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Malignant Neoplasms 185
9.3
Sinonasal Neuroectodermal Tumors
9.3.1
Olfactory Neuroblastoma
9.3.1.1
Defi nition, Epidemiology, Pattern of Growth
Olfactory neuroblastoma or esthesioneuroblastoma
is a rare neuroectodermal malignant tumor which
accounts for 5% of all malignancies of the sinonasal
tract (Dulguerov et al. 2001). Even though it has
been reported to occur at any age, from 3 to 88 years,
the lesion typically displays a bimodal distribution
with two main peaks, in the second and the sixth
decade of life (Wa l c h et al. 2000).
There is nowadays convincing evidence that olfactory neuroblastoma arises from olfactory epithelium
(Servenius et al. 1994; Carney et al. 1995), which
covers the cribriform plate, the superior third of the
nasal septum, and the upper part of the superior and
middle turbinates. However, the lesion can be occasionally detected in other adjacent areas, as the nasopharynx and the paranasal sinuses (Kairemo et al.
1998). Olfactory epithelium is made up of three types
of cells: olfactory neurosensory cells, sustentacular
supporting cells, and basal reserve cells. Olfactory
neuroblastoma is thought to take origin from the
basal progenitor cells (Dulguerov et al. 2001).
Based only upon light microscopic features, it
would be sometimes very diffi cult to differentiate olfactory neuroblastoma from other sinonasal malignant neoplasms, such as sinonasal undifferentiated
carcinoma, neuroendocrine carcinoma, rhabdomyosarcoma, plasmacytoma, malignant melanoma, and
some non-Hodgkin’s lymphoma (Lund and Milroy
1993). Diagnosis is therefore supported by using an
adequate panel of immunohistochemical studies;
positivity for neuron specifi c enolase, synaptophysin, chromogranin, S-100 protein, neurofi laments are
usually detected.
Olfactory neuroblastoma is a slow-growing but
aggressive malignancy, characterized by a tendency
to early spread along the olfactory phyla into the anterior cranial fossa and to give origin to regional and
distant metastases.
Cervical nodes are the most frequently involved
metastatic site; secondary localization to bone, lung,
pleura, liver, spinal epidural space can also be observed (Sheehan et al. 2000).
9.3.1.2
Clinical and Endoscopic Findings
Due to the slow growth and the high vascularization
of the tumor, unilateral nasal obstruction and epistaxis are the most frequent presenting complaints
(Dulguerov et al. 2001). Additional signs and symptoms are usually suggestive for an advanced-stage
tumor. Olfactory neuroblastoma may also produce
vasopressin, thus causing the syndrome of inappropriate antidiuretic hormone secretion (Osterman et
al. 1986; Ahwal et al. 1994), characterized by hypona-
tremia without edema and increased urinary sodium
loss (Vasan et al. 2004).
Palpable cervical nodes may be present at diagnosis. According to Levine et al. (1999), the rate of
patients with nodal metastasis increases from 6%
to 25% when the entire clinical history of patients
is considered. These data are in keeping with those
from Rinaldo et al. (2002a) and Ferlito et al. (2003),
who extensively reviewed the literature and found an
overall rate of lymph node metastases (synchronous
and metachronous) from olfactory neuroblastoma of
approximately 23%. At endoscopy, olfactory neuroblastoma appears as a broad-based, highly vascularized mass, with polypoid appearance. It usually has
an irregular, lobulated surface and a color varying
from gray to red (Wa l c h et al. 2000). Particularly in
the early stages, the mass is typically confi ned to the
olfactory cleft, but more advanced lesions frequently
extend through the upper part of the nasal septum to
involve both nasal fossae.
9.3.1.3
Staging Systems
Different staging systems based on the extension
of the lesion (Kadish et al. 1976; Dulguerov and
Calcaterra 1992) have been specifi cally proposed
for olfactory neuroblastoma (Table 9.4, 9.5).
The main source of criticism towards Kadish classifi cation is that it groups together in the C category
situations with a different impact on prognosis as, for
example, skull base involvement and widespread disease. Dulguerov and Calcaterra (1992) provided
a more reliable prognostic stratifi cation of patients,
by creating a T4 category for patients with brain involvement. However, their staging system is strictly
focused on the local extent of the tumor and does not
take into account regional as well as distant metastases.
