2 Rare Diseases of the Nose, the Paranasal Sinuses, and the Snterior Skull
Base
Rare diseases of the nose, paranasal sinuses, and skull base may be classified into
the following categories:
-
Diseases/syndromes of the olfactory system
-
Malformations
-
Ventilation and functional disorders
-
Benign and malignant tumors
-
Inflammatory/granulomatous diseases
An article from 2015 by Martin Laudien already described rare rhinological diseases
focusing on a granulomatous genesis [15] so
that the present contribution will concentrate on the first four aspects. Hereby,
the most important rare diseases of the olfactory system, malformations, cancer
diseases, and functional disorders of the nose, the paranasal sinuses, and the
anterior skull base are discussed taking into account the current literature.
2.1 Diseases/syndromes of the olfactory system
The genesis of disorders of the olfactory system is manifold. Possible origins
are rhinological diseases, traumas, neoplasms, and congenital disorders or they
are called idiopathic [16]
[17]. Furthermore, many viral diseases exist
that may be accompanied by temporary or permanent hyposmia or anosmia. Due to
the motto of the annual meeting, the present article does not focus on all rare
diseases but only on those that concern primarily the smelling function. Those
are the following syndromes and malformations:
2.1.1 Isolated congenital anosmia
Isolated congenital anosmia is extremely rare. Worldwide only 15 cases of
isolated congenital anosmia have been described up to now [18]. In these cases, the anosmia is
already present since birth. The origin is a developmental disorder of the
olfactory bulb that may occur on one or both sides [19]. Another possible genesis may be
the replacement of olfactory epithelium by respiratory epithelium which
lines the nasal cavity. The origin is an autosomal-dominant disorder with
incomplete penetrance. There is no causal therapy for this malformation.
2.1.2 Kallmann syndrome
Kallmann syndrome describes an inherited developmental disorder, in its
context, a congenital hypogonadotropic hypogonadism develops due to a
gonadotropin-releasing hormone (GnRH) deficiency. In addition, affected
patients suffer from hyposmia or anosmia (in cases of hypoplasia or aplasia
of the olfactory bulb) that indicates an interrupted embryonic migration of
the GnRH synthesizing neurons of the olfactory epithelium into the area of
the hypothalamus. The inheritance is X chromosomal recessive [20]. The prevalence of Kallmann
syndrome is estimated to 3.75:100,000 [2]. Therapies aim at inducing the puberty and later fertility.
While in this context good therapy outcomes may be achieved, treatment of
hyposmia or anosmia is not possible.
2.1.3 Johnson neuroectodermal syndrome
The neuroectodermal syndrome, Johnson type, comprises the symptoms or
alopezia, anosmia or hyposmia, conductive hearing loss, malformation of the
auricles, microtia and/or atresia of the external auditory canal and
hypogonadotropic hypogonadism. According to the first descriptions, it is
also called Johnson-McMillin syndrome [21]
[22]. The inheritance
occurs autosomal-dominantly, however, the exact etiology is unknown. It is
assumed that an embryological defect during the differentiation of the
neural crest of the head region is responsible.
The prevalence of this syndrome is estimated to clearly less than
1:1 000 000. Therapy for hyposmia or anosmia associated with
this syndrome does not exist.
2.2 Malformations of the nose and paranasal sinuses
In the current literature, more than 300 syndromes involving the nose are
described. In many of these syndromes, also the development of the nose may be
impaired, however this pathology may be considered as subordinate in the
overview of the pathologies occurring in the context of the syndrome. For
reasons of clarity, the following paragraph will describe pathologies that
primarily affect the nose or – in cases of severer disease –
also the paranasal sinuses and the anterior skull base. The following
malformations are included:
-
Arrhinia/hemirhinia
-
Bifid nose
-
Craniorhinia
-
Craniofacial clefts and paramedian cleft nose
-
Duplication anomalies of the nose
-
Lateral proboscis
-
Fistula of the nasal ridge
2.2.1 Arrhinia/hemirhinia
Congenital arrhinia is an extremely rare malformation where the nose is not
or only rudimentarily developed ([Fig.
1]). Its pathogenesis is not yet completely clarified. It is
assumed that a developmental disorder of the geminated nasal placodes
between the 3rd and 10th week of gestation plays a
role in its genesis. The early fusion of the median nasal processes, missing
resorption of the nasal epithelial plug as well as an abnormal migration of
cells of the neural crest are discussed as further possible mechanisms.
Arrhinia may occur as singular malformation or in the context of syndromes
such as the Treacher-Collins syndrome that consists of oto-mandibular
dysplasia with various defects in the head and neck area and the Bosma
arrhinia-microphthalmia syndrome or Bosma-Henkin-Christiansen syndrome, a
combination of arrhinia, choanal atresia, and microphthalmia.
Fig. 1 Clinical appearance of a 5-month-old patient with
arrhinia without rudiments.
Worldwide, about 20 cases have been described [2]. Even rarer are cases of congenital
unilateral arrhinia (hemirhinia, missing side of the nose [Fig. 2]). In some cases, completely
missing nose with palpatorily solid base is described ([Fig. 1]), other cases reveal a
rudimentary nose with blind ending hump or dimple [23].
Fig 2 Female patient with condition after reconstruction of
the right half of the nose in the context of hemirhinia
Most cases of arrhinia that have been reported, have occurred sporadically
and show an inconspicuous karyotype [24]
[25]. The survival rate
of patients with this malformation is rather low because the findings may
lead to severe upper airway obstruction, stridor, and infections of the
airways as well as malnutrition [26].
Surgery is the therapy of choice, however, only few data are available with
regard to the technique and the optimal time for treatment. Tracheostomy
should be performed initially in order to secure breathing. It is generally
recommended to plan reconstructive measure up to the preschool age at the
latest.
2.2.2 Bifid nose
The bifid nose is a rare congenital malformation that is probably
autosomal-dominantly or recessively inherited. Characteristic is a nasal
cleft, which presents in various manifestations. It may be a nearly
unremarkable fold at the columella ([Fig.
3]) up to complete split of the underlying bone and cartilage
which may lead to the development of two half noses. In the context of this
malformation, the airway is usually adequately developed. Bifid nose may be
considered as mild type of frontonasal dysplasia [27], but also other malformations like
hypertelorism and midline cleft of the lip are observed in relation with the
nasal malformation [28].
Fig. 3 Mild appearance of bifid nose.
The origin of frontonasal dysplasia is unknown. Regarding the etiology, a
deficient development of the nasal capsula is assumed, probably the
migration of the olfactory epithelium into the nasal capsula is interrupted
in the course of the 4th and 6th week of
embryogenesis. The capsule cannot be fully developed and the primitive brain
tissue fills the space between the dehiscent nasal ridge [29].
CT scan or MRI is urgently required prior to surgery because also mild forms
of frontonasal dysplasia may be associated with intracranial anomalies.
In cases of mild types of bifid nose, surgery typically consists of open
rhinoplasty [27] which allows a good
overview of the site and preserves the vascular supply of the skin and the
soft tissue of the nose. It is assumed that the columella incision as well
as the lifting of the nasal skin applied in open technique do not influence
the growth of the child’s nose [30].
2.2.3 Craniorhinia
The characteristics of craniorhinia are brachycephaly, receding forehead, and
sclerotic skull base, however without craniosynostoses. The nasolacrimal
duct is not developed. The configuration of the nose is broad, the ala of
the nose appear distended and anteverted. A nasal hirsutism and bilaterally
symmetric, round, cystic structures with small fistulas are observed
directly below the nose. Hypertelorism may be found in addition. Probably,
the inheritance is autosomal-dominant, however, cases with consanguine
parents allow the assumption that pseudo-dominant autosomal-recessive
inheritance cannot be fully excluded [31]
[32]. Worldwide, four
affected families have been described [2].
2.2.4 Craniofacial clefts and paramedian cleft nose
Craniofacial clefts and are extremely rare malformations of embryogenesis.
Primary or true clefts occur between the 4th and 8th
week of gestation because the fusion between the different facial processes
could not be fully completed. Secondary or pseudo-clefts appear later. They
concern the mesenchymal differentiation and may be considered as dysplasia.
In both situations, the future growth potential is reduced compared to the
remaining parts of the face. The incidence of craniofacial clefts amounts to
1.4–4.9:100 000 [33].
The cleft formation may concern brain tissue, soft tissue, and bones. Bony
malformations occur at the front, orbita, ethmoid sinus, maxilla, and
palate. Meningoceles and meningoencephaloceles may develop in cases of
intracranial involvement.
Median and paramedian facial clefts are often associated with hypertelorism,
anterior or basal encephalocele, positional anomaly of the maxilla and nasal
deformities ([Fig. 4]). Also
malformations of the soft parts such as cleft lip and palate and eyelid
coloboma can present [33].
Fig. 4 Median facial cleft, frontonasal dysplasia.
The paramedian nasal cleft is a rare developmental defect during
embryogenesis that is characterized by unilateral or bilateral coloboma of
the nose ([Fig. 5]). It is a mild
form of craniofacial cleft. The malformation can appear as small notch
leading to an unimportant deviation of the nasal septum up to nasal clefts
of different size that can be associated with small cysts of the paranasal
sinuses in the nasal midline. Paramedian nasal clefts occur in an isolated
way or in combination with cleft lip and/or other craniofacial
anomalies (e. g. hypertelorism, broad nasal root, midline cleft).
Nasal ridge and tip are usually well developed [34].
Fig. 5 Paramedian nasal cleft.
2.2.5 Duplication anomalies of the nose: polyrhinia and accessory
nostril
Duplication anomalies of the nose comprise polyrhinia (double nose) and the
accessory nostril. Both nasal deformities occur extremely rarely (according
to Orphanet, their incidence is estimated to less than
1:1 000 000). In the literature, a total of 8 cases have
been described, 4 of them had polyrhinia and 3 an isolated accessory nostril
as well as one patient with accessory nostril in combination with cleft lip
[35].
Polyrhinia is a congenital malformation appearing as a complete duplication
of the nose. All published cases were sporadic. It is assumed that the
malformation is based on an embryonic developmental defect with duplication
of the medial nasal process [36].
Also the accessory nostril is a very rare congenital malformation that is
characterized by the presence of one or several accessory nostrils with or
without accessory cartilage. The accessory nostrils are located medial,
above, below, or lateral to the other nostrils. In contrast to polyrhinia,
no duplication of the nasal septum is found. The accessory nostril is
frequently associated with other malformations of the head and neck [37]
[38].
2.2.6 Lateral proboscis
Lateral proboscis is an extremely rare malformation that was first described
in 1861. The deficient side of the nose shows a trunk-like rudimentary nose
that may start at every point along the embryonic fusion line between the
anterior maxilla and the frontonasal process. In most cases, the location of
this rudiment is at the medial part of the orbital roof [39].
The exact embryonic mechanism that is responsible for the development of
lateral proboscis could not yet be clarified. The more popular theories
suppose the incomplete fusion of the lateral nasal and maxillary processes
and the irregular fusion of the maxillary process of the affected side with
the medial nasal process [40]
[41]
[42].
According to existing data, it is recommended to start surgical therapy early
in childhood in order to reduce or avoid psychosocial consequences. The
final esthetic reconstruction of the nose, however, should be performed in
later adolescence when the growth of the nasal skeleton is completed.
There are different surgical techniques for initial correction of lateral
proboscis. The technique that is frequently described consists of
deepithelialization of the middle and distal part of the rudimentary trunk
that is then inserted into the opened and malformed ipsilateral nasal wall
[39].
2.2.7 Fistula of the nasal ridge
Fistula of the nasal ridge is a rare malformation that is defined by the
presence of a dermoid cyst on the nasal ridge. The incidence amounts to
1:20 000–1:40 000 [43]. Clinically, it presents as a solid palpable, slowly growing
mass that contains skin and dermal elements such as hair follicles and
sebaceous glands. Intermitting or chronic secretion of sebum and serous
liquid as well as local infections may occur. In single cases, an
intracranial connection is found so that history taking should focus on
complaints of meningitis and seizures. In very rare cases, intracranial
abscesses can develop. The therapy of choice consists of complete excision
of the findings, depending on the extension also in cooperation with a
neurosurgeon. Recurrences are rarely observed after complete resection [44].
2.3 Ventilation and functional disorders
2.3.1 Silent sinus syndrome
The silent sinus syndrome is usually a unilateral disease of the maxillary
sinus that is associated with a reduced volume, collapse of the orbital
floor and resulting downward displacement of the bulb (hypoglobus) [45]. Already in 1964, Montgomery
described 2 cases of enophthalmos with maxillary mucoceles [46], the term of silent sinus syndrome
came up in the context of the description of a case series of 19 patients
with enophthalmos and a unilateral collapse of the maxillary sinus [47]. In extremely rare cases, the
ethmoid or the frontal sinus are affected [48]
[49]. Worldwide, 98
cases have been described up to now [2].
Affected patients are mostly free of sinonasal complaints, however, they
sometimes report about pressure of the affected side of the maxilla [50]
[51]. Despite the changed visual axis due to the enophthalmos and
hypoglobus, visual disorders are only rarely present because of the slowly
progressing symptoms.
The most probable origin for the development of the silent sinus syndrome is
an obstruction of the ostium of the affected paranasal sinus. Consecutively,
negative pressure occurs as well as retracted bony walls and subsequent
retention of secretion [52]
[53]
[54]
[55]
[56]. The original hypopthesis of
maxillary sinus hypoplasia could be refuted by means of trials that showed
computed tomographic scans from the time before the disease where a normally
configured maxillary sinus was seen [54]
[57]
[58]. Also chronic rhinosinusitis is
discussed as possible origin [56].
Endoscopy reveals a severely retracted, sometimes atelectatic uncinate
process. Computed tomography reveals a seemingly hypoplastic maxillary sinus
with regular retraction of all walls. The lumen of the sinus may be free or
obstructed with secretion [59].
Coronary tomography may depict the orbital floor retracted in caudal
direction which leads to a consecutive obstruction of the orbital content
([Fig. 6]). Magnet resonance
imaging shows a hyperintense signal in the T2 weighting with homogenous
imaging of the lumen [51]
[59]
[60]
[61].
Fig. 6 Coronary CT reconstruction of a patient with left-sided
silent sinus syndrome. The maxillary sinus is obstructed, the
orbital floor is pulled downwards.
In cases of complaints, maxillary sinus fenestration type 2–3 [56]
[62]
[63]
[64] is indicated to restore
ventilation. After opening the lumen, normal to slightly hypertrophic mucosa
is seen and according to the findings also mucocele-like secretion that is
suctioned.
In cases of visual disorders, the correction of the orbital floor is
intensively discussed. For reconstruction or lifting of the orbital floor
alloplastic or autologous material may be used [55]
[65]. Several case reports, however, showed regression of the
enophthalmos and hypoglobus [52]
[57]
[65]
[66] so that surgical
therapy should be performed one year after restoration of the maxillary
sinus ventilation at the earliest in order to allow spontaneous remission
[62]
[65]
[67].
2.3.2 Hypersinus
The term of hypersinus describes a paranasal sinus that significantly exceeds
the usual borders with a normal configuration of the bony borders and
ventilation situation [68]. The extent
of the affected sinus is within the borders of the cranial bone without
– as in cases of pneumosinus dilatans or pneumocele –
displacing it. Hence, the patients do not have any esthetic or functional
impairment. [Figure 7] shows the
bilateral pneumatization of the frontal sinuses. The sagittal reconstruction
also depicts the frontal sinus reaching in cranial direction, however,
without impairing the outline of the front.
Fig. 7 Coronary and sagittal CT reconstruction of a patient
with bilateral frontal hypersinus.
Hypersinus does not cause any complaints so that this anatomical variation is
not considered as pathology. Despite a classification established in 1987
[69], the terms of hypersinus,
pneumosinus, and pneumocele are sometimes used as synonyms so that the
differentiation of the hypersinus is mentioned in this context.
