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Fig. 1.83 Rosai-Dorfman disease of nasal cavity. A Low to medium magnification typically reveals alternating bands of dark-staining and light-staining cells. B The presence of spindly cells in a vague storiform growth pattern may lead to a misdiagnosis of fibrohistiocytic tumour. C The characteristic histiocytes are usually much larger than the typical histiocytes with round nuclei, distinct nucleoli, abundant light-staining cytoplasm, and indistinct cell borders. There are typically many admixed plasma cells. D Immunostaining for S100 protein selectively highlights the distinctive histiocytes. Both the nuclei and cell bodies are stained, while the phagocytosed lymphocytes become much more evident because of the negative staining.

cervical lymph nodes. Extranodal involvement is frequent (about 40% of cases), especially the upper aerodiges-tive tract {791,923,1378,2760}. The patients with upper aerodigestive tract disease present with nasal obstruction, sinusitis, epistaxis, facial pain or saddle nose deformity.

Histologically, low magnification examination reveals alternating pale and dark-staining areas. The pale areas show proliferation of a distinctive type of very large histiocytes with large round nuclei, distinct nucleoli, and voluminous lightly eosinophilic cytoplasm whose borders are often difficult to define. Some histiocytes show emperipolesis, with lymphocytes, plasma cells or neutrophils in the cytoplasm. These characteristic histio-cytes can be few in number in extranodal sites. The lesion may be mistaken for rhinoscleroma. In some cases, a propor tion of histiocytes can exhibit atypical or irregular nuclei, and may lead to a misdiagnosis of malignancy such as histiocyt-ic sarcoma or melanoma. The dark areas consist of large aggregates of plasma cells and small lymphocytes. Fibrosis is usually a prominent feature in extranodal disease, and the fibrotic bands can impart a nodular appearance. Together with spindling of some of the cells, the histologic features may strongly mimic those of fibrohistiocytic tumours or inflammatory pseudotumours. Immuno-histochemically, the large histiocytes co-express S100 protein and the histiocytic marker CD68, and are negative for CD1a.

Most cases are treated by excision alone, with steroid, radiotherapy and chemotherapy having been given in a minority of cases. In general, the prognosis is excellent, most patients being free of disease or with stable disease. However, some patients may develop recurrent disease in the original site or other body sites.

Neuroectodermal tumours

B.M. Wenig P. Dulguerov S.B. Kapadia

M.L. Prasad J.C. Fanburg-Smith L.D.R. Thompson

Ewing sarcoma (EWS) / Primitive neuroectodermal tumour (PNET)

Definition

A high-grade, primitive, round cell tumour of neuroectodermal phenotype. EWS and PNET represent a group of small round cell neoplasms with variable degrees of neuroectodermal differentiation, and are considered together in this section under the rubric of EWS/PNET.

ICD-O codes

Ewing sarcoma PNET

9260/3 9364/3

Synonyms

Peripheral neuroepithelioma, peripheral neuroectodermal tumour, peripheral neu-roblastoma

Epidemiology

Sinonasal Ewing sarcoma / primitive neuroectodermal tumour (EWS/PNET) is rare. This is mostly a tumour of children and young adults, with a peak in the 3rd decade {2211}. In children, approximately 20% of EWS/PNET occur in the head

Fig. 1.84 Ewing sarcoma (EWS). A A "small blue round cell" tumour is comprised of intermediate sized cells with scant cytoplasm, although there are an increased number of mitotic figures. B While non-specific, the neoplastic cells are strongly and diffusely immunoreactive with CD99. The nuclei have very delicate nuclear chromatin, with margination to the periphery.

Fig. 1.84 Ewing sarcoma (EWS). A A "small blue round cell" tumour is comprised of intermediate sized cells with scant cytoplasm, although there are an increased number of mitotic figures. B While non-specific, the neoplastic cells are strongly and diffusely immunoreactive with CD99. The nuclei have very delicate nuclear chromatin, with margination to the periphery.

and neck, with about 20% of these arising in the sinonasal tract {2122}. On rare occasion, older adults may be affected {2611}. There is a very slight male predominance {2122}.