Moreover, Hyams (1982) developed a histopathological grading system, based on six parameters
186
R. Maroldi et al.
Table 9.4. Kadish staging system (1976)
Stage Features
A Tumor confi ned to the nasal cavity
B Tumor confi ned to the nasal cavity, involving one or
more paranasal sinuses
C Tumor extending beyond the nasal cavity and parana-
sal sinuses. Includes involving of the orbit, skull base,
intracranial cavity, cervical lymph nodes and distant
metastatic sites
Table 9.5. Dulguerov and Calcaterra staging (1992)
Stage Features
T1 Tumor involving the nasal cavity and/or paranasal
sinuses, sparing the most superior ethmoidal cells
T2 Tumor involving the nasal cavity and/or paranasal
sinuses, including the sphenoid, with extension to and
erosion of the cribriform plate
T3 Tumor extending into the orbit or protruding into the
anterior cranial fossa
T4 Tumor involving the brain
related to growth pattern and to other histological
fi ndings (lobular architecture, mitotic index, nuclear
polymorphism, presence of rosettes, fi brillary matrix, and necrosis). Lesions can be classifi ed in four
grades, from 1 to 4, according to the increasing cellular dedifferentiation.
9.3.1.4
Treatment Guidelines and Outcome
According to the results of a recent meta-analysis
(Dulguerov et al. 2001), the combination of surgery
and radiotherapy was associated with the highest 5year survival rate (65%). In particular, the management of olfactory neuroblastoma has been radically
changed by the introduction of anterior craniofacial
resection, which has the advantage to ensure an adequate margin of excision even at the level of the
anterior cranial fossa. This approach, followed by
postoperative radiotherapy, is currently considered
the gold standard for lesions without gross brain
infi ltration. In case of advanced-stage disease or of
a poorly differentiated olfactory neuroblastoma, patients should instead undergo chemotherapy, either
alone or combined with surgery and/or radiotherapy
(Levine et al. 1999). Cisplatin, doxorubicin, etoposide, and vincristine have been used in different combinations (Eich et al. 2001; Simon et al. 2001; Lund
et al. 2003). However, platinum-based regimens seem
to be associated with the best responses (Sheehan
et al. 2000).
In recent years, promising results in the management of selected cases of olfactory neuroblastoma
mostly limited to the naso-ethmoidal complex have
been reported with the use of a micro-endoscopic
approach (Stammberger et al. 1999; Casiano et
al. 2001; Cakmak et al. 2002). Postoperative stereotactic radiotherapy has been added with the
intent to optimize the local control of the disease
and, at the same time, to minimize the morbidity
(Wa l c h et al. 2000). Additional experience with a
long postoperative follow up is certainly warranted
to definitively establish the role of such an alternative approach.
The presence of cervical node metastasis requires
an adequate neck dissection and/or radiotherapy
(according to the treatment selected for the primary
lesion). Since an extremely variable rate of cervical
metastases is reported in the literature, elective treatment is a matter of debate. As a matter of fact, it seems
reasonable to assess the status of retropharyngeal as
well as of cervical lymph nodes by imaging studies
and to treat the neck only in those patients who have
positive nodes.
Local recurrence, which occurs in 17%-30% of
patients, is the most frequent cause of treatment
failure, whereas regional recurrence and distant
metastases may account for up to 20% and 4%,
respectively (Lund et al. 2003). While local and
regional recurrences are amenable to salvage
treatment in 33-50% and one third of patients,
respectively, distant metastases almost invariably
carry an ominous prognosis (Dulguerov et al.
2001).
A very peculiar finding to keep in mind with
olfactory neuroblastoma is that local recurrences
may occur even many years after treatment. In
the paper by Lund et al. (1998), 5-year actuarial
survival was 62%, but at 10 year survival dropped
down to 47%. The high rate of late recurrences explain why in olfactory neuroblastoma patients follow up surveillance must be extended for at least
10 years.
Prognosis of olfactory neuroblastoma is correlated not only to the extension of the lesion, but
also to Hyams’s histopathologic grade (Miyamoto
et al. 2000). Other factors having an impact on survival are the presence of metastatic lymph nodes
(Koka et al. 1998) and shrinkage of the lesion after
chemotherapy (McElroy et al. 1998; Morita et al.
1993).
Malignant Neoplasms 187
9.3.1.5
Key Information to be Provided by Imaging
Assessment of critical extents and volume of the
primary lesion (see section 9.1.6)
Presence of lymph node metastases
Presence of distant metastases
9.3.1.6
Imaging Findings
The imaging features of olfactory neuroblastoma are
nonspecifi c. Nevertheless, this neoplasm should be
suspected when a mass is detected in the superior
nasal cavity, causing either remodeling or destruction of adjacent bony structures, and erosion of the
cribriform plate or of the fovea ethmoidalis (Som et
al. 1986; Woodhead and Lloyd 1988; Li et al. 1993;
Derdeyn et al. 1994; Schuster et al. 1994; Pickuth
et al. 1999).