2.3.3 Pneumosinus dilatans
Pneumosinus dilatans is a massive extension of usually one paranasal sinus
and manifests in most cases at the frontal sinus. Also the ethmoid, the
sphenoid, and the maxillary sinuses may be affected by the extraordinarily
strong pneumatization [56].
Protrusions of the frontal bone or intracranial, ethmoidal, and orbital
extension may be found [69]. The
disease is not always associated with complaints but in some cases the sense
of pressure and cephalgia may result. While the affection of the frontal
sinus can lead to esthetic impairment of the patients, case reports have
been published describing ophthalmological complications in the context of
ethmoid or sphenoid location [70]
[71]
[72] due to a compression of the optic nerve.
The number of cases reported worldwide amounts to 134 [73]
[74]. The etiology of this disease is unknown. Possible origins
are spontaneously draining mucoceles, infection with gas-forming
microorganisms, genetic predisposition or fibro-osseous dysregulation as
well as hormone-related dysregulation [74]. The currently most probable hypothesis is a valve mechanism
of the draining pathways of the paranasal sinuses that leads to a slow and
regular extension of the sinus due to the increased pressure and to
spontaneously draining mucoceles. Publications of the last 20 years further
indicate an association with meningiomas and arachnoid cysts [73]
[75]
[76]
[77].
Nasal endoscopy mostly shows inconspicuous findings of the middle nasal
meatus and the affected ostia if they can be assessed. Computed tomography
reveals a regular protrusion of the affected sinus (mostly), generally
without thinning of the bone. [Figure
8] shows a coronary CT scan of a patient with pneumosinus
dilatans. The sagittal reconstruction describes the protrusion of the
anterior wall of the frontal sinus as well as the altered nasofrontal
angle.
Fig. 8 Coronary and sagittal CT reconstruction of a patient
with pneumosinus dilatans with protrusion of the frontal bone.
A curative therapy approach is currently not available. Assuming a valve
mechanism, a functional sinus surgery may be taken into consideration with
dilation of the ostium and thus elimination of the stenosis. For patients
with esthetic impairment because of pneumosinus dilatans frontalis,
techniques of surgical modelling of the anterior wall of the frontal sinus
were described by Draf et al. [78]. In
cases of visual problems, the decompression of the optic nerve may be
discussed in dependence of the complaints and the location of the pathologic
findings. Even pneumosinus dilatans of the maxillary sinus may develop which
appears primarily as outward deformity [56].
2.3.4 Pneumocele
Pneumoceles are extensions of a paranasal sinus beyond the normal borders. In
contrast to pneumosinus dilatans, irregularities of the bony borders of the
affected sinus with thinning and partly integrity loss are found [69]
[79]. The symptoms are similar to the ones of pneumosinus
dilatans. When located in the maxillary, frontal, and ethmoid sinus, a
displacement of the orbital content with consecutive bulbar protrusion may
result [80]
[81]
[82]. One case report describes temporary visual loss in the
context of pneumocele of the sphenoid sinus [83]
[84].
As origin for the development of pneumocele, a valve mechanism in the area of
the ostium is assumed that inhibits a rapid pressure equalization between
the nasal cavity and the affected sinus.
In cases of bulbar protrusion, the orbita may be decompressed by resecting
the lamina papyracea. If the optic nerve is compressed in the area of the
sphenoid sinus because of imbalanced pressure of the nasal cavity and the
sphenoid sinus, the surgical restoration of the ventilation of the sphenoid
sinus is the therapy of choice. In the above-mentioned case report, a polyp
was resected that had obstructed the ostium.
2.3.5 Organized hematoma
Sinonasal organized hematomas are a rare benign disease. Repeated bleedings
occur that possibly develop a mass due to a very small ostium and/or
insufficient mucociliary clearance of the affected sinus. In the further
course, fibrosis and neovascularization occur. Because of the expansive
growth, surrounding structures may be destroyed so that imaging may be
similar to malignant growth or a pathology with locally aggressive expansion
of an inverted papilloma or fungal sinusitis [85]
[86]. Several trials have analyzed the characteristics of the
disease, however, without providing exact data regarding the incidence [85]
[86]
[87].
Primary complaints are often recurrent epistaxis, pains, pressure sensation
in the face, and sometimes hypesthesia in the supply area of the
infraorbital nerve [85]
[86]
[87]
[88].
CT scan and MRI reveal sinuses with expansive tissue masses, frequently with
extension to the ipsilateral nasal cavity [87]. Locally aggressive growth may lead to an expansion into the
ethmoid sinus, orbita, pterygopalatine fossa and infratemporal fossa, cheek,
and even the hard palate. Computed tomography depicts heterogenic areas with
irregular spotty contrast enhancement. Calcifications may occur. MRI shows
comparable contract enhancement in the T1 weighting with rather hypointense
rim.
Histopathology shows bleedings with fresh and older areas, extensively
dilated vessels, amyloid material with irregularly configured vessels, zones
with clear neovascularization as well as hemosiderin deposits and fibroses
[87].
Explorative endoscopy under general anesthesia is recommended for diagnosis
and therapy. The hematoma should be removed via an endonasal access. In the
context of the intervention, frequently diffuse bleedings occur. In order to
prevent further encapsulation of the findings, it is recommended to create
sufficiently wide accesses to the affected sinus. Recurrences are rarely
described in the currently available literature [85]
[86]
[87]
[88].
The expected endoscopic and radiological findings regarding silent sinus
syndrome, organized hematoma, and pneumosinus dilatans are listed in [Table 2].
Table 2 Expected endoscopic and radiological findings in
cases of silent sinus syndrome, organized hematoma and
pneumosinus dilatans, published in [56].
|
Disease
|
Endoscopic findings
|
Radiological findings
|
|
Silent sinus syndrome
|
Lateralization of the uncinate process
|
CT scan:
-
Reduction of the volume of the maxillary
sinus
-
Retraction of the maxillary sinus walls
-
Shift of the orbital floor in caudal
direction
-
Increased orbita volume
-
Homogenous opacification of the maxillary
sinus
-
The uncinate process is close to the orbita
|
|
Organized hematoma
|
Increasing tissue in the middle nasal meatus and the
nasal cavity, fibrin, granulations. Partly polypous
mucosal swellings and protrusion of the lateral nasal
wall
|
CT scan:
-
Blurred delimitations
-
Inhomogeneous contrast enhancement
-
Thinning of the walls of the maxillary sinus
-
Smoothly delimited bone destruction
MRI:
-
T1: homogeneous isointense with muscles,
heterogenic contrast enhancement
-
T2: inhomogeneous with hypointense margins
|
|
Pneumosinus dilatans
|
Inconspicuous findings
|
CT scan: Enlargement of the maxillary sinus beyond the
natural borders without thinning of the bony walls
|
2.3.6 Young syndrome
Young syndrome was first described by the urologist David Young who found
that 54% of the patients with obstructive azoospermia had pulmonary
defects [89]. In 1978, sinonasal
complaints were included in the list of symptoms. Since then, the disease is
defined as triad of obstructive azoospermia, chronic rhinosinusitis, and
pulmonary ectasia or chronic bronchitis [90]
[91].
With regard to the incidence of Young syndrome, no reliable data are
available. Mercury exposition seems to be associated with the development of
the disease. This assumption seems to be confirmed by the fact that the
initially described high incidence of 1:500 males is reduced to very few
cases today which might be due to the general elimination of mercury from
industry and medicine [92]. According
to the current stage of knowledge, a positive family history is no
predisposition for the development of the disease.
Young syndrome affects young males. The initial reason why they seek medical
advice is mostly infertility, only rarely chronic sinonasal or pulmonary
complaints. The chronic sinonasal complaints disappear at the end of
adolescence while pulmonary complaints persist [93]
[94]
[95].
The mucociliary clearance of affected patients is significantly longer,
which, however, is not a specific diagnostic criterium [96]. Initially assumed structural
deficits of the dynein arms within the cilia could not be confirmed as
origin. Instead, currently an altered consistency of the nasal mucosal film
is discussed that is made responsible for the patients’ complaints
[91].
Differential diagnosis must exclude cystic fibrosis, primary ciliary
dyskinesia, and Kartagener syndrome.
Wang et al. analyzed a cohort of 33 patients with obstructive azoospermia and
described 4 patients with documented history of chronic rhinosinusitis,
conspicuous imaging of the paranasal sinuses, positive family history as
well as medication that may impair the mucociliary clearance. As the number
of the cases described in the literature since the first description has
significantly decreased and because of the definition of chronic
rhinosinusitis that was inconsistently used for a long time, the existence
of Young syndrome was even doubted by Arya et al. in 2009 [91].
2.3.7 Primary ciliary dyskinesia
Primary ciliary dyskinesia is a structural and functional disorder of the
mobile cilia of the nasal and paranasal mucosa that leads to chronic
sinonasal and pulmonary complaints. Primary ciliary dyskinesia is
characterized by breathing complaints in infants, early year-round cough,
and nasal obstruction. Because of the missing ciliary function, the mucosal
film persists in the nose and the paranasal sinuses leading to purulent
secretion in affected patients. The correct diagnosis is a real challenge
because numerous diseases exist with similar symptoms. The Kartagener
syndrome is a triad of chronic rhinosinusitis, bronchial ectasia, and the
presence of situs inversus as consequence of ciliary dyskinesia [97].
The reason is a genetic disorder that leads to a disturbed ultrastructure of
the cilia of the nasal mucosa and thus to their functional loss. Currently,
33 genes are known that are associated with the development of primary
ciliary dyskinesia; the majority of them follows an autosomal-recessive
inheritance [97]. The prevalence
amounts to 1:15 000 live births.
In the context of primary ciliary dyskinesia, mutations of genes that code
for axonal structures lead to functionally impaired cilia. In cases of
primary ciliary dyskinesia, defects may include outer dynein arm defects,
inner dynein arm defects, central microtubular anomalies, radial radius
defects, and outer ultrastructural anomalies. Also the sperm tail and the
fimbria of the fallopian tube have mobile cilia so that infertility may
occur in men and women. Anatomical anomalies are possible because the defect
of the mobile cilia leads to an abnormal thoraco-abdominal development
during embryogenesis. Situs inversus is seen in 50% of the cases of
primary ciliary dyskinesia because the regular movement of the cilia is
disturbed and visceral rotation thus occurs accidentally [97]
[98]
[99].
The diagnosis if made based on a combination of symptoms and the results of
nasal or bronchial brush biopsy for confirmation of a disturbed ciliary
ultrastructure and ciliary motility. The analysis of the nasal mucosa with
high-velocity video-microscopy for assessment of the ciliary motility is
very sensitive and specific.
In patients older than 5 years, nasal nitrogen monoxide measurement is
sensitive and may facilitate the diagnosis. The content of the nitrogen
monoxide produced by the mucosa is significantly lower in patients with
primary ciliary dyskinesia compared to healthy individuals. Because of the
partly similar symptoms, sweat-chloride test and also genetic tests are
reasonable in order to exclude cystic fibrosis [97]
[100]
[101]
[102].
Large randomized long-term trials regarding the therapy of primary ciliary
dyskinesia are not available so that many care-related aspects are based on
empirical recommendations of other pulmonary diseases with similar
pathologies. Despite the attempt to find a European consensus from the
experience of important specialized centers, there are enormous differences
regarding the approach to treat the disease [103]
[104].
Regular care in narrow intervals by a pulmonologist is required. Regular
spirometry, sputum cultures, and chest x-ray controls are recommended.
Especially in children, the regular ENT-specific follow-up is necessary
because of recurrent otitis and resulting conductive hearing loss.
Nasal symptoms usually manifest as rhinorrhea and nasal obstruction. Polyp
development in affected children is rarely observed. Prophylactic antibiotic
therapy may help to reduce the infectious element of rhinosinusitis. The
indication of sinus surgery should be made reluctantly because its effect is
controversially discussed. There is no evidence for the benefit of
intranasal steroids, however, they may be helpful in the treatment of
additional allergic rhinosinusitis. Improved genetic diagnosis is the first
step towards a future gene-based treatment strategy such as for example gene
replacement therapy, aminoglycoside-induced translational read-through, and
pharmacogenetic approaches [105].
2.4 Tumors
Tumors of the sinonasal tract and the anterior skull base may develop primarily
in this region or have their origin in a remote location of the head and neck
area, however, manifesting within the sinonasal tract or at the skull base. The
classification of the World Health Organization of 2017 indicates another group
of neoplasms. Their occurrence within the sinonasal tract and at the anterior
skull base is important from the point of view of differential diagnosis. The
following classification of benign and malignant entities of the sinonasal tract
and the anterior skull base was made based on the classification of the WHO
[106].
2.4.1 Benign tumors
Benign tumors of the sinonasal tract are classified into three main
categories that will be described in the following chapters:
2.4.1.1 Tumors of the soft parts, nerves, and vessels
2.4.1.1.1 Mucosal papillomas
Three different variations of mucosal papillomas are described. They
all have in common the development from the so-called Schneiderian
membrane that lines the nasal cavity and the paranasal sinuses [107]
[108]
[109]
[110]. The ciliated mucosa of
ectodermal origin develops as an invagination of olfactory ectoderm
in the 4th week of embryonic development [111]. From a pathological point
of view, the difference is made between 3 sinonasal (Schneiderian)
papillomas:
-
Exophytic papilloma
-
Oncocytic papilloma
-
Inverted papilloma
Exophytic papilloma
This entity is also known as fungiform of septal papilloma and
represents 6–50% of all Schneiderian papillomas. In
contrast to the inverted papilloma, it appears mainly in males
around the age of 20–50 years. In most cases it manifests at
the anterior nasal septum, sometimes also at the lateral nasal wall.
Multifocal occurrence is possible, bilateral manifestations have
only very rarely been described [112]. Manifestation in the sinuses is extremely rare. The
exophytic papilloma imposes macroscopically as rosy to grey mass
with pleated surface. The therapy of choice is its excision.
Malignant degeneration has not been described.
Oncocytic papilloma
With 2–26%, this entity is the rarest appearance of
Schneiderian papillomas. The gender distribution is nearly balanced,
a manifestation is mostly apparent after the 5th decade
of life. Oncocytic papillomas develop exclusively at the lateral
nasal wall, the ethmoid or maxillary sinus [113]
[114]. They are very similar to
inverted papillomas so that some authors describe oncocytic
papillomas as microscopic variation of inverted papillomas [111]
[115]
[116]. Malignant degeneration is
possible – in analogy to inverted papillomas (see the
following chapter).
Inverted papilloma
Inverted papillomas represent the most frequent entity of
Schneiderian papillomas with 47–78%. The have a
polypous, mostly lobular growth, microscopically the epithelium
grows downward into the mucosal stroma. In 48%, the site of
origin is the ethmoid sinus, in 28% the maxillary sinus, in
7.5% the sphenoid sinus, and in 2.5% the frontal
sinus. Also manifestations at the mucosa of the nasal septum are
possible. Typically, unilateral manifestation is found. Bilateral
manifestation has only rarely been described [117]
[118]. Secondary metachronous
malignant degeneration has been observed in up to 4% of the
inverted papillomas with squamous cell carcinoma as most frequent
entity. In cases of recurrence of an inverted papilloma, this rate
increases to up to 11% [119]
[120]
[121].
The incidence of inverted papillomas amounts to
0.5–1.5:100 000 people per year with an age peak
between the 5th and 6th decade. Males are more
frequently affected (m:f 2–5:1) [108]
[118]
[122].
Patients suffering from inverted papilloma report about nasal
obstruction, epistaxis, and epiphora if an affection of the lacrimal
drainage or the inferior nasal meatus is present. Depending on the
location and invasive growth behavior, mucoceles or bulbar
protrusion may develop.
Clinically, mostly an edematous, rather transparent polyposis is
seen. However, the appearance is highly variable because the
polypous masses may impose as inflammatory and fleshy [123].
Computed tomography is the imaging technique of choice because bone
erosions indicating malignant transformation become visible. Often,
hyperostosis or sclerosis of the bony borders is found at the point
of origin of the inverted papilloma. Calcification within the mass
may also occur [124].
