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Esthesioneuroblastoma metastatic to the trachea. Metastasi tracheale da estesioneuroblastoma
Автор F. Mattavelli, N. Pizzi, E. Pennacchioli1, S. Radaelli1, G. Calarco2, P. Quattrone3, L. Patelli4   

Esthesioneuroblastoma is a rare tumour, for which a multimodal approach, including a combination of surgery and radiation

, appears to

provide the best disease-free and overall survival. Well-known for its tendency for local recurrence and distant spreading by both lymphatic

and haematogenous routes, the most common sites of metastases are lungs and bones, followed by liver, spleen, scalp, breast, adrenals and

ovary. One single case of metastasis to the trachea has been reported in the literature. The case is reported here of a patient who developed

metastatic esthesioneuroblastoma to the trachea 18 months after primary surgery and radiation therapy. The patient was treated by two

subsequent N-YA G laser endoscopic resections and chemotherapy.


L’estesioneuroblastoma è un raro tumore, per il quale un approccio combinato comprendente chirurgia e radioterapia permette di ottenere

la migliore sopravvivenza libera da malattia e la miglior sopravvivenza globale. Noto per la propensione alla recidiva locale e per la

diffusione a distanza, per via linfatica ed ematica, le più comuni sedi di metastasi sono il polmone e l’osso, seguiti da fegato, milza, cuoio

capelluto, mammella, surrene e ovaio. In letteratura un solo caso di metastasi tracheale è stato riportato sino ad oggi. Noi riportiamo il

caso di una paziente che ha sviluppato una metastasi tracheale da estesioneuroblastoma 18 mesi dopo la chirurgia del primitivo e la radioterapia.

La paziente è stata trattata con due successive resezioni endoscopiche con N-YAG laser e chemioterapia.


Esthesioneuroblastoma (ENB), also known as olfactory

neuroblastoma, is an uncommon neoplasm arising from

the olfactory neuroepithelium of the upper nasal cavity at

the interface with the anterior cranial fossa
1 2. This neurogenic

tumour has very little in common with neuroblastomas

elsewhere in the body. It accounts for 6% of nasal and

paranasal sinuses tumours and for 0.3% of upper aerodigestive


ENB occurs with a bimodal peak in the second and sixth

decades of life and without predominance of sex or race.

It is often locally aggressive, with symptoms related to

local extension of the disease: nasal obstruction, intermittent

epistaxis, local pain, headache, rhinorrhea, anosmia,

diplopia. The mean time from the initial symptoms to diagnosis,

by computed tomography (CT)-scan or magnetic

resonance imaging (MRI), is approximately 6 months

Although ENB is uncommon, some consistent features

of the disease have been established: local recurrences in

30% of patients, cervical nodes metastases in 23%, distant

metastases in 8% of cases
5 with sites involved including

lung, liver, eye, parotid, central nervous system (CNS),

bone, adrenal gland, spleen, scalp, breast, ovary, aorta
6 7.

A single case of metastasis to the trachea has so far been

reported in the literature

The first and most common staging system was developed

by Kadish et al.
8 then modified by Morita et al. 9 to obtain

a system that divides tumours into four groups:

tumour limited to the nasal cavity;

tumour involving the nasal and paranasal sinuses;

tumour involving cribriform plate, base of the skull, orbit

or intra-cranial cavity;

tumour with metastasis to cervical nodes or distant


Other staging systems have also been used, but no single

staging classification has been universally adopted for this

tumour to date, as the prognostic utility of each system

has not been proved





AC TA oto rhinolaryngologica italica 2009;29:EPUB 12/05/09

Cantщ et al. 11 suggested a classification system for ethmoidtumours, called INT classification (

Istituto Nazionale
dei Tumori classification) involving the anterior skull

base. This system is based upon anatomic, and not only

on pathologic, criteria, it considers the possibilities and

limitations of standard treatment for ethmoid tumours in

achieving radical resection and it satisfies a main goal of

tumour staging, that is i.e., the progressive worsening of

prognosis for different classes.

According to the histopathological features ENB was divided,

by Hyams et al.
12 into four grades of differentiation:

from grade I for well differentiated forms to grade

IV for undifferentiated forms.

Universal treatment of ENB has not yet been recognized:

surgery, with a combined transfacial and transcranic approach,

followed by radiotherapy at a dose of 60 Gy,

should achieve the best results. In some cases, stereotactic

radiotherapy can be considered. In recent years, endoscopic

microsurgical techniques have been employed in

the treatment of ENB. With complete endoscopic surgical

resection, followed by radiation therapy, local recurrence,

morbidity and cosmetic deformity have been minimized

13 14. Another novel therapeutic approach combines

endoscopic sinus surgery and Gamma Knife radiosurgery.