In fact, because olfactory neuroblastoma arises
from the olfactory epithelium, most cases have the
epicenter in the uppermost nasal cavity or in the adjacent ethmoid cells.
The signal characteristics of olfactory neuroblastoma - both density and intensity - overlap those of
other neoplasms in the nasal cavity (Schuster et al.
1994; Pickuth et al. 1999) (Fig. 9.24). Calcifi cations
within the mass have been reported to be frequently
observed on CT (Som and Lidov 1994). However, as
Som and Lidov (1994) pointed out, such densities
very often cannot be differentiated from residual
bone, which is a common fi nding among several malignancies. Inverted papillomas and chondroid tumors can calcify as well.
Due to its high vascularization, olfactory neuroblastoma shows either homogeneous or heterogeneous intense enhancement (Schuster et al. 1994).
Actually, a dense blush is detectable on angiography.
Though infrequent, two additional elements are
useful to suggest the diagnosis of olfactory neuroblastoma: the presence of a marginal tumor cyst
within the intracranial part and hyperostosis of adjacent bone. The cysts have not a true lining because
they are composed of compressed tumor and fi brous
tissue. Their content consists of hemorrhagic, degenerated mucoid material, and necrotic tumor. In a series of 54 lesions (neoplastic and infl ammatory) with
gross intracranial extent, marginal tumor cysts have
been observed only in olfactory neuroblastoma (3
out of 5) (Som et al. 1994).
An exuberant osteoblastic reaction has been described to be associated with olfactory neuroblastoma
in few cases. Conversely, less specifi c bone changes
such as remodeling – particularly bowing of sinusal
walls - and erosion are more common (Regenbogen
et al. 1988).
9.3.1.6.1
Pathways of Spread
Because endoscopy accurately delineates the intranasal extent, the key point of imaging studies is to
a b
Fig. 9.24a,b. Olfactory neuroblastoma. a Coronal CT shows a soft tissue mass with its epicenter within the right ethmoid, as-
sociated with contralateral invasion and remodeling of right lamina papyracea. b On coronal T2 sequence the epicenter is
more precisely located close to the lamina cribrosa. While on CT the lamina cribrosa appears regular, MR demonstrates that
the tumor extends into the anterior cranial fossa with bilateral involvement and with an associated cystic lesion on right side.
The olfactory neuroblastoma has a low- to intermediate signal
188
R. Maroldi et al.
demonstrate the precise relationship of olfactory
neuroblastoma with the skull base, the orbit, and
to detail the intracranial extent. Of course, the
assessment of intrasinusal invasion is also important.
At an early stage, olfactory neuroblastoma can
be totally confined within the nasal cavity or the
ethmoid, without contacting the roof. More frequently, the lesion abuts the cribriform plate or
the fovea ethmoidalis. In this setting, imaging is
required to assess the degree of anterior skull base
involvement (Fig. 9.25). Absence of changes of the
bony interface on CT does not reliably exclude subtle intracranial spread. MR is ideally suited for this,
because it shows even small neoplastic projections
that travel through the sieve-like openings across
the fenestrations of the cribriform plate, whereas
positivity on CT requires bone destruction (Li et
al. 1993).
Unfor tunately, even MR may fail, most frequently
because of overestimation, particularly when dealing with focal abnormalities of the anterior cranial
floor. However, it achieves a superior confidence in
the planning of an exclusively endonasal approach,
though intraoperative mapping (with frozen sections) is necessary (Lloyd et al. 2000).
Advanced lesions tend to spread into the anterior
cranial fossa fl oor and into the contralateral nasal
cavity through the destruction of the nasal septum.
9.3.2
Sinonasal Neuroendocrine Carcinoma and
Sinonasal Undiff erentiated Carcinoma
9.3.2.1
Defi nition, Epidemiology, Pattern of Growth
Sinonasal neuroendocrine carcinoma and sinonasal
undifferentiated carcinoma are two rare and aggressive malignancies, which have been only in recent
years recognized and categorized. They share the
prevalent site of origin (i.e., superior part of the nasal cavity, upper ethmoid) as well as some imaging,
clinical and histological features. Both the identifi cation and the distinction of the two histotypes require
an evaluation of the immunohistochemical profi le
(Smith et al. 2000), which is otherwise essential for
the differentiation from other malignant neoplasms
such as olfactory neuroblastoma, lymphoma, Ewing’s
sarcoma, and melanoma.