The therapy of choice consists of excision including the directly
surrounding mucosa. A safety margin of 1–1.5 cm should be
considered [62]
[125]
[126]. Furthermore, the removal
or thinning of the bone in the area of the point of origin is
required. Recurrences occur frequently if the resection has been
insufficient [127]. In cases
of defensive polypectomy or local excision, recurrences have been
described in up to 78% [128]. Within the last few years, more efficient accesses
to all areas of the maxillary sinuses could be established due to
the introduction of medial maxillectomy and its variations [64]. This technique has mostly
replaced the former Caldwell-Luc access [129]
[130]. A review article with
position paper showed equal, if not even better outcomes for
endoscopic resection of inverted papillomas. If the findings are
located in the maxillary sinus, the endonasal access is preferred to
the open approach with regard to the incidence of recurrences [121]
[131]. If a prelacrimal access
is chosen, the recurrence rate is even lower [125]. In general, long-term
results are the better, the more thorough the pathologic mucosa is
resected [118].
2.4.1.1.2 Leiomyomas
Leiomyomas are benign tumors with muscular differentiation. In cases
of angioleiomyomas, additionally a vascular differentiation is
present.
In the head and neck region, they are found extremely rarely and
represent not even 1% of all leiomyomas occurring [132]. In most cases, the
patients are adults without preference of one gender. Most
leiomyomas occurring in the sinonasal tract are have a vascular
differentiation [106]
[132]
[133].
The tumor growth remains unnoticed and leads to unspecific symptoms
such as pressure sensation and slowly progredient nasal obstruction.
Epistaxis and pain may develop later.
Macroscopically, nasal leiomyomas present as polypoid to nodular and
well delimited lesions with a whitish/brownish cutting
surface. The mass is usually located below intact mucosa.
Ulcerations rarely occur. Spindle-shaped tumor cells are arranged in
overlapping fascicles with oval, long, cigar-shaped cell nuclei
without atypia. Eosinophilic, fibrillary cytoplasm is present. In
contrast to leiomyosarcoma, there are no mitotic alterations.
Angioleiomyomas additionally have prominent vessels that are
surrounded by muscle cells and closely connected to them [106].
Despite their rare occurrence, malignant transformation to
leiomyosarcoma is possible. Hence, therapy should not be delayed.
The therapy of choice is tumor resection. In cases of complete
excision, the prognosis is very good and recurrences are extremely
rare [134]
[135]
[136].
2.4.1.1.3 Hemangiomas
In 1897, the French physicians Poncet and Dor were the first who
described lobular capillary hemangiomas which they called
botryomycosis hominis [137].
Originally it was assumed that this disease was transferred from
horses to humans, which was refuted by Hartzell some years later
[138]. Today the terms of
granuloma pyogenicum, capillary hemangioma, and epulis gravidarum
are used as synonyms.
Mucosal hemangiomas represent about 10% of all head and neck
hemangiomas and about 25% of all non-epithelial neoplasms of
the sinonasal tract [106]
[139]
[140].
Hemangiomas have their origin in the capillary vessels when their
density becomes too high and they nonetheless keep their original
architecture with trunk and ramifications as well as surrounding
pericytes. A reactive development of lobular capillary hemangiomas
is also discussed due to the association with traumata or
manipulations and hormonal changes during pregnancy [141]. An accumulation is
further reported in the context of the application of the protein
kinase inhibitor Vemurafenib [142].
Lobular capillary hemangiomas (granuloma pyogenicum) occur in all
ages, however, an increased incidence is observed in children and
adolescent males as well as females of childbearing age. Beyond the
age of 40, the gender distribution is balanced.
The lesions may grow up to a size of 5 cm. Their surface is red
bluish and located under intact mucosa. The tumor is soft on
palpation, compressible, and sometimes appears polypous.
Histologically, lobular capillary hemangiomas show a trunk and
branch-like pattern of capillary proliferation surrounded by
pericytes. The single lobuli are separated by a fibromyxoid stroma.
Inflammatory infiltrations mainly occur in ulcerated surfaces [141].
The primary clinical symptom is unilateral epistaxis followed by
painless obstructive masses. The most frequent manifestation sites
are the anterior nasal septum and the head of the inferior
turbinate. A development in the paranasal sinuses is also possible
as well as an affection of the outer nose.
The therapy of choice consists of tumor excision. More extended
findings may be embolized before surgery in order to reduce the risk
of bleeding. Pregnant patients may expect regression after birth.
Multiple recurrences must be expected mainly in children after
incomplete resection [143].
2.4.1.1.4 Schwannomas
Schwannomas are benign tumors originating from Schwann cells. They
are also known as neurilemmoma and benign peripheral nerve sheath
tumors.
25–45% of all schwannomas develop in the head and
neck region. Most frequently, manifestations are found in the
mentioned area along the vestibulo-cochlear nerve. Only about
4% of all schwannomas manifest in the sinonasal tract.
According to Orphanet, the incidence of benign schwannomas amounts
to 6:100 000, the sinonasal occurrence can be expected to be
even lower. The age span of sinonasal manifestations is rather wide
with 17–81 years and has its peak at the age of 50 without
preference of one gender [106]
[144].
The origins are found along the branches of the 5th and
9th cranial nerve as well as the autonomous neural
system. The developing tumors may affect the nasal cavity and all
paranasal sinuses [144]
[145].
Primary symptoms are nasal obstruction, epistaxis, hyposmia, and
sometimes pains as well as the development of Horner’s
syndrome. Imaging techniques show an inhomogeneous mass with low
density and sometimes bone arrosion. Differential diagnosis must
exclude esthesio-neuroblastoma, adenoid cystic carcinoma, and
squamous cell carcinoma. [Figure
9] shows a computed tomography scan of a big schwannoma of
the maxillary nerve that originates in the foramen rotundum. Magnet
resonance imaging shows a hyperintense, inhomogeneous signal of the
mass in the T1 weighting.
Fig. 9
a, b, coronary and sagittal CT reconstruction
of a patient with schwannoma of the maxillary nerve. In
[fig 9b], the
origin is seen at the right foramen rotundum. [Fig 9c] shows a
T1-weighted coronary MRI of the schwannoma of the right
side.
Schwannomas have a globular, well delimited configuration. The tumor
is solid on palpation and has a yellowish brounish, sometimes cystic
surface [106]. Histologically,
schwannomas are uncapsulated tumors that are composed of so-called
myxid Antoni A areas rich in cells with nuclear palisades as well as
myxoid Antoni B aeas that are poor in cells. The tumor cells present
a fusiform image with cytoplasmatic extensions giving them an
undulated to spindle-shaped appearance. Mitoses are extremely
sparse, necrotic areas do not exist [106].
In exceptional cases, degeneration of a schwannoma is possible. After
complete tumor resection, recurrences are very rare. Due to the very
slow tumor growth, subtotal tumor resection is possible in cases of
strong adherence to crucial neurovascular structures [144]. Fibers of the affected
nerve running within the tumor are generally without any function so
that resection does not lead to neurological deficits [146]. In cases of cervical
schwannomas, intracapsular dissection is recommended in order not to
destroy the neural fascicles surrounding the tumor [147]. Due to the narrow
circumstances and the small access, however, it is only possible to
a limited extent in cases of schwannomas of the paranasal
sinuses.
2.4.1.1.5 Neurofibromas
Neurofibromas are benign peripheral nerve sheath tumors of schwann
cells, perineural-like cells and intraneural fibroblasts. Also the
term of fibroneuroma is used as synonym.
Sinonasal manifestations of neurofibromas are very rare and may occur
in all ages. The peak of affected patients is at the age of 50. For
patients suffering from neurofibromatosis type 1, it is at the age
of 35 [148]. The prevalence of
neurofibromatosis amounts to 21:100 000. Neurofibromatosis
is responsible for about 10% of sinonasal neurofibromas.
They are most frequently located at the nasal entrance and the
maxillary sinus with predominantly unilateral manifestation.
Affected patients complain about nasal obstruction, epistaxis, and
pains of the affected areas [148]
[149].
Neurofibromas have a shiny, fusiform, and sometimes polypoid surface
and are solid on palpation [148]
[149].
Also neurofibromas are unencapsulated tumors that are closely
associated with neural branches. Modified schwann cells, intraneural
fibroblasts, and perineural hybrid cells with coarse collagen
strains as well as mast cells in a mucopolysaccharid-rich stroma
determine the histopathological picture. Oval to spindle-shaped
cells with undulated, pointed nuclei with thin cytoplastmatic
processes extending to the stroma are present.
In cases of complete tumor resection, the prognosis is very good.
Recurrences occur in 5% especially when the tumor is
resected incompletely. Malignant transformation is extremely rare
[150].
2.4.1.1.6 Meningiomas
Meningiomas are benign tumors of meningothelial origin. Sinonasal
menigniomas originate from extracranial, disseminated arachnoid
cells within nerve sheaths or vessels.
Sinonasal meningiomas are extremely rare and responsible for less
than 0.1% of all primary sinonasal neoplasms, 2% of
all meningiomas, and 24% of all extracranial meningiomas.
The difference must be made to intracranial findings with
extracranial extension to the sinonasal tract.
Patients of every age are affected and there is no predilection of
the female gender – in contrast to intracranial meningiomas.
The average of disease onset is 48 years with an age range of
13–88 years.
Manifestations are often found in the nasal cavity as well as the
paranasal sinuses. Manifestations in only one of the two locations
are even rarer. Interestingly, most tumors of this kind are located
on the left side [151]
[152]
[153].
Patients frequently present with endonasal, polyp-like masses, nasal
obstruction, epistaxis, sinonasal complaints, pains, cephalgia,
exophthalmos, periorbital edema, or visual disorders [106].
Bone infiltrations and mucosal ulcerations are possible. The cutting
surface of the tumor has a grey-whitish, brownish, or reddish color.
Calcifications and bone fragments can frequently be identified.
Microscopically, extracranial meningiomas may have very different
appearances. Often they reveal meningotheliomatous growth with
indistinct cell borders. Intranuclear pseudo-inclusions and psammoma
bodies are frequently observed.
Out of the 15 histological types of meningiomas, meningothelial,
transitional, metaplastic, and psammomatous tumors develop in the
sinonasal tract. Most tumors may be classified as WHO grade I.
Sinonasal manifestations of meningiomas grade II (atypical
meningiomas growing rapidly) or grade III (anaplastic meningiomas
with infiltrative growth) are extremely rare [154]
[155].
Differential diagnosis must exclude carcinomas, melanomas, or
aggressive psammomatous ossifying fibromas.
The complete surgical excision is the therapy of choice even if
recurrence rates of up to 30% are reported. In cases of
meningiomas that cannot be completely resected radiotherapy may be
applied to inhibit their growth [156]
[157]. The
overall prognosis of sinonasal meningiomas is favorable. Metastasis
and malignant transformation are not described [106].
2.4.1.2 Bone tumors
2.4.1.2.1 Osteomas and Gardner’s syndrome
Osteomas are benign, slowly growing tumors of the cranial bone that
manifest frequently in the paranasal sinuses and the skull base.
Most frequently, the bone proliferations are found in the frontal
sinus (70–80%), the ethmoid sinus
(20–25%), the maxillary sinus (5%), and
extremely rarely the sphenoid sinus. The incidence of osteomas in
the paranasal sinuses amounts to about 3% [118]
[158]
[159]. Thus, according to the
definition, osteomas are no rare disease of the paranasal sinuses.
However, they may be a symptom in the context of Gardner’s
syndrome so that they will be discussed also in the present
article.
The etiology of the tumors is not fully clarified. Current theories
assume embryonic malformations, traumatic or inflammatory triggers,
genetic predisposition, and disorders of the calcium metabolism as
origin of the disease [118]
[158]
[160].
Only about 10% of all osteomas of the paranasal sinuses
become symptomatic. Complaints of affected patients are often
associated with obstructions of the drainage of the paranasal
sinuses, i. e. recurrent acute sinusitis and also chronic
sinonasal complaints. Pressure sensation, facial pains, and
rhinorrhea are classic symptoms. When neighboring structures of the
paranasal sinuses are involved, the orbita or the optic nerve may be
compressed, in cases of intracranial involvement, pneumatocephalon
may result [158]
[161].
Computed tomography shows hyperdense, homogenous, well delimited
areas. Magnet resonance imaging may help excluding ossified fibromas
or fibrous dysplasia in the context of differential diagnosis [118].
According to the current consensus, asymptomatic osteomas should be
treated by means of “wait and scan” strategy [162]
[163]
[164]. Regular CT controls every
2 years reveal information about the growth rate of the tumor [165]. In cases of symptomatic
osteomas, the possibly complete resection is the method of choice.
Depending on the location, endonasal or open surgical procedures are
applied.
Gardner’s syndrome
With an incidence of 1:8000, Gardner’s syndrome is considered
as rare disease [166]. In the
USA, the prevalence currently amounts to 1:1 000 000
people. Patients suffering from Gardner’s syndrome often
have (multiple) osteomas, soft part tumors, and intestinal polyposis
(especially in the colon). Gardner’s syndrome is inherited
autosomal-dominantly.
A genetic correlation with the development of Gardner’s
syndrome was identified in a mutation of the gene for adenomatous
polyposis coli (APC) located on chromosome 5. This tumor suppressor
gene is responsible for the production of the APC protein regulating
the cell growth in the cell cycle [167]
[168]
[169].
Regular colonoscopy is obligatory for affected patients. If APC gene
mutation is confirmed, the development of colon cancer is considered
as sure as of an age of 40 years so that colectomy is recommended if
20 or more colon polyps are found [166]. Hence, differential diagnosis should always exclude
Gardner’s syndrome if multiple osteomas are present.
2.4.1.2.2 Fibrous dysplasia
In cases of fibrous dysplasia, mesenchymal bone development disorder
is found that is caused by postzygotic somatically activating
mutations. This leads to an activation of the adenylyl cyclase and
increased cyclic AMP that affects the subsequent signaling pathways
and causes the substitution of healthy bone by fibrous tissue and
abnormally structured bone [170]. The incidences amounts to
1:4000–10 0000 [171]
[172].
Depending on the location of the bone disease centers, the patients
report about cephalgia and pressure sensation. If located at the
tabula externa of the cranial bone, deformities with respective
esthetic impairment become visible. Manifestations at the ostia or
key points of the sinus drainage may lead to sinonasal complaints
that can mask the basic disease for a long time.
Because of the rare occurrence of the disease, only few data exist on
the treatment of fibrous dysplasia. Causal therapy currently does
not exist. Pain reduction was reported after the application of
bisphosphonates [173]
[174]
[175]. Suppression of the
osteoblastoma activity, however, could not be found [176]. In cases of asymptomatic
course, wait-and-see is the preferred strategy. Functional
impairment and complaints such as cephalgia justify surgical
procedure depending on the location of the manifestation.
Prophylactic surgical therapy is not recommended, instead regular
imaging controls should be performed according to available data
[177]
[178].
2.4.1.2.3 McCune-Albright syndrome
McCune-Albright syndrome was first described in 1936 as a triad of
fibrous dysplasia, café-au-lait spots of the skin and
precocious puberty [179]. The
clearly variable phenotype that is known today makes McCune Albright
syndrome an interdisciplinary challenge.
The reason for the development of the syndrome is a mutation of the
GNAS1 gene (guanine nucleotide binding protein alpha stimulating
activity polypeptide 1) which is located on chromosome 20.
The rareness of this disease leads to an insufficient
characterization of the sinonasal involvement in patients with
McCune-Albright syndrome. Current knowledge about the symptoms comes
mainly from case reports describing complications of the disease.
The prevalence of the disease is estimated to 0.55:100 000
[2].