Localization

Sinonasal EWS/PNET most commonly occurs in the maxillary sinus {1518} and nasal fossa {1424,2069}.

Clinical features

Symptoms include pain, mass, and obstruction {2069}. The tumour can be polypoid when arising from the nasal cavity {2069}. Bony erosion may or may not be present {2069}.

Macroscopy

EWS/PNET is a grey-white and glistening tumour with haemorrhage and often ulceration {2069}. It tends to be much smaller than that arising in other sites.

Tumour spread and staging

Intranasal tumours usually spread into

Fig. 1.85 Olfactory neuroblastoma. A CT with intravenous contrast. The tumour (T) extends through the floor of the anterior fossa. The lamina papyracea is bowed but the orbital fat (arrow) is normal indicating that the periorbita has not been breached. B T1 weighted image. The tumour (T) obstructs the sphenoid sinus. The right side shows secretions with low protein (white arrow). The left has higher protein and higher signal (black arrow). Carotid artery (C)

Fig. 1.85 Olfactory neuroblastoma. A CT with intravenous contrast. The tumour (T) extends through the floor of the anterior fossa. The lamina papyracea is bowed but the orbital fat (arrow) is normal indicating that the periorbita has not been breached. B T1 weighted image. The tumour (T) obstructs the sphenoid sinus. The right side shows secretions with low protein (white arrow). The left has higher protein and higher signal (black arrow). Carotid artery (C)

the paranasal sinuses {2069}. When metastases develop, they are mainly to the lungs and bone {2122}. Staging is according to the Clinical Groups of the Intergroup Rhabdomyosarcoma Study {2122}.

Histopathology

The tumour is composed of densely distributed, uniform, small to medium sized, round cells with a high nuclear to cytoplasmic ratio and fine chromatin. Mitotic activity is high, and coagulative necrosis is common. Some cases show more densely clumped chromatin or a greater degree of nuclear pleomorphism. Homer Wright rosettes are rare.

Immunoprofile

The immunophenotype includes reactivity for CD99 (MIC2, O13, HBA-71, p30/32, and 12E7), {2472} vimentin, and on occasion focally for keratins. Some cases express neural markers, such as synaptophysin, S100 protein, NSE, neurofilament protein, GFAP, and chromo-granin. Fli-1 (one portion of the gene fusion product of EWS/FLI1) can be detected by immunohistochemistry.

Electron microscopy

Electron microscopy reveals, to a variable extent, interdigitating neuritic processes, neurofilaments, microtubules, neurosecretory granules and glycogen {1743,2069}.

Differential diagnosis

The differential diagnoses include malignant melanoma, melanotic neuroectoder-mal tumour, rhabdomyosarcoma, slnonasal undifferentiated carcinoma, lymphoma, olfactory neuroblastoma, and pituitary adenoma.

Histogenesis

A pluripotential fetal neuroectodermal cell is considered the progenitor.

Somatic genetics

Most EWS/PNET have a characteristic t(11 ;22) with EWS/FLI1 juxtaposition or other translocations involving EWS {2646}. Molecular analysis by PCR or FISH is helpful in diagnosis.

Genetic susceptibility

Sinonasal EWS/PNET has been reported in association with retinoblastoma {627, 1330}.

Prognosis and predictive factors

EWS/PNET has much better prognosis in the head and neck than in other anatomic sites {2122}. Size and stage are the most important prognostic factors. Tumours demonstrating the EWS/FLI1 fusion are reported to have a better prognosis than those with less common gene fusion types {552}. With improvements in imaging techniques and multimodality treatment, a 5-year survival of 60-70% can be achieved {23}.

Olfactory neuroblastoma

Definition

A malignant neuroectodermal tumour thought to originate from the olfactory membrane of the sinonasal tract.

Synonyms

Esthesioneuroblastoma, esthesioneuro-cytoma, esthesioneuroepithelioma, olfactory placode tumour.