This treatment has led to favourable results and can be

considered a promising approach
15. Chemotherapy is employed

in patients with recurrent or metastatic disease and

in the neoadjuvant setting to reduce the extent of tumour

before surgery.

The mean 5-year survival, according to the Kadish-Morita

staging system, is approximately 72% for group A,

59% for B, 47% for C, 29% for D. According to the histopathologic

classification, mean 5-year survival is 56%

for grades I/II and 25% for grades III/IV, the presence of

nodal metastases at presentation being the most important

prognostic factor for survival (5-year overall survival is

reported to be 29% in patients with nodal metastases at

presentation vs 64% in patients without metastases). Local

recurrence can occur even more than 10 years after

primary treatment: therefore long-term follow-up is mandatory


Loco-regional and distant spreading are through the lymphatic

and haematogenous routes. The possible routes of

metastases to the trachea are discussed, and previous reports

of tumours metastatic to the trachea are reviewed.

Case report

In June 1998, a 50-year-old female was referred to the

IRCCS Istituto Nazionale dei Tumori, Milan, on account

of progressive left nasal obstruction and rhinorrhoea.

A CT scan of the craniofacial district revealed a polypoid

mass projecting into the lumen of the left nasal cavity.

A histological diagnosis of adenoid-cystic carcinoma was

formulated according to a trans-nasal biopsy.

Pre-operative staging of disease did not reveal any distant

metastases, therefore the patient underwent anterior

craniofacial resection.

The definitive histological diagnosis was not in agreement

with the biopsy sample, identifying an olfactory neuroblastoma,

staged T2 N0 M0 (WHO Staging System).

Adjuvant radiotherapy was performed with a total dose

of 60 Gy.

The patient was observed at regular follow-up until January

2000, when she was admitted to our Institution for

more severe dyspnoea.

A chest X-ray excluded pneumonia or hypertensive pneumo-


Due to hypoxia, at arterial blood gas measurement, and

acute respiratory failure, the patient was submitted to an

emergency flexible endoscopic laryngo-tracheal examination

(Fig. 1a), which reavealed stenosis of the trachea, due

to the presence of a mass penetrating into the tracheal lumen.

Bleeding from two detached mucous vegetations was

detected 5 cm below the glottis. The first was located on

the left side of the tracheal lumen, the second on the
membranacea of the tracheal wall. The longitudinal extension

was 2 cm, resulting in a lumen reduction of 95%.

A N-YA G laser resection of the mass was performed, with

subsequent introduction of two expansible metal stents

(Nitinol stents, introduced by means of a rigid endoscope),

diameter 1.4×4 cm), leading to a satisfactory grade of

tracheal patency (Fig. 1b) and complete recovery from

respiratory symptoms. A CT-scan of the thorax showed

a significant tissutal thickening of the tissue between the

trachea and oesophagus, without evidence of mediastinal

or lung metastases (Fig. 2).


A biopsy specimen of the mass revealed ENB, histologically

identical to the primary tumour (Fig. 3).

Further endoscopic laser treatment was performed, a few

days later, to remove necrotic tissue and to improve tracheal


MRI of the brain, whole body bone-scan and oesophagogastroduodenoscopy

(EGD) did not reveal any other

sites of disease.

One month later, the patient presented recurrence of increasing

respiratory stress and a fibroendoscopic laryngotracheal

examination demonstrated a new stenosis of the

trachea, just above the first tracheal stent, with a longitudinal

extension of 2 cm.

Photocoagulation with N-YA G laser was again performed

and a third metal stent was introduced.

Due to the aggressive behaviour of the disease, the patient

underwent 2 cycles of systemic chemotherapy with epirubicine

and hiphosphamyde.

A further fibroendoscopic laryngo-tracheal examination,

in March 2000, showed normal tracheal canalization and

no further relapse of disease.

Another four cycles of chemotherapy were performed.

Two months later, MRI of the neck and thorax revealed

the presence of pathological tissue on the left wall of the

trachea and posteriorly, around the initial tract of the right

superior lobar stump. The tracheal carena was deformed

and able to capture gadolinium.

Following evidence of multiple sites of loco-regional relapse

of the disease, the patient underwent palliative radiotherapy

Three months later, multiple hepatic metastases were

found. The patient died on account of progression of the

disease both loco-regionally and at distant sites.