Sinonasal neuroendocrine carcinoma, fi rst identifi ed by Silva et al. (1982), is supposed to take origin
from submucosal glands (Smith et al. 2000). Most
neuroendocrine carcinomas occur in the lung, but an
extra pulmonary origin from several anatomic areas
is possible (We st erve l d et al. 2001). In the head and
neck, the most common site of origin is the larynx,
with only a few cases involving the sinonasal tract.
The immunohistochemical profi le shows positivity
b
Fig. 9.25a,b. Olfactory neuroblastoma arising from left ethmoid. The per-
pendicular plate is displaced towards the left, the mass projects inferiorly down to the level of the horizontal middle turbinate. Laterally, the
tumor spreads through the vertical lamella of the middle turbinate. The
lesion contacts both the horizontal and vertical laminae of the cribriform
a
plate. b Blockage of the small left sphenoid sinus results in mucus fi lling.
Permeated invasion of the ethmoid cells is present
Malignant Neoplasms 189
for neuroendocrine markers such as neuron specifi c
enolase, chromogranin A, synaptophysin and also for
other markers as Cam 5.2 and AE1:AE3; conversely, S100 and neurofi laments are usually negative (Perez-
Ordonez et al. 1998). Although the neoplasm has
been described at any age between 16 and 77 years, the
prevalent distribution is in the fi fth and sixth decade
(Perez-Ordonez et al. 1998; Smith et al. 2000).
First described by Frierson et al. (1986), sinonasal undifferentiated carcinoma consists of undifferentiated cells supposed to derive from schneiderian
epithelium or nasal ectoderm (Greger et al. 1990).
The immunohistochemical evaluation shows positivity for cytokeratin, epithelial membrane antigens,
and possible positivity for neuron specifi c enolase,
whereas vimentin and S-100 protein are usually
negative (Gorelick et al. 2000). Sinonasal undifferentiated carcinoma is usually diagnosed in the sixth
decade of life, with a range between 31 and 81 years
(Musy et al. 2002).
Due to their aggressiveness, both sinonasal neuroendocrine and undifferentiated carcinoma tend to
early involve adjacent bony structures, with invasion
of soft tissue, orbit and anterior cranial fossa (Kim et
al. 2004).
9.3.2.2
Clinical and Endoscopic Findings
Clinical manifestations of sinonasal neuroendocrine
and undifferentiated carcinoma are nonspecifi c,
though suggestive for a rapidly growing neoplasm.
Therefore, involvement of multiple sinonasal structures as well as extension into the orbit and/or the
cranial cavity are not infrequently detected at presentation (Musy et al. 2002).
Paraneoplastic hypersecretion of ACTH and calcitonin have been reported in two cases of sinonasal
neuroendocrine carcinoma (Kameya et al. 1980); more
recently, also a syndrome of inappropriate antidiuretic
hormone secretion has been diagnosed in association
with a neuroendocrine carcinoma (Vasan et al. 2004).
In sinonasal undifferentiated carcinoma, cervical
node metastases are detected at diagnosis in a rate of
patients ranging between 13% (Musy et al. 2002) and
50% (Smith et al. 2000), whereas distant spreading is
present in up to 31% (Jeng et al. 2002).
9.3.2.3
Treatment Guidelines and Outcome
Surgery with platinum-based postoperative chemotherapy should be considered the treatment of
choice for sinonasal neuroendocrine carcinomas
with limited local extent (Perez-Ordonez et al.
1998). According to Galera-Ruiz et al. (2001b), advanced lesions are best treated by a regimen similar
to that of small cell lung cancer, which includes a
combination of chemotherapy (cisplatin + etoposide) and radiotherapy. Differently, in the experience
of Memorial Sloan Kettering Cancer Center, a good
response was obtained with platinum-based neoadjuvant chemotherapy and radiotherapy followed by
surgery (Perez-Ordonez et al. 1998). A similar combination of chemotherapy, radiotherapy, and possibly
subsequent surgery has been proposed by Fitzek
et al. (2002). In case of disseminated disease, platinum-based chemotherapy is the treatment of choice.
Radiotherapy may also have a role in the palliation
of non resectable lesions.
Even though local recurrence is the most common cause of treatment failure, regional and distant
spreading (especially to the brain and spine) may also
occur (Smith et al. 2000). In the series from Perez-
Ordonez et al. (1998), after a 37-month follow up,
only one patient (16.7%) affected by sinonasal neuroendocrine carcinoma was free of disease, one (16.7%)
died for local recurrence and distant metastases, and
the remaining four (66.6%) were alive with disease
(local and/or distant recurrence).
