Background

Cancers of paranasal sinus (PNS) are rare and constitute only around 3% of all the head and neck cancers [1]. Majority of these arise in the maxillary sinus, and a very small proportion constitute ethmoid sinus tumors (EST). It is more common in males. The most common histology is squamous cell carcinoma, adenoid cystic, adenocarcinoma and esthesioneuroblastoma [2]. Rare histology tumors often arise in ethmoid sinus including sarcoma, lymphoma, sinonasal undifferentiated carcinoma (SNUC), small cell neuroendocrine cancer (SCNEC), and large cell neuroendocrine carcinomas (LCNEC). The most common presenting symptoms of PNS tumors are facial pain, headache or nasal obstruction [3]. In initial stages, ESTs are often asymptomatic or have minor symptoms of nasal stuffiness. Locally advanced lesions can extend into the anterior cranial fossa through cribriform plate resulting in anosmia and into the orbit through lamina papyracea causing retroorbital pain or diplopia. Diagnosis is established by imaging with computerized tomography (CT) or magnet resonance imaging (MRI) with contrast and biopsy by nasal endoscopy. Origin of malignancy in ethmoid sinus itself confers poor prognosis compared to other PNS tumors [4]. Metastatic cervical lymph node involvement is rare with ESTs compared to other head and neck malignancies and is a poor prognostic feature [5].

LCNEC which is found more often in lung and gastrointestinal tract is rare to arise from PNS.  Histological findings include trabecular pattern of growth, peripheral palisading, necrosis, abundant cytoplasm, and coarse or vesicular chromatin. Pathologic diagnosis is typically confirmed by cell morphology along with the presence of immunohistochemical (IHC) markers of neuroendocrine differentiation like synaptophysin and chromogranin A. High grade tumors have worse survival compared to lower grade tumors [6]. Due to the rarity of the condition, there is limited data guiding treatment. Treatment decisions are often made from extrapolated evidence from studies on SCNEC or SNUC and few case reports of LCNEC of ethmoid sinus. We present the case of a patient with locally advanced LCNEC of ethmoid sinus. Although the clinical presentation, management, and outcome of this patient is crucial in understanding this rare malignancy, it is merely to be used as a guide to treat future patients with this malignancy.

Case Presentation

We present the case of a 55-year-old White male with no significant past medical history that had three months of unresolving headache. He was a former smoker with 10 pack-year history and quit 22 years ago. He presented to his primary care provider and was started on treatment with oral antibiotics for suspicion of sinusitis. Symptoms did not improve with treatment. The headache was worse on lying down and was associated with loss of taste and smell. He later developed numbness at the roof of his mouth on the right side. A computerized tomography (CT) with and without contrast demonstrated a 4.9x 2.9x 2.6 cm mass in the posterior ethmoid sinus invading the cribriform plate and fovea ethmoidalis (Figure 1).

Figure 1: Axial (A1) and Sagittal (A2) views of CT of head and face with contrast at diagnosis (A1, A2) with contrast showed 2.9x 2.6x 5 cm mass = involving the right superior nasal passage, ethmoid air cells, and sphenoid sinus with local osseous destruction and septal resorption (marked by yellow arrow). It penetrates the cribriform plate with an intracranial component lying along the distribution of the right olfactory glove. No intra-axial infiltration of the right frontal lobe was noted.

CT of the neck, chest, abdomen and pelvis did not show any other site of disease. MRI brain and orbit confirmed the findings. Patient’s symptoms worsened rapidly and developed diplopia and pain behind right eye in the next two weeks. He underwent nasal endoscopy with biopsy of the ethmoid sinus mass. Pathology revealed high grade LCNEC with Ki-67 of 95% and mitotic count of 30-40/10 high power field (HPF). Due to rapid worsening of symptoms, he underwent craniofacial resection of the PNST for debulking with nasoseptal flap and repair of dura mater. The tumor was found to have invaded skull base during the surgical procedure. The surgery was complicated by cerebrospinal fluid leak requiring transsphenoidal repair. A repeat CT scan six weeks following surgery showed persistent large central skull base mass now involving sphenoid sinus, anterior clinoid process, right inferior and superior orbital fissures, and pterygopalatine fossa with sphenoid roof destruction.

Since the tumor was located near the optic chiasm and right optic nerve, treatment with radiation was concerning due to the potential side effects of visual defects.  Hence, he was started on chemotherapy with cisplatin 60mg/m2 Day 1 and etoposide 100mg/m² Days 1-3 repeated every 21 days with plans to add radiation after adequate cytoreduction. Chemotherapy resulted in clinical response with symptomatic improvement within 2 weeks of initiation of treatment. He had complete resolution of symptoms after 2 cycles of chemotherapy and discontinued all pain medications. MRI after 4 cycles showed significant reduction in tumor size with enhancing signal now involving only the frontal sinuses, extending to the superior margin of the ethmoid air cells measuring 2.3x4.4cm (Figure 2). After completing 6 cycles of chemotherapy, he is currently undergoing radiation with a target dose of 70 Gy.

Figure 2: Axial (B1) and sagittal (B2) views of MRI brain post-chemotherapy with previous frontal craniotomy changes, with rim enhancing signal abnormality involving the frontal sinuses and extending to the superior margin of the ethmoid air cells measuring 2.3x4.4cms.

Discussion

NECs of the sinonasal tract are extremely rare, often poorly differentiated with high malignant potential and have an overall poor prognosis. These tumors are again subdivided into small-cell and large-cell NECs. Retrospective registry analysis of sinonasal NECs, especially the LCNEC category is difficult due to lack of proper classification. These tumors are often classified under SNUC or Not Otherwise Specified (NOS) leading to underrepresentation of this entity in clinical studies.

