Keywords
concurrent chemoradiotherapy - large cell neuroendocrine carcinoma - nasal cavity
Introduction
Large cell neuroendocrine carcinoma (LCNEC) is a rare epithelial neuroendocrine malignancy.
The most common site is the lung; however, LCNEC might occur at different sites like
the gastrointestinal tract, pancreas, cervix, kidney, prostate, larynx, and multiple
other primary sites. LCNEC is associated with only 20% 5-year overall survival (OS)
according to a Dutch registry (47,800 patients) and the reported incidence was increased
by 1.79 per 100,000 people.[1] To the best of our knowledge, there have only been four cases of LCNEC of the nasal
cavity described to date, making it an extremely rare condition. For a patient to
survive, a cancer with such a rare occurrence and inadequate 5-year OS exploring efficient
treatment is crucial. As of now, both radiotherapy and surgery followed by chemoradiotherapy
have been adopted as the initial and mainstay treatment modality, but a complete agreement
on adequate management is lacking.[2]
Patient Report
A 48-year-old male patient presented to us with a history of epistaxis and left-sided
nasal blockage for almost 1-year duration. The patient was a smoker (15 pack years)
and consumed alcohol in moderation. Examination of the left nasal cavity revealed
a mass abutting the nasal choana. Nasal endoscopic examination revealed a left sinonasal
bleeding polypoidal mass. Endoscopy-guided nasal biopsy was done for histopathological
examination. On contrast-enhanced computed tomography (CT) of the neck and face, an
ill-defined moderately enhancing solid mass was noticed in the left nasal cavity,
ethmoidal air cells, and extending into the nasopharynx posteroinferiorly and laterally
into the left orbit through the left lamina papyracea. Fluorodeoxyglucose (FDG)/positron
emission tomography (PET) revealed an FDG-avid solid lesion in the left nasal cavity.
Microscopic examination of the lesion revealed a tumor composed of sheets of malignant
cells having high N:C (nuclear to chromatin ratio), scanty cytoplasm, monomorphic
nuclei with stippled chromatin, and few cells showing prominent nucleoli. There was
no evidence of prominent nuclear molding, Azzopardi phenomenon, necrosis, keratinization,
or brisk mitosis. On immunohistochemistry (IHC), the cells showed positivity for synaptophysin
but were negative for Pan CK, p40, and CD45. The proliferation index (Ki-67) was 55
to 60% and p53 was wild-type. A final diagnosis of poorly differentiated LCNEC was
confirmed ([Fig. 1]).
Fig. 1 (A) Hematoxylin and eosin (H&E) (100 × ) photomicrograph of tumor composed of sheets
of malignant cells with high N:C ratio. (B) H&E (400 × ) higher magnification view showing tumor cells with scant to moderate
amount of cytoplasm, monomorphic nuclei with stipple chromatin, and few cells showing
prominent nucleoli. (C) Immunohistochemistry (IHC) showing positivity for synaptophysin (200 × ). (D) IHC showing positivity for chromogranin (200 × ). (E) IHC showing positivity for p40 (200 × ).
The patient was managed with neoadjuvant chemotherapy (NACT) with cisplatin + etoposide,
for three cycles (with growth factor support). This was followed by concurrent chemoradiotherapy
(CCRT) of 70 Gy divided into 35 fractions, delivered over 6 to 8 weeks along with
cisplatin weekly during the radiotherapy. End of therapy PET CT after 12 weeks revealed
FDG-avid bilateral neck nodes (standardized uptake value 4.4), while the primary lesion
in the left nasal cavity and left ethmoidal air cells were not appreciated. A biopsy
was done which showed chronic inflammation without any malignant features. The patient
is under regular follow-up with no evidence of recurrence.
Discussion
Accounting for less than 5% of the sinonasal malignancies, LNCEC of the nasal cavity
is overall a rare entity. Epistaxis is one of the most common symptoms in the presentation
of LCNEC of the nasal cavity. Nasal obstruction, epiphora, and facial pain are the
other common symptoms. Local extension to skull base, brain, or nasopharynx can cause
symptoms of mass lesion or exophthalmos. In addition to metastases to lungs, bone,
or liver, the entity may be associated with paraneoplastic syndrome of inappropriate
antidiuretic hormone secretion.[3]
[4] Human papilloma virus may be positive in some sinonasal LCNEC and these have aggressive
course with poor prognosis.[5] Histopathology and IHC remain the mainstay for the differential diagnosis of NEC
with the major histologic feature being the presence of high mitotic activity with > 10
mitoses in 10 high-power fields distinguishing it from moderately differentiated NEC.