Treatment of tracheal metastases, in ENB, is no different

from any other neoplastic stenoses of the airways, clinically

characterized by severe respiratory failure.

The first publication on endotracheal metastases goes

back to 1954, when Divertie et al.
16 described a case of

metastatic colorectal adenocarcinoma.

These metastases are very unusual, representing 2-5% of

all autopsy surveys in patients dying from cancer

More recently, with improvements in endoscopic techniques,

it is possible to obtain earlier and more precise

diagnosis, even if all cases of endotracheo-bronchial me-

tastases have to be considered as advanced disease with

an unfavourable prognosis.

Many different kinds of tumours can metastasize to the

trachea: breast and colorectal carcinoma being the most

common, melanoma, thyroid carcinoma, sarcoma and


A few Authors have described endobronchial metastases

from distant malignancies, generally as sporadic events

The first case of tracheal metastases of ENB was published

in 1987, by Franklin et al.
7 who reported a case similar

to that described here: a patient submitted to craniofacial

resection who presented a single site of relapse to the trachea

one year later.

The Authors also presented a detailed and pertinent review

of the literature regarding tracheal primitive neoplasms

and mestastases, from which the rarity of the primitive

forms are primarily related (< 0.1% among all patients

who died from cancer) compared with those in a laryngeal

site, which are 75 times more frequent.

From a clinical point of view, an endotracheal mass produces

characteristic symptoms when the tracheal lumen

is reduced to 75%. For this reason, diagnosis is usually

achieved only when the tumour is already of large dimensions.

A significant difference between tracheal and endo-bronchial

lesions is that, in the former, inspiratory “cornage is

typically present”, which is absent in the latter.

Tracheal deviation is rarely provoked by an endotracheal

mass; instead, this is a common finding in an extraluminal

mass arising in the lung, oesophagus or thyroid.

Following correct evaluation of an endotracheal tumour, it

is necessary to plan appropriate treatment aimed at removing

the obstruction and preserving endoluminal patency.

The first step in the treatment of tracheal malignancies

consists in establishing the airway, by means of endoscopic

removal, photodynamic therapy, electro-coagulation

and endo-cavitary brachitherapy.

Patients’ clinical features, entity of the tracheal obstruction,

number of lesions, experience in using one of these

techniques, will determine the choice of therapy.

In our patient, N-Yag laser was used and was repeated each

time relapse of the disease occurred, until possible

Once the airway has been established, it is necessary to

introduce metal stents compatible with eventual radiation


Following endoscopic resection, a clinical check-up is

necessary to confirm correct placement of the stent and to

exclude relapse of the disease. When necessary, the endoscopic

procedure can be repeated, eventually associated

with chemo or radiotherapy.

The patient described in this report achieved immediate

recovery of shortness of breath and a satisfactory local

control of the disease. Prognosis of the patient was determined

by distant metastases, despite multiple local recurrences.

As far as concerns the pathogenesis of the peculiar location

of these metastases, we can exclude the possibility of

insemination of the trachea, by ethmoidal tumoural cells,

during oro-tracheal intubation, when the patient undergoes

anterior cranio-facial resection for primary tumour.

The lymphatics, as a route giving rise to metastases in the

trachea has been definitely ruled out, following evidence

that the lymphatic circulation is completely independent

in the head/neck and the tracheo-bronchial anatomic districts,

as demonstrated by Welsh in 1964

It is more likely that the trachea is reached by ENB cells

through the blood circulation, as is the case for metastases

to the trachea from a carcinoma.

Also in the present case, when considering the aggressive

behaviour developed by the disease, the detection of

metastasis seems to have matched the onset of haematogenous


Research on multifaceted aspects of micrometastasis, including

proliferation and differentiation of various clones

from the primary tumour, the acquisition of adhesion molecules,

the process of lymphangiogenesis
vs. angiogenesis,

and host interaction with the microscopic tumour,

may lead to a better understanding of the mechanisms of


In this perspective, future biological models of clinical

cancer behaviour will have to incorporate aspects focusing

on understanding the metastatic cascade, and particularly

the host factors that permit progressive growth from

micrometastases to clinical metastases.


Endotracheal obstruction, due to primary carcinoma or

metastases from extrapulmonary tumours, is a rare and

life-threatening complication in cancer patients. The trachea

is an extremely rare location for metastases from

non-lung tumours. The present report refers to a patient

with ENB who developed almost complete obstruction of

the trachea and who was successfully managed by endoscopic


To our knowledge, this is the second report describing

metastatic tracheal dissemination from ENB.


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