Patients with McCune-Albright syndrome primarily suffer from weakness
of the extremities or pain sensation. Most frequently, the proximal
femur is affected. Fractures of the affected bone areas are often
seen in childhood with decreasing incidence in direction of
adolescence [180]. Bone
deformations under strain are characteristic leading to the
craniofacial stigmata that are typical for the disease. Craniofacial
manifestations of fibrous dysplasia show a slow growth with painless
swelling that sometimes lead to a clear asymmetry of the midface
([Figs 10] and [11]). Mild courses are often
diagnosed accidentally in the context of X-ray of the teeth and of
computed tomography performed in cases of polytrauma [170]. Severe courses frequently
lead to pain sensation, paresthesia, occlusion disorders, hearing
impairment, and visual disorders [170]
[178]
[181]
[182]. In up to 50%,
affected patients have impairment of the thyroid function, mostly
hyperthyroidism. In about 15% of the patients, GNAS leads to
an increase of prolactin and GH in the pituitary gland. The latter
leads to characteristic craniofacial changes that are obvious in
most patients [183].
Fig. 10 Typical craniofacial changes of a patient
suffering from McCune-Albright syndrome.
Fig. 11 Coronary and axial CT scan of a patient with
McCune-Albright syndrome.
DeKlotz et al. could show craniofacial alterations in 112 patients of
a cohort of 130 patients with McCune-Albright syndrome [182]. 33% of them
report about cephalgia or facial pain, nasal obstruction was found
in 29% of the cases and chronic sinonasal complaints as well
as hyposmia in 7%, respectively. Progress of the sinonasal
involvement of fibrous dysplasia after adolescence is rare. Severe
complications in the context of normal progress of the disease are
rarely found ([Fig. 12]).
Fig. 12 Hemangioendothelioma of the left nasal cavity with location at
the nasal septum (on the left side) as sanguinolent mass.
Such as for fibrous dysplasia, there is no causal therapy.
Bisphosphonates do not show relevant therapy success [184]
[185]
[186]. According to the general
consensus, the conservative procedure is favored, while surgical
measures are applied in cases of significant symptoms or compression
of vital structures [187]
[188]
[189]
[190].
2.4.1.3 Other soft tissue tumors
In the following chapter, rare benign entities of the sinonasal tract
will be discussed that have an epithelial, odontogenic, and neuroglial
origin. Those are:
2.4.1.3.1 Respiratory epithelial adenomatoid hamartoma
(REAH)
Respiratory epithelial adenomatoid hamartomas have been described in
1995 for the first time [191].
In the context of this disease, tumor-like proliferation of glands
in the stroma develop that is covered by multiple-row ciliated
epithelium. Manifestations are found in the paranasal sinuses, the
nasal cavity, and the nasopharynx. Uni- or bilateral manifestations
as well as associations with chronically polypous rhinosinusitis are
possible. The number of cases described worldwide fluctuates between
60 [191]
[192]
[193]
[194]
[195]
[196] and about 200 [197]
[198]. Because of its low
incidence, the syndrome is considered as rare disease.
Especially males between 30 and 90 years of age are affected by the
neoplasm [191]
[195]. The symptoms usually
correspond to those of chronic rhinosinusitis, i. e.
pressure sensation and nasal obstruction, epistaxis and rhinorrhea,
facial pain and hyposmia [191]
[192]
[193]
[199]
[200].
Most frequently, the epithelial adenomatoid hamartoma in the nasal
cavity manifests at the posterior nasal septum. Frequently, both
sides are affected [191]
[192]
[193]
[194]
[195]
[196]
[199]. Often, it is diagnosed in
the context of nasal polyposis. In cases of manifestation at the
olfactory fossa, clear enlargement may develop which is relevant
with regard to differential diagnosis of nasal polyposis [201]
[202]. An enlargement of the
olfactory fossa in cases of local affection, missing contrast
enhancement in the CT scan and otherwise inconspicuous paranasal
sinuses, should lead to the suspicion of epithelial adenomatoid
hamartoma.
Due to the initial impression, the diagnosis is often confirmed by
biopsy. Regarding therapy, the complete excision should be
performed. Recurrences have not been observed in the trials that are
available within a period of 5 years [191]
[193]
[199]
[203]
[204].
2.4.1.3.2 Sinonasal ameloblastoma
Ameloblastomas are benign, but aggressive odontogenic tumors in most
cases affect the mandible. Only about 15% occur in the
maxilla. A subgroup are sinonasal ameloblastomas that probably
originate from the epithelial lining of the paranasal sinuses.
Locations of manifestation are the paranasal sinuses, in some cases
also the involvement of the nasal cavity.
Primary symptoms are a painless mass leading to nasal obstruction and
pressure sensation. In contrast to ameloblastomas of the maxilla,
sinonasal variations show a solid image with partly opacification in
radiography [205].
Histologically, sinonasal ameloblastomas are identical with
manifestations of the oral cavity, with classic characteristics of
palisaded columnar basal cells surrounding a central proliferation,
similar to the radial reticulum of a developing tooth. In the
paranasal sinuses, an ameloblastoma-like proliferation can be
depicted under the intact mucosa. These findings are – with
at the same time absent connection of the maxilla – a
confirmation for a primary sinonasal origin of the tumor. In
contrast to the gnathic variation, the prevalence of the sinonasal
ameloblastoma is increased in males. Overall, the incidence amounts
to about 0.5:100 000 000 [206]
[207]. The age peak is at about
60 years [208] and thus about
15–20 years higher than the variation localized at the jaw
[106].
The treatment success and thus the absence of recurrences depend on
the complete surgical excision of the findings. Detailled imaging is
essential in order to avoid residues. In most cases, recurrences
occur within 1–2 years, however, they may also develop after
a clearly longer time [205].
Descriptions of mortality caused by sinonasal ameloblastoma,
metastasis or malignant transformation do not exist in the current
literature.
2.4.1.3.3 Chondromesenchymal hamartoma
Chondromesenchymal hamartomas are benign, slowly growing masses with
locally destructive, tumor-like growth and different mesenchymal
parts. The terms of nasal chondromesenchymal hamartoma and
mesenchymom are used as synonyms.
The tumor is rare and mostly occurs in children, rarely also in
adolescents and adults with a slight predilection of the male
gender. In the current literature currently 60 cases have been
published [209].
Paranasal sinuses, nasal cavity, and orbita may be affected.
Extension along the skull base and in intracranial direction are
possible [209]
[210].
Affected patients complain about symptoms of nasal obstruction and
pressure sensation of the affected region. Because of the
destructive growth with bone arrosion, imaging may lead to the
impression of malignancy.
Macroscopically the solid and whitish tissue looks like cartilage.
Microscopically, a lobular proliferation pattern of mature and
immature hyaline cartilage is seen with various cellular and fibrous
background. The cartilage and stroma parts can be penetrated with
bony trabecular structures or surround bony islands [106]
[211].
After complete tumor resection, the recurrence rate is very low and
the prognosis is favorable.
2.4.1.3.4 Nasal glioma
Nasal gliomas (also known as heterotopic CNS tissue) are
accumulations of heterotopic neuroglial tissue. Manifestations may
occur in the nose and at the outer nose. In 60% the mass
appears at the nasal ridge, in 30% within the nasal cavity.
Even rarer, in about 10% of the cases, the tumors are
diagnosed in both locations that are connected through a defect of
the bone [212].
In most patients, the tumor is already present at the time of birth.
About 90% of the cases are diagnosed at the age of 2 years
with an equal distribution over both genders.
Clinically, a well delimited, smooth tumor is seen that is localized
submucously and cannot be compressed.
In cases of findings located within the nasal cavity, nasal
obstruction may occur that is the main symptom of nasal glioma
– beside the esthetic impairment of findings located at the
nasal ridge.
More rarely, manifestations are found in the paranasal sinuses,
pharynx, nasopharynx, tongue, palate, tonsils, and within the orbita
[213].
In contrast to paranasal celes, gliomas do not increase in cases of
venous congestion and do not pulsate. This may be differentiated by
means of the Fürstenberg test consisting of compression of
the jugular vein. Additionally, CT scan and MRI reveal a soft tissue
mass without intracranial part or a bony defect at the transition to
the anterior cranial fossa.
Macroscopically, the tumor appears as polypoid, soft, grey-brownish
mass with a size of 1–3 cm. Microscopically, the tumor is
uncapsulated and composed of islands of glia tissue with different
size. Inbetween, astrocytes and ribbon-like strains of vascularized
connective tissue are found. The glia tissue flows into the stroma
of the dermis. Mitosis is not found.
Differential diagnosis must exclude nasal encephaloceles where CNS
tissue with easily identifiable neurons is found in comparison to
nasal gliomas. Nonetheless, recurrences may lead to fibrous changes
of the tumor that make an exact differentiation of a nasal glioma
very difficult.
Complete excision of the nasal glioma is the therapy of choice. In
cases of incomplete resection, recurrences may occur in about
30% of the cases. Locally aggressive behavior or a tendency
of malignant transformation are not observed [212].
2.4.1.3.5 Cholesteatoma
Cholesteatomas are chronic-putrid inflammations caused scattered
keratinizing squamous epithelium leading to bone destructions.
Typically, these pathologies are found in the middle ear, however,
nearly 30 case reports are found in the current literature
describing manifestations within the nasal cavity [214]
[215]. The most frequent
manifestation site is the frontal sinus, followed by the maxillary
sinus and the ethmoid cells. A recent report presents a
manifestation in the sphenoid sinus ([Figs 13] and [14]).
Fig. 13 T2-weighted MRI of a cholesteatoma of the sphenoid sinus (on
the left, axial, on the right sagittal layer) (courtesy of Prof. Dr. S.
Kösling, Department of Radiology, University Hospital of Halle).
Fig. 14 Endoscopic image of the intraoperative findings of the
cholesteatoma of the ethmoid sinus (courtesy of A. Gey, Prof. Dr. S.
Plontke, Dr. A. Glien, Department of Oto-Rhino-Laryngology, University
Hospital of Halle).
The origin may be a congenital cell scattering in the context of
embryogenesis or secondary scattering e. g. by surgical
interventions. Also metaplasia in the context of chronic
inflammations are discussed as origin [215].
The complaints depend on the location and may include cephalgia,
visual disorders, pressure sensation, rhinorrhea, and failure of the
cranial nerves.
The therapy of choice is the surgical and possibly complete resection
that under certain circumstances is not always possible. The
objective of the surgery should be a possibly wide drainage of the
affected cavity in order to allow postoperative controls and if
needed cleaning if the cholesteatoma could not completely be
resected.
2.4.2 Malignant tumors
Malignomas of the nasal cavity and the paranasal sinus represent
0.2–0.8% of all malignant neoplasms in humans [10]. The incidence of malignomas in the
nasal cavity and the paranasal sinuses amounts to 1.5:100 000 in
males and less than 1:100 000 in females. Consequently, all
malignant entities in this anatomic region must be considered as rare
diseases.
2.4.2.1 Malignant epithelial tumors
2.4.2.1.1 Squamous cell carcinomas
2.4.2.1.1.1 Keratinizing squamous cell carcinoma
Sinonasal squamous cell carcinomas are malignant neoplasms that
originate at the surface of the epithelium of the nasal cavity and
the paranasal sinuses and have a differentiation of squamous
epithelium.
The affection of the sinonasal tract by squamous cell carcinomas is
rare. It is the location of the head and neck that is less
frequently affected by this entity [216]. The age of disease onset is between the
6th and 7th decade of life with
significantly more male patients (m:w=2:1) [106]
[216]
[217]
[218].
Tobacco consumption increases the risk of the development of squamous
cell carcinomas in the sinonasal tract, however significantly less
than in other locations of the head and neck [219]
[220]
[221]. High-risk HPV infections
are mostly associated with the occurrence of non-keratinizing
squamous cell carcinomas. In rare cases, sinonasal papillomas can
transform after malignant degeneration into keratinizing or
non-keratinizing squamous epithelium [222].
The most frequently observed site of manifestation is the maxillary
sinus, followed by the nasal cavity and the ethmoid sinus. Affection
of the sphenoid or frontal sinus is extremely rare [106].
Initially, affected patients have unspecific complaints such as nasal
obstruction, epistaxis, and rhinorrhea or sinonasal complaints.
Pains about the region concerned, bulbar protrusion or diplopia and
paralysis are symptoms of more extended disease. In older patients,
it may manifest by a maxillary prosthesis that does no longer fit
when the hard palate is infiltrated.
Macroscopically, the tumor grows exo- or endophytically with variable
ulcerations, necrotic areas, and hemorrhagic parts. Microscopically,
the tumor has identical characteristics as manifestations in other
head and neck regions. Those are irregular nest formation and
ribbon-like alignments of eosinophilic cells that show important
keratinization and induce desmoplastic stroma reaction. The
difference is made between well, moderately, and poorly
differentiated keratinizing squamous cell carcinomas.
The therapy of choice is the tumor resection with adjuvant
radiotherapy. In cases of inoperable findings, primary
radiochemotherapy should be performed. The 5-year survival rate for
sinonasal squamous cell carcinomas amounts to 50–60%
and strongly depends on the tumor stage at the time of diagnosis.
Carcinomas of the nasal cavity have a more favorable prognosis than
manifestations within the paranasal sinuses because they only lead
to complaints in higher tumor stages [216]
[217]
[218]
[223]
[224].
2.4.2.1.1.2 Non-keratinizing squamous cell carcinoma
Non-keratinizing squamous cell carcinomas are characterized by a
distinct ribbon-like growth pattern with missing or impaired
maturation.
Other terms that are used are Schneiderian carcinoma, cylinder cell
carcinoma or transition carcinoma.
Non-keratinizing squamous cell carcinomas represent about
10–27% of the sinonasal squamous cell carcinomas.
They affect patients in the 6th and 7th decade
of life, among them clearly more male patients are found [225]
[226]
[227]
[228].
The risk factors are similar to those of keratinizing squamous cell
carcinomas of the sinonasal tract, however, in
30–50% of the cases, transcriptionally active
high-risk HP viruses can be identified. Between 2 and 10% of
the sinonasal papillomas may transform to malignant keratinizing and
more rarely to non-keratinizing squamous epithelium [106]
[222].
Macroscopically, the tumor shows a variable exophytic and/or
inverted growth pattern with fragile structures and necrotic as well
as hemorrhagic areas. Microscopically, the tumors grow as extending
foci or anastomosing ribbon-like alignments of cells in the
submucosa with a lining of smooth stroma. Papillary properties can
be identified within or at the surface of the tumor [106].
Similar to keratinizing sinonasal squamous cell carcinoma the
endonasal or open tumor resection should be performed followed by
adjuvant radiotherapy, alternatively to primary radiochemotherapy
for non-resectable findings. The overall 5-year survival rate of
non-keratinizing squamous cell carcinomas amounts to about
60%. HPV-associated carcinomas have better survival chances
even if the prognostic significance is not so strongly supported as
for tumors of the oropharynx [226]
[229]. Lymph
node metastases are present at the time of first diagnosis in 3.3 to
26% of the cases [230]
[231].
2.4.2.1.1.3 Spindle cell/sarcomatoid squamous cell
carcinomas
Spindle cell squamous cell carcinomas or sarcomatoid carcinomas of
the sinonasal tract are special forms of squamous cell carcinomas
that are defined by the presence of predominantly malignant spindle
cells and/or pleomorphic cells.
This special type manifests mainly in older male patients. The tumor
is extremely rare in the sinonasal tract and represents less than
5% of all squamous cell carcinomas in this region [226]
[232]
[233]
[234].
The development of spindle cell squamous cell carcinomas is closely
associated with tobacco consumption and exposition to radiation. In
the few cases that are known up to now, no HPV infection could be
identified [226]
[235]
[236].
Symptoms of affected patients are initially unspecific and mostly
express as nasal obstruction and epistaxis. In higher tumor stages,
facial swellings and diplopia as well as pains of the affected areas
may occur [106].
Spindle cell squamous cell carcinomas grow as polypous masses with
ulcerating surface and are similar to the macroscopic appearance of
more frequently occurring laryngeal findings. They originate from
squamous epithelium and show variable differentiation with
epithelial mesenchymal transition. The tumors may contain residues
of dysplastic squamous epithelium and often reveal areas with
transition to malignant spindle or pleomorphic tumor cells [106].