ICD-O code

9522/3

Epidemiology

Olfactory neuroblastoma is an uncommon neoplasm representing approximately 2-3% of sinonasal tract tumours. The incidence has been estimated at 0.4 per million {2584}. Patients range in age from as young as 2 years to 90 years, and a bimodal age distribution has been noted in the 2nd and 6th decades of life {625,626,663,1159}. Both genders are affected equally. No racial predilection has been noted.

Etiology

There are no known etiologic agent(s) for human olfactory neuroblastoma. Injection of diethylnitrosamine in Syrian hamsters and N-nitrosopiperidine in rats has produced tumours histologically identical to human olfactory neuroblas-toma {1078,2697}.

Localization

The most common site of origin is in the upper nasal cavity in the region of the cribriform plate. Included in the areas of the proposed origin are Jacobson's organ (vomeronasal organ), sphenopala-tine (pterygoid palatine) ganglion, olfactory placode, and the ganglion of Loci (nervus terminalis). "Ectopic" origin in lower nasal cavity or within one of the paranasal sinuses (e.g., maxillary sinus) may occur. Olfactory neuroblastoma may

Fig. 1.86 Olfactory neuroblastoma. A Tumour lobules separated by a highly vascularized stroma. B Olfactory neuroblastoma accompanied by the hyperplasia of the olfactory epithelium.

Fig. 1.86 Olfactory neuroblastoma. A Tumour lobules separated by a highly vascularized stroma. B Olfactory neuroblastoma accompanied by the hyperplasia of the olfactory epithelium.

mm mm

mm mm

c ifflBmmmMtjmmm

Fig. 1.87 Olfactory neuroblastoma. A Lobules of tumour separated by fibrovascular septa. B The lobules of tumour are separated by dense fibrovascular tissue. A large pseudorosette (Homer Wright) shows a central area of neurofibrillary matrix. C A high grade olfactory neuroblastoma showing a true Flexner-Wintersteiner rosette and increased mitotic figures. D The "small blue round cell" neoplasm has scant cytoplasm surrounding variably hyperchromatic nuclei. Granular nuclear chromatin can be seen. Mitotic figures are noted in higher grade lesions.

on occasion present as an intracranial (frontal lobe) mass with involvement of the superior aspect of the cribriform plate or rarely, occur intracranially with no intranasal component {987}.

Clinical features

Signs and symptoms

The main presenting symptoms are unilateral nasal obstruction (70%) and epistaxis (46%); less common manifestations include anosmia, headache, pain, excessive lacrimation and ocular disturbances. Typically, these tumours are slow-growing resulting in long-standing symptomatology, the mean delay between the appearance of the first symptom and the diagnosis being 6 months {626}.

Imaging

The radiologic features include the presence of a "dumbbell-shaped" mass extending across the cribriform plate. The extent of disease is best determined by pre- and postcontrast MR imaging in which there is intense signal in T2-weighted images with marked enhancement of T1-weighted images after gadolinium injection {2815}. Details of bone erosion (lamina papyracea, cribriform plate and fovea ethmoidalis) are better demonstrated by CT scan. Calcifications producing a speckled pattern on radiographic studies can be identified. Angiographic studies disclose a hypervascular neoplasm.

Macroscopy

The gross appearance includes a glistening, mucosa-covered, soft, polypoid, often highly vascularized mass varying from a small nodule measuring less than 1 cm to a large mass filling the nasal cavity and extending into paranasal sinuses, orbit and/or cranial cavity.

Histopathology

Characteristically, the tumours are localized to the submucosa, growing in circumscribed lobules or nests separated by a richly vascularized fibrous stroma. Less often the tumour shows a diffuse growth pattern. The overwhelming majority of tumours are not associated with an in-situ component. The neoplastic cells have uniform, small round nuclei with scant cytoplasm, dispersed ("salt and pepper") coarse to fine nuclear chro-matin and inconspicuous nucleoli. Nuclear pleomorphism, mitotic activity and necrosis are usually absent. However, in higher-grade tumours, nuclear pleomorphism with prominent nucleoli, increased mitotic activity and necrosis may be present. The cells do not have distinct borders and are surrounded by a neurofibrillary matrix, which corresponds to tangles of neuronal cell processes. Rosettes of the Homer