Due to the aggressiveness of sinonasal undifferentiated carcinoma and to its high probability of
systemic spreading, almost all authors concur on the
need of a treatment which should include a combination of radiotherapy and chemotherapy. By contrast,
the role of surgery is controversial.
Some authors (Gorelick et al. 2000; Musy et al.
2002; Kim et al. 2004) have proposed an integrated
therapeutic protocol which included surgery. The
choice of this therapeutic protocol is supported by
either the detection in the majority of patients of viable neoplastic cells within the fi eld of irradiation
(Musy et al. 2002) and by the observation of a better
survival when surgery was added to chemotherapy
with radiation (Kim et al. 2004). In the paper by Musy
et al. (2002), the overall 2-year survival for patients
affected by sinonasal undifferentiated carcinoma was
47%; when stratifi ed by treatment modality, survival
was as high as 64% for patients who underwent craniofacial resection and 25% for those who did not.
However, some bias related to treatment selection in
relation to the stage of the lesion might have infl uenced the results. More recently, Rischin et al. (2004)
reported promising results in the treatment of locally
advanced sinonasal undifferentiated carcinoma with
a regimen of neoadjuvant chemotherapy (5-fl uoro-
190
R. Maroldi et al.
uracil and platinum) followed by concurrent chemoradiation. With this protocol, they achieved a 2-year
disease-free and overall survival of 43% and 64%, respectively. Surgery should be reserved only for those
patients with residual resectable disease.
Local-regional and distant metastases develop in
a high rate of patients (63% and 50%, respectively),
prevalently within two years from treatment (Kim et
al. 2004).
9.3.2.4
Key Information to Be Provided by Imaging
Assessment of critical extents and volume of the
primary lesion (see section 9.1.6)
Presence of lymph node metastases
Presence of distant metastases
9.3.2.5
Imaging Findings
Sinonasal neuroendocrine carcinoma is not associated with distinctive CT or MR imaging features
(Kanamalla et al. 2000). On CT, it may appear as
a well-defi ned and homogeneous soft tissue mass.
Bone remodeling and/or bone destruction may also
be noted. Expansion of sinusal walls, rather than destruction, could be a useful indicator that the tumor
is not a conventional squamous cell carcinoma. In
the series of Kanamalla et al. (2000), no evidence of
intra-tumoral calcifi cation was found. A single report
in the literature described partially calcifi ed low density naso-ethmoidal neuroendocrine carcinoma with
intracranial extension (Manome et al. 1990). On MR,
the lesion has been described to appear hypointense
on T1 images and heterogeneously hyperintense on
T2. It shows minimal heterogeneous enhancement
after contrast agent administration (Kanamalla et
al. 2000) (Fig. 9.16).
The biological aggressiveness of undifferentiated
carcinoma often results in large, rapidly growing lesions with extensive bone destruction and invasion of
adjacent structures. Lesions tend to arise in the ethmoid and superior nasal cavity, as they probably derive from schneiderian epithelium or nasal ectoderm.
Intracranial and intraorbital invasion are frequent. In
the series of Phillips et al. (1997), the imaging features of undifferentiated carcinoma were not specifi c.
On CT, tumor usually did not show calcifi cations and
enhanced variably. It appeared isointense to skeletal
muscles on T1, iso- to hyperintense on T2 with nonhomogeneous enhancement after contrast agent administration (Fig. 9.26).
9.3.3
Ewing’s Sarcoma
9.3.3 1
Defi nition, Epidemiology, Pattern of Growth
Ewing’s sarcoma, a tumor arising within bone marrow, is included in the group of primitive neuroectodermal tumors, which encompasses three different
subtypes: 1) neuroblastoma 2) central nervous system
tumors like medulloblastoma 3) peripheral neuroectodermal tumors like Ewing’s sarcoma (Batsakis et
al. 1996).
Even though two variants (skeletal and extra-skeletal) of Ewing’s sarcoma are traditionally recognized,
it is sometimes diffi cult to separate the two entities
(Mills and Fechner 1989).
Ewing’s sarcoma is usually found in long bones
of the extremities in children and young white
adults, with a peak incidence in the second decade
(Howarth et al. 2004). There is a constant male pre-
dominance (Howarth et al. 2004). It is considered
the second most common pediatric bone tumor, with
an incidence of 3 new cases per 1,000,000 inhabitants
per year (Paulussen et al. 2001).
Head and neck area is rarely involved either by
skeletal (Howard and Daniels 1993) and extra-
skeletal subtype (Vaccani et al. 1999; Boor et al.
2001), with the mandible and the skull being the
preferential sites of origin (Siegal et al. 1987).