With regard to the prognosis and predictive factors in cases of
sinonasal manifestation, no exact data are available because of the
extremely low number of cases.
2.4.2.1.2 Lymphoepithelial carcinoma
Lymphoepithelial carcinomas are poorly differentiated squamous cell
carcinomas or histologically undifferentiated carcinomas. A
prominent lymphoplasmatic infiltration that is similar to
nasopharyngeal carcinomas is typical for the microscopic appearance
of the tumor.
This entity is very rare and occurs – similar to
nasopharyngeal carcinomas – mostly in Southeast Asian
countries. The age peak is between 50 and 70 years, preferably in
males (m:w=3:1). Etiology shows an association of
lymphoepithelial carcinomas with Epstein-Barr visus [10]
[237].
Manifestations can often be found in the nasal cavity, the paranasal
sinuses are less frequently affected. Infiltrative growth into the
palate, the orbita or the skull base are possible.
Symptoms reported by affected patients are pressure sensation, nasal
obstruction, epistaxis, and in cases of infiltration of the orbita a
bulbar protrusion. Neurological deficits may occur in the context of
intracranial infiltration [237]
[238]. Lymph
node or distant metastasis is possible. Thorough endoscopy and
biopsy of the nasopharynx should be performed in order to exclude
loco-regional extension of a nasopharyngeal carcinoma.
Due to the low number of cases, there is no standard therapy. Because
of the high radiosensitivity, most cases undergo loco-regional
radiotherapy that is very effective even when cervical lymph node
metastases are present. Radiochemotherapy followed by salvage
surgery is possible in cases of extended findings [239]. However, it is difficult
to assess the data situation because of the low number of cases.
2.4.2.1.3 Sinonasal undifferentiated carcinoma (SNUC)
Sinonasal undifferentiated carcinomas were first described in 1986 by
Frierson et al. [240]. It is a
highly aggressive carcinoma which show a locally extensive growth.
Pleomorphic tumor cells and numerous tumor necrosis area are
characteristic for the appearance. It is a high-grade epithelial
neoplasm with invisible histogenesis with or without neuroendocrine
differentiation. An exact delimitation with regard to
lymphoepithelial carcinoma and olfactory neuroblastoma is decisive
[10]
[240].
The incidence is very low with about 100 cases described in the
literature. The age range is between 30 and 90 years with a higher
incidence in males (m:w=2–3:1) [237]
[241].
There is no association with the Epstein-Barr virus. Some cases
occurred after previous radiotherapy in the context of
nasopharyngeal carcinoma [237].
SNUC mostly manifests in the nasal cavity, the maxillary and ethmoid
sinuses with frequent infiltration of neighboring structures. In up
to 50% of the cases, patients already show infiltrations of
the dura and 30% infiltrations of the orbita at the time of
confirmed diagnosis [242]
[243]. In a trial that analyzed
the percentage of the T stage in relation to the examined carcinoma
histologies, 69% of the patients already had stage T4 of
SNUC [244].
Similar to lymphoepithelial carcinomas, affected patients initially
suffer from nasal obstruction, epistaxis, later bulbar protrusion,
periorbital swellings as well as facial pains and in cases of
intracranial infiltration failures of the cranial nerves.
SNUC shows a high rate of local recurrences and distant metastasis
with frequent vascular and neural infiltration [245]
[246]. According to a recent
trial analyzing 318 patients with SNUC in the USA, the 5-year
survival rate amounts to 34.9% and the 10-year survival rate
to 31.3% [247]. In
most cases, the poor prognosis is caused by the already high tumor
stage at the time of diagnosis and the resulting inoperability.
Another reason is the fact that the majority of the published case
series contains less than 20 patients so that no standardized
therapy approach or a guideline are available regarding the therapy
of SNUC [242].
Considering the current literature, there is a consensus that
multimodal aggressive therapy should be performed consisting of
surgery, radio- and chemotherapy. This approach was confirmed by 2
large SEER (Surveillance, Epidemiology, and End Results program)
database trials [247]
[248]. The tumor resection
followed by adjuvant radiochemotherapy or primary radiochemotherapy
are possible therapeutic approaches depending on the resectability
of the tumor. Approaches of targeted therapy with lapatinib, which
suppressed the human epidermal growth factor receptor 2 (HER2)
signaling pathways in vitro as well as in vivo, showed first
promising results that allow prospects to more effective therapies
[249].
2.4.2.1.4 Adenocarcinoma
2.4.2.1.4.1 Adenocarcinoma of the intestinal type
The morphological structure of sinonasal adenocarcinomas of the
intestinal type is similar to the one of adenocarcinomas of the
gut.
The occurrence is very rare and is estimated to amount to an
incidence of less than 1:1 000 000 people per year.
However, the incidence varies significantly and increases regarding
the prevalence by factor 500 in people working in wood and leather
processing industries. The carcinoma is thus a recognized
occupational disease (BK4203). Men are affected 3–4 time
more frequently than women which is probably due to the employment
in the professions. The age of disease onset is mostly between the
6th and 7th decade of life [106].
Manifestations are often near the lateral nasal wall and the middle
turbinate. According to estimations, 40% of the tumors
develop in the ethmoid sinus, 28% in the nasal cavity, and
23% in the maxillary sinus [250]
[251].
Symptoms are unilateral nasal obstruction, epistaxis, and rhinorrhea.
More rarely, pains, facial swelling and diplopia, or bulbar
protrusion may occur. Destruction of the surrounding bone and
infiltration into neighboring regions are frequently observed [106]
[251].
Macroscopically, a polypoid, partly papillary and nodular mass with
fragile consistency and ulcerating, hemorrhagic as well as rarely
gelatinous or mucous parts are seen [106]
[250]
[251]. Microscopically,
exophytic, papillary and tubular or mucinous growth consisting
mainly of signet ring cells. The grade of differentiation is highly
variable. In 6–10%, KRAS mutation can be found. BRAF
mutation occurs clearly more rarely with less than 10% [252]
[253]
[254]
[255].
Because of the poor radiation sensitivity of the tumors, radical
tumor resection with free resection margins is the therapy of
choice. Due to the development of the endoscopic technique, the
transnasal resection is possible in some cases also with orbital and
intracranial infiltration [256], sometimes with consideration of complex
reconstructive measures [257].
Low-grade adenocarcinomas of the intestinal type with low tumor
stages can be treated by radical tumor resection. In all other
stages and entities, adjuvant radiotherapy should be performed [258]. Intensity modulated
photon irradiation may be discussed as part of the therapy strategy
[259]. Up to now, no
phase-III trials are available with regard to chemotherapy so that
current outcome reports are mainly based on case reports and small
retrospective case series. In the context of a prospective phase-II
trial, primary complete remission could be achieved in 16%
of the patients treated with neoadjuvant chemotherapy with PFL
(cisplatin, 5-fluorouracil, and leucovorin) [260]. In these cases, the
3-year survival rate amounted to 100% compared to
43% in the other patients.
Low-grade papillary adenocarcinomas have the best 3-year survival
rate with<80 and<60% after 5 years. Grade 2
and 3 tumors have a 3-year survival rate of 54 and 35%,
respectively. Mucinous tumors with alveolar growth have similar
survival rates like papillary tumors of grade 2. The most aggressive
growth is found in signet ring adenocarcinomas. In cases of
infiltration of the orbita, the skin, the ethmoid or sphenoid sinus
as well as the skull base, the prognosis is significantly poorer.
Lymph node metastases can be found in 8% and distant
metastases in 13% of the cases at the time of diagnoses
[106]
[251].
2.4.2.1.4.2 Adenocarcinoma of the non-intestinal type
Sinonasal adenocarcinomas of the non-intestinal type do not show
characteristics of salivary gland carcinomas and do not have an
intestinal phenotype. The mentioned tumor category is heterogenic.
Nonetheless, it has specific entities that are singular
(e. g. the renal cell-like carcinoma) [106].
Sinonasal low-grade non-intestinal adenocarcinomas occur very rarely,
they do not show a predilection of a specific gender and may be
diagnosed within an age range of 9–89 years. The mean age at
the time of diagnosis is within the 6th decade of life.
High-grade non-intestinal adenocarcinomas are rare, affect male
patients more frequently, also have a broad age span with a peak
within the 6th decade of life. Neither for low-grade nor
for high-grade non-intestinal adenocarcinomas of the sinonasal
tract, the etiology is known.
Most frequently, these tumors manifest in the nasal cavity
(64%), followed by the ethmoid sinus (20%). About
half of all high-grade non-intestinal adenocarcinomas already have
an advanced stage at the time of diagnoses with infiltration of the
nasal cavity and the paranasal sinuses [261]
[262]
[263]
[264].
Symptoms of the low-grade variation are frequently unspecific and
comprise nasal obstruction, epistaxis, and pain sensation.
High-grade tumors frequently cause deformities of the facial skin
and bulbar protrusion when the orbita is infiltrated.
Morphologically, the imaging of low-grade non-intestinal
adenocarcinomas as solid mass filling the nasal cavity or the
paranasal sinuses whereas high-grade non-intestinal adenocarcinomas
have a clearly more destructive growth with osseous infiltration and
invasion of the surrounding anatomical areas [106].
Macroscopically, low-grade tumors impose as red, polypoid or
raspberry-like solid structures. Histologically, papillary
and/or tubular characteristics with complex growth patterns.
A single layer of uniform, mucinous, cuboid to columnar epithelial
cells surrounds the tumors. High-grade tumors show significantly
more histological diversity. Solid growth with occasionally
interspersed glandular structures as well as singular mucocytes are
typical. Some variations show nest-like distribution patterns with
infiltrative behavior. Numerous mitosis types and necrotic areas are
found [106].
The therapy of choice consists of radical tumor resection. Despite
the sparse data situation due to few described cases, surgical
therapy alone – tumor-free resection margins provided
– seems to be decisive for the prognosis [265]. A recently performed
National Cancer Database analysis did not reveal any influence of
radiotherapy on the survival of patients with low-grade
adenocarcinoma [266]. Patients
with high-grade adenocarcinomas show a clearly better survival rate
in case of multimodal therapy including radical tumor resection and
adjuvant radiotherapy. Due to the low number of cases, the role of
systemic therapy could not be definitely clarified [256].
Recurrences are found in 25% of the low-grade variation and
only about 6% of the affected patients die of their disease.
The prognosis for patients with high-grade non-intestinal
adenocarcinomas is significantly poorer. Most patients die within 5
years after diagnosis of the disease. Local and distant metastasis
occasionally develops [261]
[262]
[263].
In the few cases reported about renal cell-like carcinoma, neither
recurrences nor metastasis were found [267].
2.4.2.1.5 Salivary gland like carcinomas
Salivary gland neoplasms in the nose or the paranasal sinuses are
extremely rare. The majority of the cases consists of malignant
entities. An analysis of Daniel K. Heffner shows the following
distribution of the entities in a total of 311 patients with
sinonasal salivary gland like tumors [268].
The following list consists of the malignant sinonasal entities:
2.4.2.1.5.1 Adenoidcystic carcinomas (ACC)
Adenoidcystic carcinomas mainly occur in the major and minor salivary
glands. However, manifestation may be found in all areas where
secretory glands are localized (breast, cervix, colon, prostate,
nasal cavity, and paranasal sinuses). It is the most frequent
malignoma of the sinonasal tract with an age span of 11–92
years. Sinonasal manifestations are found in the maxillary sinus
(60%) and the nasal cavity (25%). Adenoidcystic
carcinomas represent 5% of all sinonasal malignant neoplasms
with an incidence of 25% referring of all salivary gland
carcinomas [269]
[270]
[271]
[272]
[273]. It grows slowly and
infiltrates surrounding structures along the involved cranial
nerves. Hematogenic metastasis is frequently observed and may occur
even years after first diagnosis. Due to the late occurrence of
symptoms, affected patients have high tumor stages which leads to a
corresponding morbidity when the tumor is resected or primary
radiotherapy is performed. Due to the low radiation sensitivity,
doses of>80 Gy are required which leads to collateral damage
of neighboring structures (orbita, optic nerve, cerebrum) [274]
[275]
[276]. The therapy of choice
consists of radical tumor resection and postoperative radiotherapy
for R1/R2 resection in cases of perinodal infiltration and
advanced tumor stages (T3/T4), even if some trials could
confirm a better outcome in all tumor stages (T1–4) [274]
[277]
[278]
[279]
[280].
Due to the high tumor stages at the time of first diagnoses and the
frequently occurring late recurrences, the prognosis of patients
with adenoidcystic carcinomas is poor. The 5-year survival rate
amounts to 38–64% after conventional irradiation.
With application of proton radiation, the local tumor control
reaches 50–70% and even up to 93% in cases
of neutron radiation [271]
[274]
[275]
[281]
[282]
[283]
[284]
[285].
2.4.2.1.5.2 Acinar cell carcinoma
Acinar cell carcinomas are rare malignomas of the salivary glands
that are mainly found in the parotid gland. After tumor resection
with or without postoperative radiotherapy, the 20-year survival
rates amount to nearly 90% [286]. Manifestation in the maxillary or ethmoid sinus, at
the turbinate or the nasal septum is extremely rare. The current
English literature describes 19 cases, their follow-up reaches from
1 to 22 years. 5-year and 10-year survival rates amount to more than
90% [287]
[288]
[289]
[290].
2.4.2.1.5.3 Mucoepidermoid carcinoma
Sinonasal mucoepidermoid carcinomas are malignomas of the minor
salivary glands that manifest in the oral cavity and the oropharynx
and have a 5-year survival rate of 87% at these locations
[291]. Lymph node
metastases occur in 15% of the cases.
Sinonasal mucoepidermoid carcinomas represent about 1.5% of
all sinonasal malignomas and thus they are very rare. Most frequent
locations are the maxillary sinus and the nasal cavity [292] where high-grade
mucoepidermoid carcinomas may be diagnosed in 46%. Symptoms
of affected patients are nasal obstruction, chronic sinonasal
complaints, facial pain, epistaxis, and cephalgia. Small monocentric
trials show a 5-year survival rate of 35.9% to 44.1%
in sinonasal manifestation [204]
[293]. Tumor
resection with adjuvant radiation is the therapy of choice, however,
data regarding the effectiveness are not available due to the low
number of cases [292].
2.4.2.1.5.4 Epithelial-myoepithelial carcinoma
Epithelial-myoepithelial carcinomas represent an extremely rare
malignant entity which predominantly manifests in the major salivary
glands and makes up about 1% of all salivary gland
malignomas. Even rarer is the manifestation in the nasal cavity or
the paranasal sinuses, only few case reports exist here [295]. The largest cohort trial
includes 468 patient with epithelial-myoepithelial carcinomas. 18 of
these patients had manifestations in the sinonasal area [296]. 80% of the
patients were older than 50 year. Female patients were affected more
frequently (f:m=1.5–6:1) [296]. Due to the low number of
cases, the description of the pathophysiology and the therapeutic
strategies is not systematic because a high percentage of the
relevant literature consists of case reports.
The term of epithelial-myoepithelial carcinomas is a
histopathological term describing the proliferation of tubular
structures with two-layer cell lining. The inner layer consist of
cubic or low-cylindrical duct cells, the outer layer consists of
bright epitheloid cells. The tumor stroma may be hyalinized [297].
According to the location, patients present with symptoms such as
epistaxis, pressure sensation and pains, swellings, and rhinorrhea.
Endoscopy frequently reveals hemorrhagic masses. Computed tomography
shows a heterogenic contrast enhancing soft part structure win the
affected paranasal sinuses. Osseous destructions of neighboring
structures are not typical, however, they may occur [295].
Current reports show only low glucose uptake in the PET/CT
which is due to the low-grade potential of malignancy and makes the
significance of preoperative imaging difficult with regard to the
diagnosis [298]
[299].
The therapy of choice is the generous surgical excision. Due to the
inhomogeneous biological behavior and response, the effectiveness of
adjuvant radiotherapy is unknown [300].