SEER database analysis: With the above limitations in mind, we reviewed all cases of sinonasal LCNEC in SEER database between 2000-2018 and identified 11 patients (Table 1). 90.9% of the patients were over 55 years of age. All but one patient was White. Ethmoid sinus was the predominant site of origin (54.5%), followed by maxillary sinus (27.2%). 7 out of the 11 patients presented in locally advanced/metastatic stage. Five patients underwent surgery while it was not reported in the remaining patients and the database lacked information on RT or chemotherapy. The median survival of this patient group was 8 months with only 6 patients remaining alive at follow-up.

Table 1: SEER database of patients with sinonasal LCNEC diagnosed between 2000-2018.

Literature review: Our review of existing literature for reports of sinonasal LCNEC yielded 18 cases (Table 2). Majority of the patients were male (70.6%). Median age was 66 (range 14-82 years). Nasal obstruction was the most common presenting symptom (66.7%) followed by ocular symptoms (55.5%). 82% cases with staging information available were stage IVA/B (per AJCC 8th edition staging) with only one case being metastatic at diagnosis. Cytokeratin and synaptophysin were universally positive in all cases which reported these IHC stains while chromogranin-A was positive in all except two cases. Median Ki-67 index was 60% (range 30 to >80%) and mitotic index 20/HPF (range 6-33/HPF). Most of the patients underwent multimodality treatment with surgery (68.8%), radiation (100%) and chemotherapy (81.3%) involved in varying sequence. Seven patients had complete response while 5 died from the malignancy. Survival ranged between one month to 53 months. In a study of 10 LCNECs of head and neck (including three cases of sinonasal primary included in the review), HPV positivity was found in 3 cases including one in the sinonasal tract. However, HPV-positivity did not impart a prognostic advantage in this group [7].

Abbrev.: NC- nasal cavity, ES-ethmoid sinus, SS-sphenoid sinus, MS-maxillary sinus, FS-frontal sinus, CK-cytokeratin, CgA- chromogranin A, Syn-synaptophysin, EMA-epithelial membrane antigen, Vim-vimentin, MI-mitotic index, RT-radiotherapy, IMRT-intensity mediated RT, EBRT- external beam RT, NED- no evidence of disease, CR- complete response, PR- partial response, LR- local recurrence, DM- distant metastasis, AWD- alive with disease, DOD- dead of disease, DOC- dead of other causes.

Table 2: Cases of sinonasal LCNEC from review of literature with clinicopathological characteristics.

Treatment decisions for sinonasal LCNEC is mostly extrapolated from studies on patients with SNUC. Based on the limited evidence and poor outcomes with single modality treatments, recommendations from National Comprehensive Cancer Network (NCCN) are to include systemic therapy routinely to the overall treatment of patients with SNUC with neuroendocrine features. Combined modality treatment including surgery, chemotherapy and/or radiation have shown to be the major factor affecting local and regional control, however with increased toxicity [8, 9]. Although surgical resection is often considered similar to squamous cell or adenocarcinoma of sinonasal tract, it is limited in NEC due to the involvement of critical structures such as brain, cranial nerves, and eyes and incomplete resection is common. However, with improved surgical techniques and reconstruction, the complications and morbidity from the procedures have been reduced in recent times [10]. Incomplete resection, high risk pathologic features like high-grade disease, positive margins, intracranial and/or intraorbital extension necessitates need for systemic chemotherapy and radiation among these patients. Radiation alone or concurrent chemoradiation is commonly employed as neoadjuvant or adjuvant treatment. RT for paranasal sinus tumors can be associated with risk of blindness, which is reduced with intensity modulated radiation techniques [11].

In a retrospective study of 95 patients with SNUC, concurrent chemoradiation (platinum-etoposide with 60-70 Gy at 2Gy/fraction) after induction chemotherapy (cisplatin 60-80mg/m2 on D1 and etoposide 100-120mg/m2 or docetaxel 75mg/m2 on D1-3 every 21 days) and resection was associated with a 5-year disease-specific survival rate of 81% (95% CI 69-88%), compared to 59% (95% CI 53-66%) in the entire study population [12]. After partial response to induction chemotherapy, surgery and adjuvant chemoradiation, the disease-specific survival was however lower at 39% (95% CI 30-46%). The patients who did not have at least partial response to induction chemotherapy had 5-year disease-specific survival (DSS) of 0% (95% CI 0-14%). In an analysis of SNUC cases from National Cancer Database between 2003-2014, surgery followed by chemoradiotherapy was associated with improved survival than definitive chemoradiotherapy alone (55.8% vs 42.6%, p = 0.007) [13]. However, these results may be skewed with patients with late-stage disease not receiving surgery. In late-stage tumors, there was no difference in survival between both groups (p = 0.22). The positive margin was associated with poor survival with 5-year survival of 0%. It should also be noted that awaiting surgical wound healing and possible surgical complications may delay the initiation of chemotherapy and radiation. Hence in our opinion, upfront surgical resection should be reserved for early-stage disease and advanced-stage symptomatic disease from tumor mass. For metastatic disease which carries a very poor prognosis, systemic chemotherapy with platinum and etoposide with or without concurrent RT as used in high-grade neuroendocrine tumors is recommended. The use of immunotherapy remains unclear and is recommended based on tumor agnostic indications like high tumor mutation burden or microsatellite instability-high tumors.

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