Sinonasal tract involvement is extremely rare, with
about 50 cases reported in the English literature.
Most of them were observed in the maxillary sinus, whereas less than 10 cases each involved the
ethmoid and the nasal fossa. Race, gender and age
features are similar to those reported for lesion with
a skeletal localization, even though the lesion may
occur at an older age.
The pathogenesis of the tumor is still unclear;
however, a specifi c chromosomal translocation
(t11:22) (q24:q12), which is present in up to 90% of
cases (Vaccani et al. 1999), is considered to play an
important role.
Ewing’s sarcoma has a slow growth but also a high
tendency to develop distant metastases, more frequently to lungs, bone and bone marrow (Burdach
et al. 2003).
Histological diagnosis of Ewing’s sarcoma is based
on identifi cation of the aforementioned specifi c
chromosomal translocation (Yoshida et al. 1997)
and immunohistochemical profi le (positivity for S100 protein, CD99, FLI-1). Intracytoplasmic glyco-
Malignant Neoplasms 191
Fig. 9.26a–c. Sinonasal undifferentiated carcinoma
arising within the right ethmoid. a Axial CT shows
irregular and diffuse erosion of ethmoid cells. Fat
sat TSE T2 (b)and enhanced T1 (c) obtained at the
same level of CT show a low intensity mass invading both ethmoid sinuses, partially surrounded by
fl uid, and the nasal bones. Enhancement is rather
heterogeneous
a
gen is found in up to 90% of cases (PAS and PAS-d
positivity) (Cotran et al. 1989; Vaccani et al. 1999).
Differential diagnosis includes other small cell tumors, such as hemangiopericytoma, olfactory and
primitive neuroblastoma, small cell osteosarcoma,
mesenchymal chondrosarcoma, some non-Hodgkin
lymphomas, rhabdomyosarcoma, and undifferentiated carcinoma.
9.3.3.2
Clinical and Endoscopic Findings
Ewing’s sarcoma shares similar clinical presentation
and endoscopic appearance with other sinonasal
neoplasms. Since Ewing’s sarcoma in its skeletal variant has an osseous origin, pathologic fracture of nasal
bones may be the presenting complaint (Howarth et
al. 2004). Pain, which is the most frequent symptom
in long bones localization, is less frequently observed
in head and neck area.
cb
Sinonasal lesions are associated with a lower rate
of regional and distant dissemination than the skeletal counterpart. At diagnosis, distant metastases
are detected in 15%-30% of patients (Johnson and
Pomeroy 1975).
9.3.3.3
Treatment Guidelines and Outcome
Prognosis of Ewing’s sarcoma has radically changed
with the advent of chemotherapy, which includes
different regimens based on vincristine, adriamycin,
doxorubicin, and cyclophosphamide or ifosfamide
with or without etoposide (Wexler et al. 1996).
Chemotherapy is currently used in a neoadjuvant setting, followed by radiotherapy. Surgery is indicated
for residual or recurrent lesions. More aggressive protocols include also adjuvant chemotherapy.
Some authors instead proposed multimodality
regimens including surgery (Vaccani et al. 1999).
192
R. Maroldi et al.
Treatment protocol was modulated according to
the extension of the lesion and to its response to
chemotherapy (Vaccani et al. 1999). Whenever a
patient with a resectable lesion showed a good response to chemotherapy, surgery was performed.
Conversely, in presence of an unresectable lesion
and/or of a poor response to systemic therapy,
radiation therapy was delivered. Nevertheless,
in all patients chemotherapy was prolonged for
the full course of the treatment (30-48 weeks).
Radiotherapy is also useful in cases not amenable
of complete surgical excision, unless unacceptable
morbidity (Dunst et al. 1991). Whenever meta-
static disease is detected at diagnosis, palliative
protocols including chemotherapy and radiotherapy are available.
High doses chemotherapy and/or total body radiation therapy and possibly bone marrow transplant
can give a chance of control to patients with distant
metastases (Horowitz et al. 1993).
Unfavorable prognostic factors are trunk localization, high tumor volume, low response to chemotherapy, and development of distant metastases (Hayes
et al. 1989; Evans et al. 1991; Picci et al. 1993; Vlasak
and Sim 1996). The latter, in particular, has shown to
signifi cantly decrease 5-year survival (Howarth et
al. 2004), which drops from 65% to 30% (Wo od et
al. 1990).