Lymph node metastases are rare and occur in less than 5% of
the cases. The 5- and 10-year survival rates amount to 72.7 and
59.5%, respectively [296].
2.4.2.2 Neuroendocrine neoplasms
The term of neuroendocrine neoplasms comprises several entities. Beside
the neuroendocrine carcinoid and the classic neuroendocrine carcinomas,
also esthesioneuroblastomas (see 2.4.2.6.2) as well as sinonasal and
undifferentiated carcinomas (SNUC, see 2.4.2.1.3) belong to the
neoplasms with neuroendocrine differentiation [301].
Neuroendocrine neoplasms express neuroendocrine markers such as
synaptophysin and chromogranin A. Large membrane-bound
(hormone-containing) vesicles are characteristic. Epithelial
neuroendocrine carcinomas (well, moderately, or poorly differentiated
carcinoid) develop from cells of the diffuse neuroendocrine cell system,
that express cytokeratins and are located in the mucosa. Blastomas of
the olfactory nerve and paragangliomas are of neuroectodermal origin and
develop from the olfactory membrane or head and neck paraganglia [302]. According to the WHO
classification, neuroendocrine tumors are considered as grade I
neoplasms (formerly known as low-grade neuroendocrine tumors or typical
carcinoid), grade II neoplasms (formerly called intermediary
neuroendocrine tumor or atypical carcinoid), and grade III neoplasms,
small-cell carcinoma (formerly called high-grade neuroendocrine tumor or
small-cell carcinoma) as well as grade III neoplasms, large-cell
carcinoma (formerly known as high-grade neuroendocrine tumor or
large-cell neuroendocrine carcinoma) [303].
Neuroendocrine carcinoid (typical carcinoid, grade I
neoplasm)
More than 90% of neuroendocrine carcinoids manifest in the
larynx (supraglottic). Sinonasal manifestations occur more rarely
and lead to well delimited, submucous and often polypoid tumors
[304]. Especially poorly
differentiated neuroendocrine carcinomas are found in the nasal
cavity, the paranasal sinuses, or at the skull base. The 5-year
survival rate amounts to 5–20% [106].
The symptoms depend of the manifestation sites. In cases of excessive
hormone production, carcinoid syndrome is possible, especially in
cases of hepatic metastasis, and it occurs in about 10% of
all patients with carcinoids. The typical triad comprises attacks of
redness of the face and the trunk, diarrhea, and cardiac involvement
[305].
Neuroendocrine carcinomas
Sinonasal neuroendocrine carcinomas are high-grade carcinomas with
morphological and immunohistochemical characteristics of
neuroendocrine differentiation [106]. They are subdivided into small-cell neuroendocrine
carcinomas and large-cell neuroendocrine carcinomas and represent
about 3% of all sinonasal tumors. They develop more
frequently in males of middle and higher ages (mean age of
49–65 years). In rare cases, an association with high-risk
human papilloma viruses is reported.
Primary sinonasal manifestation sites are the ethmoid sinus, the
nasal cavity, followed by the maxillary and sphenoid sinus.
Symptoms of manifestation are mostly unspecific (nasal obstruction,
rhinorrhea, and chronic sinonasal complaints). Many patients only
consult their doctor with higher tumor stages.
Endoscopically, large, hemorrhagic tumor masses are found with
necrotic parts. Morphologically, imaging shows osseous destructions
and infiltrations of neighboring anatomical regions.
With regard to the histopathology, sinonasal neuroendocrine
carcinomas are identical to neuroendocrine carcinomas occurring in
the lung and other head and neck locations. They have a highly
infiltrative growth behavior with frequent perineural and
lymphovascular infiltration. Sinonasal neuroendocrine small-cell and
large-cell carcinomas have a cytokeratin expression which allows
differentiation for example with regard to olfactory neuroblastomas
[303].
If possible, therapy should aim at tumor resection followed by
adjuvant radiochemotherapy. Especially in cases of large-cell
neuroendocrine carcinomas, neoadjuvant radiochemotherapy followed by
tumor resection seems to achieve the best outcome [301].
The 5-year survival rate amounts to 50–65%. Location
in the sphenoid sinus has a more favorable prognosis
(~80%) compared to maxillary or ethmoid
manifestations (~33%). Despite the limited data
situation due to the low number of cases, the prognosis for
large-cell neuroendocrine carcinomas seems to be more favorable than
for the small-cell variant [106].
2.4.2.3 Malignant soft tissue tumors (sarcomas)
2.4.2.3.1 Fibrosarcoma
Fibrosarcomas are malignant spindle-cell tumors with fascicular
architecture and variable collagen matrix production showing a
fibroblastic/myofibroblastic differentiation. Furthermore,
fibrosarcomas have low mitosis rates and rare nuclear pleomorphisms
or anaplastic properties.
Manifestation sites are mostly located in the extremities, only
1% of fibrosarcomas are found in the head and neck. They are
responsible for less than 3% of all non-epithelial
malignomas of the head and neck, however, they are the second most
frequent entity of head and neck sarcomas [106]
[306].
Symptoms are similar to those of other neoplasms of the nasal cavity
and the paranasal sinuses. Unspecific complaints such as nasal
obstruction and epistaxis, pressure sensation, pains, and swellings
may occur.
Fibrosarcomas have a high risk for local recurrences but only a low
risk for distant metastasis [140]
[307]. Despite
the low number of cases, a generous tumor resection is recommended
because small safety margins significantly increase the risk of
local recurrence [140]. A
database analysis of the US National Cancer Institute’s
Surveillance, Epidemiology, and End Results (SEER) investigated the
course of 51 patients with sinonasal fibrosarcomas over a period
from 1973 to 2012 [306]. The
mean age amounted to 54.5 years without a predilection of one
gender. Interestingly, 83.7% of the patients had bright skin
and only 8.2% were dark-skinned. The most frequent locations
were the maxillary sinus with 54.9% followed by the nasal
cavity (23.5%). The most frequent histological type was the
moderately differentiated (59.5%) followed by the
well-differentiated fibrosarcoma (16.2%). The follow-up
revealed local recurrence in 28.2% of the patients, in
64.1% of the cases regional metastasis developed and
7.7% had distant metastasis.
The most frequently applied therapy modality was tumor resection
alone (61.2%) followed by tumor resection with adjuvant
radiotherapy (32.7%). Also local recurrences were treated
primarily by tumor re-resection (71.4%) followed by tumor
resection with adjuvant radiotherapy (7.1%). The 5-year
survival rate amounted to 71.7% in all cases with follow-up.
Recent trials show clear advantages for patients who undergo
adjuvant radiotherapy [307]
[308].
2.4.2.3.2 Undifferentiated pleomorphic sarcoma/malignant
fibrous histiocytoma
The undifferentiated pleomorphic sarcoma (also known as malignant
fibrous histiocytoma) is a high-grade soft part sarcoma without
differentiation line. It develops in adults, sinonasal or skull base
manifestation is very rare even if it ranks third after
rhabdomyosarcoma and fibromyosarcoma as sarcoma in this location
[106].
Previous radiotherapies seem to be responsible for the development of
undifferentiated pleomorphic sacromas [309]
[310].
In particular unspecific symptoms such as painless swellings, nasal
obstruction, bulbar protrusion and diplopia as well as epistaxis may
occur. Rather rarely, regional or distant metastasis is observed
[106].
Endoscopically, a lobular grey-whitish, partly fleshy mass with
hemorrhagic parts is found. Most findings seem to be circumscribed.
Microscopically, the malignomas present spindle and pleomorphic
cells in a variably collagenized extracellular matrix, pleomorphism,
atypical mitoses, necrotic areas, histocytic and foam cells are
often found. Many tumor cells have characteristics of fibroblasts,
myofibroblasts, or histiocytes.
The undifferentiated pleomorphic sarcoma is diagnosed by excluding
mucosal melanomas, carcinomas, lymphomas, and other sarcomas.
Despite the poor data situation and independently from the situation
of the margins, tumor resection seems to be essential. Radiotherapy
increases the chance of local tumor control [106]
[310]. The 5-year survival rate
amounts to 60–70%.
In their trial, Gerrand et al. could show for sarcomas of the
extremities different outcomes depending on the histological
subtype, the application of radiotherapy, the local anatomy, and
unplanned excision prior to admission in a specific center [311]. They postulated that
patients should be transferred to specialized diagnostic and
therapeutic center with multidisciplinary sarcoma specialists if
soft part sarcoma is suspected [310].
2.4.2.3.3 Leiomyosarcoma
Leiomyosarcomas are malignant tumors originating from the smooth
muscles. Typical manifestations sites are the uterus or intestinal
tract. Sinonasal manifestations or location at the skull base are
extremely rare. Mainly adults are affected, in exceptional cases
also children. Also for leiomyosarcomas, a previously performed
radiotherapy plays a crucial role for the genesis [106].
Due to only unspecific symptoms, patients present to their doctors
with late tumor stages which leads to poorer prognoses of sinonasal
manifestation compared to other locations [312]. Clinically, a soft,
mainly polypous tumor mass presents that may cause pains, nasal
obstruction, and epistaxis. The lesions may also affect the
craniofacial bone and cause further complaints such as diplopia,
bulbar protrusion etc. depending on the infiltration.
Hematogenic metastasis into the lung, liver, other soft part areas,
bones, or cerebral structures are possible. Metastases of other
regions should be excluded before definitive tumor therapy.
Macroscopically, the tumor mass is polypoid. Clear delimitations of
the surrounding tissue as well as findings that cannot be clearly
defined are possible. Microscopically, infiltrative growth or sharp
delimitations, spindle cells aligned in interconnected fascicles are
characteristic. The eosinophilic cytoplasm often shows small
perinuclear vacuoles [106].
Computed tomography is often unspecific and shows expansive, cystic
or necrotic, heterogenic lesions within the soft tissue. MRI shows
only moderate hyperintensity in the T1 and T2 weighting which makes
exact diagnosis difficult [313].
Tumor resection is the method of choice, however, resection with
sufficient safety margins is only possible to a limited extent due
to the location and vital neighboring structures. Adjuvant
chemotherapy and/or radiotherapy are applied in patients
with locally advanced growth, recurrences, and metastases [312]
[314]. About one third of the
patients with sinonasal manifestation either dies from distant
metastasis or local recurrences that grow into vital neighboring
structures [106].
2.4.2.3.4 Rhabdomyosarcoma
Rhabdomyosarcomas are malignant mesenchymal tumors with skeletal
muscle differentiation.
The difference is made between:
-
Embryonic rhabdomyosarcomas
-
Alveolar rhabdomyosarcomas
-
Pleomorphic rhabdomyosarcomas
-
Spindle cell rhabdomyosarcomas
The terms of myosarcoma and malignant rhabdomyoma are used as
synonyms for rhabdomyosarcoma.
The incidence of sinonasal rhabdomyosarcomas amounts to
0.034:100 000 with primary manifestation in the paranasal
sinuses followed by the nasal cavity. It is the most frequent
sinonasal sarcoma in children as well as in adults. The age peak is
within the first decade of life [106]
[311]
[316]. Radiation-induced genesis
is currently investigated.
Macroscopically, a polypoid, poorly delimited tumor formation is seen
with extension to neighboring structures and fleshy, gelatinous,
brownish to grey surface.
Embryonic rhabdomyosarcomas is the entity that occurs most frequently
in the sinonasal tract. It has primitive to spindle-shaped cells
with sparse cytoplasm and hyperchromatic nuclei as well as dispersed
rhabdomyoblasts with clearly eosinophilic cytoplasm. The number of
rhabdomyoblasts typically increases significantly after
radiotherapy.
In adults, more frequently sinonasal alveolar rhabdomyosarcomas are
found [311] which have
fibrovascular septa that separate the foci from round neoplastic
cell accumulations. Giant cells with multiple peripherally located
cell nuclei may be present [106].
The outcome seems to be poorer for patients who received previous
excision or excisional biopsy for histological assessment compared
to patients who underwent directly complete tumor resection [311]
[312]. Thus it seems to be
particularly important to transfer patients to an interdisciplinary
center specialized in sarcomas if this entity is suspected.
As therapy, tumor resection with broad safety margins should be
intended. Also in cases of incomplete tumor resection, surgery seems
to be a predictive factor [311]. Five-year survival rates of 40–45%
are reported in cases of combination of surgery, chemotherapy, and
irradiation, for patients younger than 18 years and females, this
rate is slightly higher. If the skull base is infiltrated, the
prognosis is much poorer [106]
[311]
[317].
2.4.2.3.5 Angiosarcoma
Angiosarcomas are vascular malignant neoplasms. Other terms for this
entity are epitheloid hemangioendothelioma, malignant
hemangioendothelioma, malignant angioendothelioma, or
hemangiosarcoma.
In more than half of the cases, the tumor develops within the skin
and superficial tissue layers of the head and neck.
Epidemiologically, the sinonasal angiosarcoma is responsible for
less than 0.1% of all head and neck malignomas and less than
1% of all sinonasal malignomas [106].
Possible, however rarely reported risk factors for the development
are radiation exposure, vinyl chloride and carbon dust exposition
[318]
[319]
[320].
Angiosarcomas are located rather in the nasal cavity and the
maxillary sinus. They lead to initially unspecific complaints,
predominantly epistaxis and nasal obstruction. Some patients further
report about sinonasal complaints, epiphora, pains, and pressure
sensation.
Often, bone infiltration is observed with angiosarcomas that may be
made visible in computed tomography. In the T2 weighting of MRI, a
strong signal intensity can be depicted. Preoperative angiography
may be helpful to identify afferent vessels and to allow
preoperative embolization [106]
[321]. Lymph
node and distant metastasis are unusual at first manifestation.
Macroscopically, angiosarcomas present with nodular to polypoid, soft
and livid to reddish surface with ulcerations that easily bleed.
Microscopically, the malignoma develops under an intact epithelial
layer with neoplastic vessel formation that extend into the soft
tissue and neighboring bones. Hemorrhagic and necrotic areas are
accompanying symptoms. Within the neoplasm, capillary, cavernous,
and rudimentary vessels are found that are filled with erythrocytes
and lined with increased, atypical spindle-like or epitheloid
endothelial cells. Grading is not performed for angiosarcomas [106]
[321].
Due to the very low incidence, there is no standard therapy for
sinonasal angiosarcomas. In most cases, tumor resection followed by
radiotherapy is described. Other therapeutic approaches that have
been described for single cases are chemotherapy, gamma-knife
therapy and the application of interleukins [321]
[322]
[323]
[324]. With about 40%,
recurrences are frequently observed. Metastases develop within the
first 24 months [323] and are
found in the lung, liver, kidneys, and bones [321]. The overall prognosis is
poor and reveals an overall survival rate of about 60% [106].
2.4.2.3.6 Biphenotypic sinonasal sarcoma (BSS)
Biphenotypic sinonasal sarcomas have been included in the WHO
classification of tumors of the sinonasal system of 2017 as a new
entity. This is justified by the defined PAX3/MAML3
translocation that makes it an independent entity. Up to now, the
malignoma was wrongly classified as leiomyosarcoma [325]. Up to now, BSS has only
been described in the sinonasal tract.
BSS is a low-grade spindle cell sarcoma. It occurs preferably in
females (f:m=3:1) and affects people in an age span between
24 and 85 years with a mean age of 52 years [106].
Predominant manifestation sites are the sphenoid cells (57%)
and the nasal cavity (54%), often with transgressing growth
[326] and also
infiltration of the orbita or olfactory fossa.
The symptoms are unspecific. Patients report about nasal obstruction,
pressure sensation, and facial pains. Macroscopically, a polypoid,
partly solid, reddish and grey tumor mass is seen. Microscopically,
the cellular structure has focal cell-dense parts in the tumor that
are similar to adult fibrosarcoma with superficial hamartoma-like
proliferation of included, local mucosal glands. Focally, ectatic
vessels with bleeding and hemangioperycytoma-like aspect are
frequently found [326].
Due to the fact that the malignoma was described for the first time
in 2012 [327] and included in
the WHO classification only in 2017 as independent entity, it is
mostly unknown, however, it might occur more frequently than assumed
because many cases have been classified as malignant peripheral
nerve sheath or muscular tumors.