Other features under microscopy are scant cytoplasm and a high N:C ratio without molding
or crush artifacts.[6]
Recently, the suggestion to include LCNEC as an independent category within the classification
of head and neck cancers has been put forth by multiple authors rather than categorizing
such tumors as NEC-not otherwise specified. Compared to atypical carcinoid tumors,
LCNEC has a worse prognosis and behaves aggressively, much like small cell carcinoma.[7] Malignant melanoma, lymphoma, and sinonasal undifferentiated carcinoma are a few
examples of differential diagnosis. It is conceptually difficult to diagnose and distinguish
LCNEC from sinonasal undifferentiated carcinoma (SNUC) and high-grade olfactory neuroblastoma
due to the paucity of occurrences and convergent morphologic and immunohistochemical
characteristics.[8]
Owing to the extremely rare nature of LCNEC in the head and neck region, no clinical
trials have yet been undertaken to decide on the best course of action for managing
both localized and advanced disease.[9] A meta-analysis on neuroendocrine carcinomas of the sinonasal cavity revealed that
the choice of treatment method and differentiation grade constitute important indicators
of OS. Furthermore, the investigation demonstrated that sinonasal moderately differentiated
carcinomas had the highest 5-year disease-specific survival (70.2%), while undifferentiated
sinonasal carcinomas had the lowest (35.9%). The majority of sinonasal neuroendocrine
carcinoma (SNEC)s responded well to surgery employed as a monotherapy.[10]
Various other studies also suggest surgery as the mainstay for the treatment of such
high-grade tumours.[11] But, when sinonasal carcinoma (SNC) spreads to nearby sites like the orbit, ethmoidal
sinuses, and nasopharynx, they pose a challenge for surgical removal and often involve
the removal of a large portion of the abovementioned structures. NACT helps in the
reduction of tumor size and metastases, which makes surgical removal less complicated.
CCRT has been used in NEC carcinomas of the lungs and has proved beneficial compared
to the use of either chemotherapy or radiotherapy alone. The use of chemotherapy along
with radiotherapy provides solutions for radio-resistance, via mechanisms involving
either additivity or supra-additivity.[2]
Though CCRT has its benefits, its usage is limited, a prospective study conducted
in the Netherlands suggested that, due to a number of comorbidities, 59% of the 686
patients with non-small cell lung carcinoma (NSLC) cancer were deemed unfit for CCRT.[12] In another prospective cohort study of 341 randomized patients with low-risk nasopharyngeal
carcinoma, intensity-modulated radiation therapy (IMRT) alone was not inferior to
CCRT. When compared to CCRT, IMRT alone resulted in noticeably fewer grade 3 to 4
adverse events (17% vs. 46%). A case report on LCNEC reported no significant improvement
in patients with NACT, but CCRT followed by adjuvant chemotherapy led to complete
remission of solid tumors based on nasal endoscopy.[13] In a different case, a 35-year-old patient with nasopharyngeal LCNEC (T4N0M0) was
treated with six rounds of chemotherapy and then radiation treatment. Six months following
the end of treatment, the patient presented with a local and meningeal relapse despite
having previously shown clinical and radiological improvement. In the end, the patient
received palliative care till passing away.[14] Although more research is needed to confirm these findings, but two cases of Epstein-Barr
virus (EBV)-positive LCNEC were successfully treated with chemotherapy and radiation.
EBV-positive LCNEC may be more responsive to chemoradiotherapy and therefore have
a better prognosis than EBV-negative LCNEC.[15]
[16]
Conclusion
The entity of LCNEC of nasal cavity is rare and the use of a specific treatment modality
remains debatable, majorly due to few numbers reported and different treatment protocols
showing varied results. Surgery poses challenges for such high-grade tumors. Chemotherapy
or CCRT showed promising result in our case. Two cases with EBV-positive LCNEC and
one case failed to show improvement with NACT. Chemotherapy followed by radiotherapy
was not successful. The data available is insignificant to reach a consensus for treatment
protocol of LCNEC of sinonasal cavity.