9.3.3.4
Key Information to Be Provided by Imaging
Assessment of critical extents and volume of the
primary lesion (see section 9.1.6)
Presence of lymph node metastases
Presence of distant metastases
9.3.3.5
Imaging Findings
On CT, Ewing’s sarcoma arising from sinonasal tract
osseous structures or skull base is characterized by
permeative destruction of bone, usually associated
with a large soft tissue component and no calcifi cation, refl ecting the aggressive nature of the tumor
(Harman et al. 2003).
On MR, Ewing’s sarcoma usually has a homogeneous hypo- to hyperintense signal on T2 sequences,
though hemorrhagic and necrotic areas within soft
tissues can result in a more heterogeneous pattern
and often appear hyperintense on T2 sequences
(Hanna et al. 1994; Singh et al. 2002) (Fig. 9.27).
Whereas CT more easily demonstrates the erosion
of the thin lamellae of the ethmoid, MR is superior
in detecting bone marrow invasion and grading intracranial extent (Harman et al. 2003). Sclerotic
changes of the diploic bone have been described on
MR by Freeman et al. (1988).
The combination of patient’s age with the presence
of an intra- and extraosseous mass without calcifi cations can suggest the diagnosis of Ewing’s sarcoma
(Fig. 9.28).
Few extraosseous sinonasal tract Ewing’s sarcomas have been reported. Many of them arose from
nasal cavity structures and presented as a nonspecifi c
polypoid mass (Pontius and Sebek 1981; Lane and
Ironside 1990; Csokonai et al. 2001; Aferzon et al.
2003).
Chest CT, bone marrow aspirate, and/or bone
scintigraphy with technetium 99m, thallium 201, or
gallium 67 are helpful in detecting distant metastases at presentation and in post treatment follow up
(Fletcher 1991; Vaccani et al. 1999). Also FDG-
Fig. 9.27 Ewing sarcoma arising in an adult
male from the left frontal sinus. On postcontrast T1 sequence the mass has slight enhancement, its signal rather low compared
with the surrounding thickened sinusal mucosa. Erosion of the anterior wall is demonstrated (white arrows)
Malignant Neoplasms 193
a b
Fig. 9.28a,b. Ewing sarcoma arising in an adolescent female from pterygoid process. The extra-osseous component of tumor
is prevalent, with extensive invasion of the masticator space. On plain T1 coronal plane (a) the signal of the lesion is similar
to pterygoid muscles. This hypointense signal – which replaces the diploic bone within pterygoid (white arrow on a) - shows
enhancement after contrast agent administration (b) indicating the presence of intraosseous neoplastic tissue. Cortical lining
of the vidian canal is unchanged (white arrow)
PET has been purposed instead of scintigraphy in
the diagnostic work-up. Laboratory tests able to arise
a suspicion of metastases (lactate dehydrogenase, reverse transcription PCR) can be also used for staging
or during follow-up (Sorensen et al. 1993; Vlasak
and Sim 1996).
9.4
Melanoma
9.4.1
Defi nition, Epidemiology, Pattern of Growth
Melanoma is composed by a proliferation of melanocytes, which derive from the neural crest and
subsequently migrate into the skin and mucosal surfaces with an ectodermal origin (Ramos et al. 1990;
Manolidis and Donald 1997; Lund et al. 1999;
Pa n d ey et al. 1999). Malignant melanoma is usually
divided in two categories (cutaneous and mucosal),
which, despite a common cytological derivation, differ for biologic behavior. Mucosal melanoma, which
is more aggressive, is more rarely observed than the
cutaneous counterpart (Batsakis et al. 1998; Pat e l
et al. 2002b; Medina et al. 2003). In the head and
neck region, sinonasal tract and oral cavity are the
most frequently involved areas (Medina et al. 2003).
Sinonasal malignant melanoma is quite an uncommon observation, accounting for less than 1% of all
melanomas and for 2–8% of all the malignancies of
the nose and paranasal sinuses (Trapp et al. 1987;
Kingdom and Kaplan 1995; Lund et al. 1999). It is
more frequent in Caucasians and it usually occurs in
patients around the age of 50 or older, even though,
in a small rate (10-20%), also younger people may
be affected (Rinaldo et al. 2001; Pat e l et al. 2002b).
The most frequent sites of origin of sinonasal malignant melanoma are the nasal septum, the lateral
nasal wall, the middle and inferior turbinates (Lund
1993; Manolidis and Donald 1997; Medina et al.
2003). Nevertheless, also paranasal sinuses, in particular maxillary and ethmoid, nasal vestibule and
fl oor of the nasal cavity may be affected (Lund 1993).