Slow growth and local infiltration of neighboring structures are
characteristic for BSS. About 50% of the patients of the
originally described cohort have local recurrences within a period
of 9 years. Distant metastases have not been reported up to now
[327]. In addition, only
one lethal outcome has been documented for this disease [328].
The therapy of choice consists of tumor resection with sufficient
safety margins such as for other sarcomas. Adjuvant radio- and
chemotherapy can be applied in cases with advanced tumor stage. The
efficiency of adjuvant radio- and chemotherapy is unknown due to the
very low number of cases [329]
[330].
2.4.2.3.7 Malignant peripheral nerve sheath
tumor/neurofibrosarcoma
Malignant peripheral nerve sheath tumors (MPNST) develop from
peripheral nerves or the transformation of benign tumors of
peripheral nerves. Generally, they have a differentiation to one of
the components of nerve sheaths (e. g. schwann cells
[malignant schwannoma], fibroblasts, or perineural cells).
The malignomas occur mainly in adult patients with a large age range
and a peak within the 5th decade of life. In about
20–25% of the cases, the malignant peripheral nerve
sheath tumor is associated with type 1 neurofibromatosis. In these
cases, the patients are often younger (between 30 and 40 years)
[106]
[331]. An association with
previous radiotherapy is discussed [332].
In patients with type 1 neurofibromatosis, the incidence amounts to
1:3,500. Regarding the total population, the incidence amounts to
1:100,000 [333]
[334]. About 20% of all
malignant peripheral nerve sheath tumors are located in the head and
neck. Sinonasal manifestation is much more rarely observed.
Manifestation sites are located along the cerebral nerves, mainly the
vestibular and vagus nerve [106]
[331].
Clinical symptoms of affected patients are rapidly progressive
painful swellings and neurological deficits of the affected
nerves.
Malignant peripheral nerve sheath tumors are not encapsulated and
have a highly infiltrative growth. Most different cellular
morphologies are found, among them spindle-shaped, epitheloid and
pleomorphic cells). Histologically, the difference is made between
spindle cell and glandular malignant peripheral nerve sheath tumors
that are different with regard to their fascicle-like alignment or
the presence of goblet cells [106]. The malignomas are classified into low- or
high-grade entities according to the mitosis rate, the presence of
atypical mitoses, pleomorphism, and necrosis [332].
In general, these tumors are very aggressive and have a poor
prognosis. Tumor excision with sufficient safety margins is the
therapy of choice. The majority of malignant peripheral nerve sheath
tumors are high-grade sarcomas with a tendency of local recurrence
and distant metastasis. 40–65% of the affected
patients reveal local recurrences, distant metastasis develops in
30–60% of the cases, mainly in the lung, liver,
brain, bone, and adrenals. Regional lymph node metastasis is rare so
that neck dissection should not be performed as standard [333]. Adjuvant radiotherapy, if
needed in combination with chemotherapy, has a positive impact on
the 5-year survival (65 vs. 38%) [335].
2.4.2.3.8 Sinonasal synovial sarcoma
Synovial sarcomas are mesenchymal tumors with variable epithelial
differentiation and gland formation. Typically, a specific
chromosomal translocation (t(X;18) (p11:q11)) is observed that leads
to the development of an SS18-SSX fusion gene [106]
[336].
The synovial sarcoma is the most frequent non-rhabdomyosarcoma soft
part sarcoma in children, adolescents, and young adults with an age
span between the 3rd and 4th decade of
life.
The etiology is strongly associated with previous radiotherapy [337]
[338]
[339]. Manifestation in the
sinonasal tract or the skull base occurs extremely rarely.
Clinically, a palpable, mostly deeply located mass is found with or
without pain on pressure. Macroscopically, the tumor is yellow to
grey or whitish. Slowly growing synovial sarcomas are generally well
delimited. Microscopically, monophasic (spindle-cell shaped,
calcifying/ossifying, myxoid, and poorly differentiated) as
well as biphasic subtypes with glandular or solid epithelial cell
may be differentiated. Poorly differentiated tumors may contain
areas with frequent mitosis and necrosis [106].
Within the last decades, the therapy has only changed unimportantly
and consists of tumor resection for circumscribed findings, often
combined with radio- or chemotherapy. Combined therapies are applied
depending on the stage of the disease. According to a large trial,
stage I and II tumors undergo resection with postoperative
radiotherapy, in stage II, tumor resection is combined with
radiochemotherapy [340].
Neoadjuvant chemotherapy may be applied in patients with locally
advanced tumor growth where otherwise mutilating surgery would be
required. First results of immunotherapy showing an activity for
NY-ESO-1, trabectedin and a multitude of angiogenesis inhibitors are
promising [341].
2.4.2.4 Borderline and low-malignant entities of the soft
tissue
2.4.2.4.1 Aggressive fibromatosis of the desmoid type
Aggressive fibromatosis is a clonal spindle-cell neoplasm with
infiltrative growth. Distant metastases do not occur. The terms of
desmoid fibromatosis and aggressive fibromatosis are used as
synonyms of aggressive fibromatosis of the desmoid type.
The incidence is estimated to 1:250 000 to 1:500 000.
The ages of disease onset reach from 15 to 60 years, about
30% of the cases develop in childhood. The manifestation in
the head and neck concern about 15% of all aggressive
fibromatoses. The sinonasal manifestation is even rarer [106]
[342]
[343].
The etiology is still unknown. An association with Gardner’s
syndrome (see 2.4.1.2.1) and the familial colorectal polyposis is
possible [344]
[345].
Aggressive fibromatoses of the desmoid type show poorly delimited
lesions with focally infiltrative growth that macroscopically
present as solid, whitish lesions with trabecular pattern.
Immunohistochemistry of desmoids shows nuclear staining with
β catenin and additionally cytoplasmatic background [326]. Fascicular growth with
spindle-shaped cells and mild nuclear pleomorphisms may be
visualized. Atypical mitoses and necroses are not present. The
stroma can be variably collagenized and myxoid or mucous.
Adequate paint therapy is required in patients with aggressive
fibromatosis. Emori et al. could show in a series of 16 cases that
the pain accompanying desmoid tumors is associated with an
overexpression of cyclo-oxygenase 2 [346].
Generally, the complete surgical resection is the therapy of choice.
Due to the anatomical proximity to critical structures, a systemic
drug-related therapy (anti-estrogen therapy, non-steroidal
antiphlogistics), chemotherapy (vinblastine/vinorelbine,
pegylized liposomal doxorubicin), tyrosine kinase inhibitors
(e. g. imatinib, sorafenib), or radiotherapy may be applied
if the lesion is located in the sinonasal tract [326]
[343]
[347]. Within the last years,
however, more frequently a wait-and-see strategy was pursued because
available data show that only a small percentage of aggressive
fibromatoses progress [348]
which occurs within the first 36 months after diagnoses [349].
The prognosis is good in cases of R0 resection. In cases of R1
resections, recurrences usually develop within less than 2 years
[350].
2.4.2.4.2 Sinonasal glomangiopericytoma
Sinonasal glomangiopericytomas are spindle cell neoplasms that have
been included in the WHO classification of head and neck tumors as
new entity. Beforehand, this entity was classified as sinonasal
hemangiopericytoma. Within the last 60 years, the term of
hemangiopericytoma was used in order to describe a multitude of
neoplasms that have similar morphological properties. These
characteristics concern about 15% of all soft tissue
neoplasms [351] which leads to
confusion for establishing a specific tumor regime [352]. Today, the term of
hemangiopericytoma does not describe an independent neoplasm but
rather a growth pattern that is found in several neoplasms that are
very different [353].
Glomangiopericytomas represent about 0.5% of all sinonasal
neoplasms. Up to now about 100 cases have been described [352]. The age peak is in the
7th decade of life with a slight predilection of
female patients [106].
The most frequently observed manifestation site is the nasal cavity
with extension into the adjacent paranasal sinuses. Isolated cases
in the sinuses are rare. Glomangiopericytomas mostly develop only on
one side.
Affected patients report about nasal obstruction with pressure
sensation and epistaxis. The duration of the complaints until
diagnoses often lasts for more than one year [354].
Macroscopically, the tumor shows a polypoid, red to pink appearance.
The surface is soft and fleshy. On the average, the tumor measures 3
cm at the time of diagnosis. Microscopically, an unencapsulated
growth is observed under an intact epithelial layer with only rare
erosions especially in large tumors. A pattern-less diffuse
structure with partially fascicular cell arrangement is
characteristic, separated from the vascular plexus of capillaries up
to large caverns and a prominent acellular hyalinization [106]. Cellular atypia is not
found. In contrast to demoids (see 2.4.2.4.1), B catenin can be
identified in nearly all tumor cells [326].
Glomangipericytomas grow slowly and have a very good survival rate.
Recurrences occur in up to 40% of the cases, mostly as a
consequence of incomplete resection. Invasive growth behavior is
observed in cases of tumors larger than 5 cm [354]
[355].
Despite the low number of cases, tumor resection is considered as
standard therapy. Radio- and chemotherapy may be applied in the
context of unresectable tumors or distant metastasis. Adjuvant
radiotherapy is possible in order to improve the local tumor
control. Depending on the degree of vascularization, preoperative
embolization is recommended to reduce the intraoperative blood loss
[356]
[357]
[358].
2.4.2.4.3 Sinonasal solitary fibrous tumor
Solitary fibrous tumors originate from a fusion of the genes NAB2 and
STAT6 and have a fibroblastic phenotype with intensively branching
vascular structures.
As synonyms, the terms of hemangiopericytoma or giant cell
angiofibroma are used.
Solitary fibrous tumors are a rarity and responsible for less than
0.1% of all sinonasal neoplasms. They affect mainly adults
without clear predilection for one gender [106].
The tumors mostly develops in the nasal cavity and leads to nasal
obstruction and epistaxis as well as unspecific complaints such as
pressure sensation.
Macroscopically, a polypoid, solidly structured whitish tumor is seen
that is usually small because of the limited space in the sinonasal
tract [359]
[360]. Histologically,
pseudo-encapsulated tumors lying under the mucosa are found with
variable cell formations, among them spindle-shaped cell formations
that seem to be arranged randomly. The vessels are arranged radially
or antler-like [106]
[325].
The therapy of choice is the complete tumor resection which usually
leads to a cured condition. In patients older than 55 years, a tumor
size of more than 15 cm, necrotic tumor areas, and more than 4
mitoses per 10 high-resolution fields, a more aggressive growth
seems to be obvious [361]
[362]. Adjuvant radiotherapy
seems to be an additional option in these cases, in particular in
cases of incomplete resection and local recurrences [363]. The efficiency of this
therapy, however, cannot be finally assessed due to the extremely
low number of cases.
2.4.2.4.4 Epitheloid hemangioendothelioma
Epitheloid hemangioendotheliomas are low- to intermediate-grade
neoplasms from cells showing an endothelial phenotype, epitheloid
morphology, and a hyalinized, chondroid, or basophil stroma [106].
They affect in particular adults. Due to their extremely rare
occurrence and the complex differential diagnostics, an estimation
of the incidence is difficult.
Their occurrence in the head and neck is very rare. Their origin is
mostly in the soft tissue, the skin or bone. Extremely rarely, lymph
nodes are seen as primary manifestation sites [364]
[365]
[366]
[367].
Epitheloid hemangioendotheliomas grow slowly, infiltrate surrounding
structures and rarely metastasize [368]. The symptoms are mostly unspecific. Depending on
the location, epistaxis may occur.
Macroscopically, a nodular tumor mass with pale, partly reddish,
partly hemorrhagic cutting surface is found. Histologically,
endothelial and histocytic cells are seen that are arranged in
short, fibrous formations in a myxohyalinic stroma. The mitotic
activity is low. Multicellular vascular channels may be present.
Endothelial markers can be identified (CD31, ERG, FLI1). In most
cases is a gene fusion of WW-TR1-CAMTA1 is found [106].
Most cases have an indolent course. Care reports with tumor-related
mortality are available [369]
[370]
[371].
The therapy of choice is the radical tumor resection [372] that leads to a
recurrence-free situation in up to 85% [373]. Drug therapy may be
performed as curative or adjuvant treatment. It comprises a
combination of corticosteroids, cytotoxic agents, thrombocyte
aggregation inhibitors, and antifibrinolytics, and interferon-alpha.
In cases where R0 resection cannot be achieved because of the high
morbidity, additional radiotherapy may be discussed [373]
[374].
2.4.2.5 Hematolymphoid tumors
2.4.2.5.1 Extranodal NK/T cell lymphoma
The extranodal NK/T cell lymphoma is an extranodal lymphoma
with cytotoxic phenotype and mandatory association with the
Epstein-Barr virus. The terms of angiocentric lymphoma and lethal
midline granuloma are used synonymously.
The malignoma has a higher prevalence in Southeast Asia and the
indigenous population of Mexico and Central as well as South
America. In these areas, it represents up to 10% of
Non-Hodgkin lymphomas. In contrast, this percentage in North America
and Europe amounts to less than 1%. The prevalence of the
disease in Europe is estimated to less than
9:1 000 000 people [375].
The extranodal NK/T cell lymphoma grows in a destructive way
in the upper aerodigestive tract and manifests in the nasal cavity,
the paranasal sinuses and along Waldeyer’s tonsillar ring
[106].
First symptoms are nasal obstruction and epistaxis. The infiltrative
growth often leads to perforation of the nasal septum of the hard
palate and to infiltration of the skin where ulcerating lesions
develop at the penetration sites. If the lesion is located in the
paranasal sinuses, symptoms of chronic rhinosinusitis may mask the
actual disease [106].
Functional impairment is observed in cases of ocular or cerebral
infiltration.
Histopathologically, a diffuse tumor infiltrating the tissue with
angiocentric or angioinvasive growth pattern and large necrotic
areas is seen. The neoplastic cells vary with regard to their size
and number of irregularly shaped nuclei. Immunohistochemically, the
tumor expresses CD3, cytotoxic markers, and CD56 [376]
[377].
Due to the strict EBV association and the clear ethnical
predisposition, a gene defect of the immune response of affected
patients with regard to EBV infection is assumed [378]
[379].
In comparison to other T cell lymphomas, the prognosis is poor with a
median survival rate of 7.8 months and a 5-year survival rate of
40% [15]. The
plasmatic EBV DNA load is highly significant regarding the diagnosis
and prognosis. It was integrated in the prognostic algorithm
together with PET/CT results [106]
[380]. Current chemotherapy
regimen achieve long-term remissions in 70–80% of
the cases with stage I/II and about 50% with stage
III/IV [381]
[382].
2.4.2.5.2 Extraosseous plasmocytoma
Extraosseous plasmocytomas are proliferations of monoclonal plasma
cells with extraosseous manifestation without the basic multiple
myeloma. It is important to differentiate them from B cell lymphomas
with plasmocytic/plasmoblastic differentiation, especially
from MALT lymphomas and plasmoblastic lymphomas [106].
The median age of disease onset at the time of diagnosis is about 60
years, and there is an increased prevalence for male patients
(m:w=3–4:1) [106]
[383]
[384].
About 80% of extraosseous plasmocytomas manifest within the
upper airways, mainly the nasal cavity and the paranasal sinuses.
The worldwide incidence is estimated to 0.021 to 4 per
100 000 people [385].
Clinically, solitary masses are found that lead to nasal obstruction,
epistaxis, facial pain, chronic sinonasal complaints with rhinorrhea
and depending on the infiltration to cerebral deficits and bulbar
protrusion.
Less than 25% of the patients have a monoclonal serum
paraprotein, typically of the IgA type. Diagnostic characteristics
of multiple myeloma are not found [386]
[387].
