Clinical Course

Chemotherapeutic agents given to the patient are summarized in Table 1. The patient had concomitant chemoradiation, including weekly five cycles of cisplatin (35 mg/m²) started six weeks after surgery. He received a total radiation dose of 50 Gy to the bilateral neck and tumor regions, including the parotid region, with the fraction of daily 2 Gy in 25 days. Subsequently, the local tumor bed was irradiated with 10 Gy local boost with the fraction of daily 2 Gy in five days. The first postoperative MRI was performed two months after the chemoradiotherapy, and no evidence of recurrence was detected.

Table. 1.

Chemotherapy regimens and their outcomes

Regimen	Response	Cycle	Name	Dose
DCF	No	3	Docetaxel	75 mg/m2–110 mg
			Cisplatin	75 mg/m2–110 mg
			5-flourouracil	750 mg/m2–1100 mg
Concomitant cisplatin	Local recurrens and lung metastasis	5	Cisplatin	35 mg/m2–60 mg
ICE	No regression at previous region and a new metastasis at distal humerus	3	Ifosfamide	5 g/m2–8.5 g
			Carboplatin	AUC 5 (440 mg–400 mg–400 mg)a
			Etoposide	100 mg/m2–170 mg
GD	Growth continued, breathing and feeding became difficult	5	Gemcitabine	1000 mg/m2–1500 mg (received two doses of chemotherapy for one cycle, on day one and eighth)
			Docetaxel	75 mg/m2–110 mg (on eighth day with gemcitabine)
BEP	Exitus occurred after first cycle	1	Bleomisin	30 mg/day 30 mg
			Etoposide	100 mg/m2/day 190 mg
			Cisplatin	20 mg/m2/day 35 mg

^aFor first 440 mg and than 400 mg carboplatin was given for other cycles

Four months after the chemoradiotherapy, a PET/CT scan revealed a local recurrence and distant metastasis in lung parenchyma. ICE [ifosfamide 5 g/m², carboplatin AUC (area under the curve) 5, etoposide 100 mg/m²] chemotherapy regime was implemented. After three cycles of ICE chemotherapy, PET- CT scan showed progression of local tumor, and no regression of the lung metastasis. Furthermore, a new metastasis was identified at the right distal humerus bone. The chemotherapy regimen was changed to gemcitabine (1000 mg/m²) and docetaxel (75 mg/m²).

Five cycles of this chemotherapy regimen proved ineffective, and the tumor progressed to the oropharynx and nasopharynx. Gastrostomy and tracheotomy were performed to provide nutrition and airway support. A BEP (bleomycin 30 mg/day, etoposide 100 mg/m²/day, cisplatin 20 mg/m²/day) regimen was started. During the first cycle of this treatment, the patient developed neutropenia and sepsis. The patient died in the twentieth month after diagnosis.

Discussion

SMARCB1 deficiency was discovered in atypical teratoid and rhabdoid tumors of the central nervous system [2]. Sinonasal SDC was first defined in 2014, and, later, two different series were published that included a combined number of 52 cases [2–4, 8]. With the increasing availability of molecular testing of tumors, the WHO Classification of Head and Neck Tumours now includes SMARCB1 (INI-1)–deficient sinonasal carcinoma subtype under sinonasal undifferentiated carcinoma [1]. SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1, also known as INI-1 or SNF5) is a tumor suppressor gene located on chromosome 22q11.2 [2]. Polycomb repressive complex 2 (PRC2) and enhancer of zeste homologous 2 (EZH2) activity increase in its deficiency. Therapeutic agents used in treatment are EZH2 inhibitors [9].

Sinonasal SDC with yolk sac tumor differentiation was first reported by Zamecnik et al. [5]. Subsequently, Shah et al. reported three additional cases of yolk sac differentiation in their sinonasal SMARCB1 deficient adenocarcinoma series, and, recently, Li et al. published a case report [6, 7] Unfortunately, sinonasal SDCs with yolk sac differentiation is a novel, rare entity and treatment protocols are not defined. The impacts of yolk sac differentiation on prognosis are unclear. Most of the subjects with sinonasal SDCs are at advanced stage at the time of diagnosis. Due to the presence of necrosis, histopathologic examination can be non-diagnostic and repeat biopsies may be required, further delaying diagnosis [10].

Efficacy of neoadjuvant treatment is controversial. Some studies report benefit; however, neoadjuvant chemotherapy failed in our subject [11, 12]. In a case series, Kakkar et al. employed neoadjuvant chemotherapy for two patients which did not prevent distant metastases despite locoregional control [8]. Since there are reported regional recurrences in the literature, elective neck dissection may improve regional control in these aggressive tumors with advanced stages at the time of diagnosis.

Despite radical surgery and adjuvant chemoradiotherapy, local recurrence and lung metastasis developed four months after the chemoradiotherapy in our case, which is similar to some cases reported in the literature. After the development of recurrences, various chemotherapy regimens were attempted without positive response. In a publication by Agaimy et al., the largest case series reported, 9 of 39 patients were alive without evidence of disease at last follow-up (range 11–115 months; median 26) [3]. Some reports detail a positive response to chemotherapy in a subset of cases, and efficacy is likely related to the heterogeneity of tumor morphology [11].

We report the clinical course of the sixth sinonasal SDC with yolk sac tumor differentiation. According to clinical course of the reported subject, this tumor is aggressive and resistant to various therapeutic options. A potential treatment option may be the EZH2 inhibitor, tazemetostat [13].

Conclusions

Sinonasal SDCs are newly described, aggressive tumors. Effective treatment algorithms are not defined due to its rarity. Targeted therapies are still in the clinical trial phase. For now, surgery followed by chemoradiotherapy may be the best option. Since the efficacy of chemoradiotherapy is not predictable, radical surgery is an important step.

Author contributions

Study concept and design: BH, UA, YK. Acquisition of the data: BH, AE, BS, FG, OY, UA. Analysis and interpretation of the data: BH, UA, YK, AE, BS, FG, OY. Drafting of the manuscript: BH, UA, YK. Critical revision of the manuscript for intellectual content: BH, UA, YK, AE, BS, FG, OY. Technical support: BH, UA, YK, AE, BS, FG, OY.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Data Availability

All data was presented here.

Declarations

Conflict of interest

The authors have no funding, financial relationships, or conflict of interest to report.

Ethical Approval

This is a case report and literature review. Ethical approval was not needed

Consent to Participate

Written informed consent for publication of clinical details and images was obtained from the patient and his family.