Localization into the sinonasal tract may also occur
as a result of an ocular melanoma invading the sinonasal tract or of a metastatic spreading from distant
sites (Trapp et al. 1987; Pat e l et al. 2002b). The great
majority of patients present with a tumor confi ned
194
R. Maroldi et al.
to the primary site, albeit locally advanced (Stage
I); far uncommon is the observation at diagnosis of
regional (Stage II) or distant metastases (Stage III)
(Manolidis and Donald 1997; Pat e l et al. 2002b).
Due to the large size of the lesion at presentation, to
the possible presence of multiple neoplastic foci and
amelanotic areas (Manolidis and Donald 1997;
Lund et al. 1999), the real site of origin and the extent
of the lesion are sometimes diffi cult to assess.
Differential diagnosis is usually with olfactory
neuroblastoma, some non-Hodgkin lymphomas,
plasmacytoma, Ewing’s sarcoma, rhabdomyosarcoma, small cell undifferentiated carcinoma; in the
cases without typical histological features, diagnosis
may be supported by the immunohistochemical profi le (i.e., positivity for S-100 protein, vimentin, and
for HMB-45) (Stern and Guillamondegui 1991;
Lund et al. 1999; Rinaldo et al. 2001).
9.4.2
Clinical and Endoscopic Findings
Clinical manifestations of mucosal malignant melanoma are quite nonspecifi c. Metastases to cervical
lymph nodes are detected in a 5.7% to 18.7% of
patients (Manolidis and Donald 1997; Pat e l et
al. 2002b), mostly at the submandibular and upper
jugular levels. Distant metastases, in particular to
lung and brain, are found in 3.1% to 14% of patients
(Stern and Guillamondegui 1991; Batsakis et al.
1998; Rinaldo et al. 2001).
At endoscopy, mucosal melanoma appears as a polypoid lesion, with areas of necrosis or superfi cial hemorrhages (Rinaldo et al. 2001). Its color varies from
pink to brownish (Matias et al. 1988) or grayish.
This may refl ect the different grades of pigmentation
of the lesion; poorly pigmented or not pigmented
tumors may account for up to one third of all the
cases (Rinaldo et al. 2001).
9.4.3
Treatment Guidelines and Outcome
The mainstay for treatment of mucosal malignant
melanoma is surgical excision. Oncological radicality
may be reached only by a complete removal of the
lesion; in order to reduce the risk of local recurrence,
it is essential to ensure wide, free surgical margins
(Rinaldo et al. 2001). Several approaches are avail-
able, depending principally on the extent and on the
localization of the tumor. As the tumor, at diagnosis,
is often great in size, with possible extension to the
surrounding structures, such as orbit and/or cranial
cavity, external approaches (i.e. transfacial and transcranial) should be considered the fi rst choice (Lund
et al. 1999). Mucosal melanoma, due to its aggressiveness and possible multifocality, has more restrictive indications for purely endoscopic resection than
other malignant tumors. Surgery, either external or
endoscopic, may be also a valid tool for palliative
treatment of non-resectable lesions (Rinaldo et
al. 2001). Invasion of the brain, of the optic chiasm
and/or distant metastases contraindicate a surgical
treatment.
In presence of cervical metastases, a tailored neck
dissection, in relation to the dimension, the extent and
the number of nodes, must be planned. Elective neck
dissection is generally not indicated, even though the
availability of PET scan and sentinel lymph node biopsy in the pre-treatment diagnostic work-up may
change this orientation in the future (Medina et al.
2003).
The role of post-operative radiotherapy is controversial, despite some reports which advocate the use
of radical (Gilligan and Slevin 1991) or adjuvant
radiotherapy (Stern and Guillamondegui 1991).
However, recent studies (Lund et al. 1999; Pat e l et
al. 2002b) suggest that there is no evidence of the effi cacy of post-operative radiotherapy in mucosal malignant melanoma.
The high aggressiveness of mucosal malignant
melanoma is refl ected by a high rate of local, regional
and distant failure, which accounts for 50%, 20% and
40%, respectively (Pat el et al. 2002b). Tumor thickness rather than free surgical margins appears to
affect local recurrence rate (Kingdom and Kaplan
1995). Moreover, tumor thickness greater than 5 mm,
advanced clinical stage, vascular invasion at histology, and development of distant metastases have a
negative prognostic impact on treatment outcome
(Pat e l et al. 2002b).
Malignant mucosal malignant melanoma is associated with a poor survival. By reviewing 21 papers,
Pat e l et al. (2002b) found a mean 5-year disease–
specifi c survival of 17%. According to several authors
(Kingdom and Kaplan 1995; Lund et al. 1999), follow up should be extended beyond the usual 5-year
period, since the natural history of malignant melanoma is also characterized by a tendency to develop
late recurrences.
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