Histologically, a diffuse infiltration of well, moderately, or only
poorly differentiated plasma cells and sometimes amyloid deposits
are found. The difference must be made between moderately and well
differentiated extraosseous plasmocytomas and B cell lymphomas, in
particular of MALT lymphomas with extensive plasmocytic
differentiation. Poorly differentiated extraosseous plasmocytomas
must be delimited of plasmoblastic lymphomas [388]
[389]. The cells often express
characteristics of plasmocytic differentiation (C138, C38, VS38,
MUM1/IRF4) [390].
Monotypic immunoglobulin light chains can typically be
identified.
The therapy of choice is local radiotherapy which leads to a
significantly better prognosis than in cases of multiple myeloma.
The disease-specific 5- and 10-year survival rates amount to 82 and
76%, respectively, according to the current literature [391]
[392]
[393]. Local recurrences or
dissemination into other extraosseous locations are possible. About
15% of the patients develop multiple myeloma in the course
of the disease [383].
2.4.2.5.3 Langerhans cell histiocytosis
In the context of Langerhans cell histiocytosis (LCH), proliferation
and accumulation of Langerhans cells is observed in various tissue
types. The prevalence in the European population is estimated to
1–2:100 000. Primary manifestation of LCH in the
nose, the sinuses, or at the skull base is seen even more rarely.
Exact data do not exist. The disease develops frequently in
children. The age peak of affected patients is between 1 and 4 years
[394]
[395]. Typical manifestations of
LCH are found in the bone (80%), the skin (35%) as
well as the pituitary gland (25%). More rarely, organ
systems such as lung, liver, and hematopoetic system
(15–20%) are affected [396]. Severe courses may lead
to sclerotic cholangitis or neurodegenerative changes in up to
2% of the cases.
If the nose or the paranasal sinuses are affected, mostly pressure
sensation and pains of the affected regions are identified. In cases
of affected frontal or maxillary sinus, swellings in the face may
occur [397]. Due to the
space-requiring effect of the manifestation of LCH, affections of
neighboring structures such as the optic nerve are possible [398].
Imaging of the disease shows well delimited bone lesions that nearly
seem “punched out” and involve the adjacent soft
tissue. Lesions without bony erosions could also be found [399]
[400]. In an analysis of 163
patients with LCH, MRI showed an involvement of the paranasal
sinuses or the mastoids in 55% of the cases [401].
Recent trials showed that patients with disseminated disease had a
BRAF V600E mutation that is also found in malignant melanomas [402]
[403]
[404]. The option of applying a
targeted therapy with inhibitors that are already used in the
context of malignant melanoma therapy, is currently investigated.
Not least because of this mutation, the discussion persists if LCH
is a malignant disease with varying clinical manifestation.
Due to the not finally analyzed pathogenesis of LCH, the therapy is
empiric and depends on the respective manifestation and the degree
of systemic affection. The diagnosis is confirmed by means of
biopsy. The excision or curettage of the affected areas can be an
effective treatment of unifocal manifestations [405]. In cases of unifocal
manifestation, the prognosis is good. The application of 125 mg
methylprednisolone is recommended due to the inhibitor effect on the
osteolysis. Radiotherapy is mainly applied in cases of recurrences.
The prognosis is significantly poorer when systemic affection with
multifocal extent is diagnosed. For therapy, drug therapy with
vinblastine, prednisone, etoposide, and methotrexate are applied in
various combinations [406].
2.4.2.6 Neuroectodermal and melanocytic tumors
2.4.2.6.1 Ewing sarcoma, primitive neuroectodermal tumor
Ewing sarcomas and primitive neuroectodermal tumors are primitive,
round/small cell high-grade sarcomas with variable
neuroectodermal differentiation. Translocation between the WESR1
gene and chromosome 22 as well as a member of the ETS transcription
family is characteristic [106].
The terms of peripheral neuroectodermal tumor, peripheral
neuroepithelioma, peripheral neuroblastoma, or adult neuroblastoma
are used synonymously.
Ewing sarcomas and primitive neuroectodermal tumors manifest in only
2–10% of the cases in the head and neck and have a
higher incidence in males. Predominantly children and young adults
are affected [106].
Manifestation sites in the head and neck area are the skull and jaw
bones, clearly less frequently the paranasal sinuses or the nasal
cavity are affected. Most frequent location of the sinonasal tract
is the maxillary sinus and the nasal cavity. Infiltrations into the
orbita or in intracranial direction are possible [407]
[408]. [Figure 15] shows MR imaging of
the skull of a 9-year old patient who presented with left-sided
paresis of the abducens nerve.
Fig. 15 Ewing sarcoma of the left skull base,
originating from the sphenoid sinus with intracranial
infiltration.
Pains, progredient swellings, rapidly progressive nasal obstruction
are typical symptoms of affected patients.
Macroscopically, polypoid or multilobular, grey/whitish,
partly hemorrhagic tumors with ulcerations are observed.
Histologically, a clearly cellular tumor with diffuse to lobular
growth and trabecular or strain-like structure is seen. Uniform
small cells with round to oval nuclei, discrete nuclear chromatin,
pale cytoplasm and unclear cell borders are additional
characteristics. The mitotic activity is variable with 5–10
mitoses per high-resolution field [106]. In 90–95% of the cases, a
consistent, reciprocal translocation between the EWSR1 gene on
chromosome 22 and the FLI1 gene on chromosome 11 is identified [409].
Beside RMI and CT scan, PET/CT is recommended for staging in
order to exclude distant metastasis or to correctly locate it so
that possible surgical procedures may be planned adequately [410]. If possible, excision of
the findings with sufficient safety margins should be intended. Even
if Ewing sarcomas are supposed to be sensitive on radiation, the
number of patients who underwent primary radiotherapy within the
last 30 years has continuously decreased. One reason might be the
late toxicity and the risk of secondary malignomas after
radiotherapy because mainly children are affected by the disease.
The modification of chemotherapies within the last decades
significantly increased the survival rates of originally
10%. The current 5-year survival rate for sinonasal Ewing
sarcomas/primitive neuroectodermal tumors without metastatic
spread amounts to 50–75% and is better than for
other locations [408]
[411]. Chemotherapy schemes
include VACA (vincristine, doxorubicin, cyclophosphamide,
actinomycin), VAIA (ifosfamid instead of cyclophosphamide) or EVAIA
(additional etoposide), and VIDE (without actinomycin). Despite the
promising development of the prognoses, the outcome for patient with
metastases is clearly poorer [412].
2.4.2.6.2 Olfactory neuroblastoma
Olfactory neuroblastomas are malignant neuroectodermal neoplasms.
According to their genesis, they are frequently located in the
cranial parts of the nasal cavity along the olfactory region. The
term of esthesioneuroblastoma is used synonymously.
Their incidence amounts to about 4:10 000 000.
Overall, this entity represent about 3% of all malignomas of
the paranasal sinuses [106]
[413]. The age
of the affected patients reaches from 2 to 90 years in the cases
described in the literature with an age peak between the
5th and 6th decade of life. Males are more
frequently affected (1.2:1). Ethnical or familial predilection does
not exist.
The tumor may develop along the lamina cribrosa, the medial part of
the middle turbinate, or the cranial part of the nasal septum.
Originating locations are the vomeronasal organ, the sphenopalatine
ganglion, according to the embryology the olfactory placode, or the
terminal nerve that fills the ethmoid cleft of the anterior part of
the lamina cribrosa [414].
Ectopic manifestations in the sphenoid sinus are possible, however,
they are extremely rare for all other sinuses [415]
[416]. Due to the point of
origin, the skull base is generally involved in the tumor
development.
Initially, olfactory neuroblastomas often cause complaints that are
similar to benign lesions so that diagnosis is often made rather
late. Nasal obstruction and occasional epistaxis are reported.
Cephalgia, rhinorrhea, epiphora, and visual disorders are symptoms
of already advanced tumor growth. Anosmia is rare with less than
5% despite the location at the lamina cribrosa.
Paraneoplastic syndromes occur in about 2% of the cases.
Clinically, a tumor mass is observed that originates from the lamina
cribrosa and extends over large parts. Mostly the tumor grows
unilaterally and appears polypoid, soft with red-grey surface and
intact mucosa. Computed tomography and especially magnet resonance
imaging allow determining the extension ([Figure 16]) and depiction of
an infiltration of the orbita which can be seen in [Figure 17].
Fig. 16 Left: Coronary T1-weighted MRI of an olfactory
neuroblastoma. The intracranial infiltration of the left
frontobase is seen. Right: Coronary T2-weighted
intraoperative MRI after resection of the olfactory
neuroblastoma. The reconstruction of the rhinobase has not
yet been performed.
Fig. 17 Coronary T1-weighted MRI of an olfactory
neuroblastoma with displacement and beginning infiltration
of the orbital content (red arrow).
Several staging systems are available (Kadish [417], Morita [418], and according to TNM
[419] while the
classification according to Kadish is mostly used.
Olfactory neuroblastomas are classified into low-grade and high-grade
entities. Low-grade olfactory neuroblastomas show sharply
demarcated, submucously growing cellular nests that are often
separated by vascular or hyalinized connective tissue. So-called
Homer Wright rosettes/pseudo-rosettes where neoplastic cells
surround in a palisade-like way the central neural matrix are
characteristic. High-grade olfactory neuroblastomas show necrotic
tumor areas, pleomorphisms, an increased mitotic rate as well as a
less apparent lobular growth [106].
The mostly known grading system was established by Hyams et al. [420]. Hereby the difference is
made between grade I (highly differentiated) to grade IV (poorly
differentiated) lesions. The criteria are the tumor architecture,
mitotic activity, nuclear polymorphisms, fibrillary matrixes and
rosettes, necrotic areas, glandular proliferation, and
calcifications.
Mao et al. could show in an article published in 2009 that the PTCH1,
GLI1, and GLI2 signaling pathways are involved in the pathogenesis
of olfactory neuroblastomas so that a central role of the sonic
hedgehog signaling pathway can be assumed [421].
Primary therapeutic option is the tumor resection, followed by local
radiotherapy. In contrast to the traditional craniofacial resection
that was first described in 1963 [422], today the endoscopic tumor resection is favored.
Originally it was assumed that only en-bloc resection of the tumor
may secure long-term recurrence-free conditions, however, endoscopic
procedures show similarly favorable outcomes with clearly less
invasive interventions [423].
Advanced tumor growth may require additional chemotherapy.
High-grade tumors according to Hyams show better responses so that
in individual cases also induction chemotherapy can be discussed
[424].
Dulguerov et al. analyzed in a meta-analysis the courses of the
disease in dependence of the therapeutic schemes and revealed the
best outcome for patients who had undergone tumor resection followed
by local radiotherapy. Patients of this group had a 2-year survival
rate of 65% compared to 48% and 37%,
respectively, for tumor resection alone and radiotherapy alone [425]. Current study results
further show a significantly improved disease-specific survival for
patients with stage T3/T4 who received tumor resection and
radiotherapy compared to surgical therapy alone [426].
2.4.2.6.3 Malignant mucosal melanomas
Mucosal melanomas are malignant neoplasms that develop from
melanocytes of the mucosa and are biologically different from
cutaneous melanomas. Their etiology is unknown.
Mucosal melanomas are responsible for less than 1% of all
malignant melanomas [427] and
represent about 4% of all sinonasal tumors. The age span is
rather broad and has a peak within the 7th decade of life
[106].
Most frequent manifestation site is the nasal cavity with the nasal
septum and clearly more rarely the nasopharynx or the maxillary
sinus [428]
[429]. Due to the missing
exposure to sun light, the sinonasal mucosal melanoma seems to have
a different biology compared to the cutaneous malignant melanoma.
About 20% of the affected patients have multifocal foci at
the time of diagnosis, about 40% of the diagnosed melanomas
are amelanotic [430].
Malignant mucosal melanomas may present as plane, pigmented mucosal
changes ([Figure 18]) or as
polypous massive tumor formation ([Figs 19] and [20]). Symptoms at first presentation are often epistaxis and
nasal obstruction. Such unspecific complaints often lead to a
diagnosis in higher tumor stages.
Fig. 18 Malignant mucosal melanoma in front of the
starting point of the middle turbinate directly below and in
front of the agger nasi of the right side. A pigmented,
non-convex mucosal change is seen.
Fig. 19 Malignant mucosal melanoma of the inferior
turbinate as well as the lateral nasal wall of the left
side. At the turbinate head, polypous-seeming tumor growth
is seen.
Fig. 20 Malignant mucosal melanoma of the mucosa of
the nasal cavity of the left side with polypous-seeming
growth.
Macroscopically, mucosal melanomas have a polypoid structure. They
may be pigmented and fragile, light brown or grey or solidly
configured [106].
Microscopically, often ulcerations are found with mucosal covering
with variable cellular morphology that reaches from
epitheloid/undifferentiated cells to spindle-like,
plasmacytoid and rhabdoid cells with partly prominent nuclei.
Atypical mitoses are frequently observed. Nearly half of the
malignomas can show amelanotic manifestations which clearly
increases the number of possible differential diagnoses
(e. g. olfactory neuroblastoma, rhabdomyosarcoma, sinonasal
undifferentiated carcinoma, poorly differentiated squamous cell
carcinoma) [106].
In contrast to cutaneous melanomas as well as choroidal melanomas,
higher rates of KIT and NRAS mutations are found. BRAF mutations,
however, are rare [431]
[432].
It is decisive for the staging and the prognosis to correctly
differentiate mucosal melanoma from sinonasal metastasis of a
cutaneous malignant melanoma. Distant metastasis and advanced
patient age are the most decisive prognostic factors. According to
the 7th issue of the “Cancer Staging Manual of
the American Joint Committee on Cancer”, a very unfavorable
5-year survival rate of less than 30% is seen in cases of
stage T3 and T4 tumors [433]
[434]
[435].
Current treatment recommendations favor the wide local excision if
possible [436]. The role of
postoperative radiotherapy is controversially discussed. A
meta-analysis from 2012 could not reveal higher survival rates [437]. Other study results
confirm an increased 3-year survival rate from 18 to 30% as
well as a reduced local recurrence rate after postoperative
radiotherapy [438]
[439]. Treatment with anti-PD-1
antibodies as well as anti-CTLA-4 antibodies show promising results
in advanced or metastasized mucosal melanomas, however, the evidence
is too low to justify their clinical application [436]
[440].
2.4.2.7 Germ cell tumors
2.4.2.7.1 Sinonasal terato-carcino-sarcoma
Terato-carcino-sarcomas are malignant neoplasms with histological
characteristics of teratomas as well as carcino-sarcomas without
malignant germ cell parts. The terms of malignant teratoma,
blastoma, terato-carcinoma, and teratoid carcino-sarcoma are used as
synonyms.
Terato-carcino-sarcomas are very rare tumors that mainly occur in
male adults (mean patient age of 60 years).
Most frequently, the tumor develops in the nasal cavity followed by
the ethmoid and maxillary sinus. In about 20% of the cases,
intracranial involvement can be found [441].
The diagnosis is made based on the evidence of malignant epithelial
elements and two or more malignant mesenchymal components such as
for example fibroblasts, cartilage, bone, or smooth muscles. These
combinations may be similar to primitive bronchial or intestinal
structures that seem to be strange in the sinonasal tract [442].
These teratoid elements are significant prognostic factors of the
sinonasal terato-carcino-sarcoma. Fetal, clear-cell squamous
epithelium and tubular or glandular structures are further criteria
for the diagnosis. Stem cell parts are not found in
terato-carcino-sarcomas [443–447].
The treatment of the sinonasal terato-carcino-sarcoma is difficult
due to the high malignancy rate and the poor prognosis. In order to
have realistic chances for long-term tumor-free survival, radical
tumor resection is required followed by radiotherapy [448]. In cases
of intracranial extension, combined intra- and extracranial
approaches have been described to achieve en-bloc resection [449]. A
review article published by Misra et al. identified 5 reports
supporting endoscopic tumor resection [441]. The role of adjuvant
chemotherapy is not confirmed due to the low number of case reports.
Because of the extremely rare occurrence, the characteristics and
optimal therapeutic schemes are not defined.
Lymph node and distant metastasis are frequently observed. The
reported survival rates vary from 50–70% in
different analyses [106,
441].