Microscopic Features Grade 1 Grade 2 Grade 3 Grade 4

Architecture Lobular Lobular ┬▒Lobular ┬▒Lobular

Pleomorphism Absent to Slight Present Prominent Marked

Neurofibrillary matrix Prominent Present May be present Absent

Rosettes Present* Present* May be present** May be present**

Mitoses Absent Present Prominent Marked

Necrosis Absent Absent Present Prominent

Glands May be present May be present May be present May be present

Calcification Variable Variable Absent Absent

NF-neurofibrillary; *Homer Wright rosettes (pseudorosettes); **Flexner-Wintersteiner rosettes (true neural rosettes)

Wright type (pseudorosettes) and Flexner-Wintersteiner type (true neural rosettes) can be identified in up to 30% and less than 5% of tumours, respectively. The Homer Wright pseudorosettes represent the presence of cells in an annular arrangement surrounding central neurofibrillary matrix; distinct cell membranes are not present. Flexner-Wintersteiner rosettes are gland-like structures in which the annular arrangement of cells includes the presence of a distinct cell membrane. Perivascular pseudorosettes can be seen but are of no diagnostic utility. Uncommon findings include stromal calcifications, ganglion cells, melanin-containing cells and divergent differentiation. The latter may include the presence of glandular (ade-nocarcinoma-like), squamous, teratoma-tous and rhabdomyoblastic differentiation {1096,1734,2404}.

Grading

The microscopic grading {1159} includes four grades: Grade I is the most differentiated and includes lobular architecture with intercommunication of the neoplasm between lobules. The neoplastic cells are well-differentiated with uniform, small round nuclei with scant cytoplasm, dis persed ("salt and pepper") nuclear chromatin and inconspicuous nucleoli. The cells do not have distinct borders; rather, the nuclei are surrounded by a neurofibrillary material suggesting cytoplasmic extension. Homer Wright rosettes are frequently seen. Varying amounts of calcification may be noted. Interlobular fibrous stroma is often extremely vascular. Mitotic activity and necrosis are absent. Grade II tumours share many of the histologic features described for Grade I lesions but the neurofibrillary element is less well defined, and the neoplastic nuclei show increased pleomorphism. Scattered mitoses can be seen. Grade III tumours may retain a lobular architecture with a vascular stroma. These hypercel-lular tumours are characterized by cells that are more anaplastic, hyperchromatic, and have increased mitotic activity as compared to Grade I or II tumours. Necrosis is seen. The neurofibrillary component may be focally present, but is much less conspicuous as compared to Grades I or II tumours. Flexner-Wintersteiner rosettes are uncommon. Calcification is absent. Grade IV tumours may also retain the overall lobular architecture, but the neoplastic element is the most undifferentiated and anaplastic of all the histologic grades. The cellular infiltrate is characterized by pleomorphic nuclei often with prominent eosinophilic nucleoli and an indistinct cytoplasm. Necrosis is commonly seen and there is increased mitotic activity, including atypical mitoses. Rosettes are uncommon. The neurofibrillary component is generally absent. Calcification is absent. Of note is that in any given tumour there may be histologic diversity with mixed (overlapping) features.

In general, the lower grade olfactory neuroblastomas are readily recognizable and diagnostic by light microscopy. Adjunct studies, particularly in the higher histologic grade tumours, may assist in the diagnosis. The advent of immunohis-tochemistry has diminished the role of histochemical stains, but silver stains such as Bodian, Grimelius and Churukian-Schenk may still be of assistance.

Immunoprofile

The most consistently expressed marker is neuron specific enolase (NSE). Reactivity is also present in a majority of cases for synaptophysin, neurofilament protein (NFP), class III beta-tubulin, and microtubule-associated protein. S-100

Fig. 1.88 Olfactory neuroblastoma. A A true Flexner-Wintersteiner rosette is surrounded by intermediate sized cells with scant cytoplasm and prominent nuleoli. A mitotic figure is present. B Immunostaining shows strong staining for synaptophysin. C Immunostaining shows the characteristic S100 protein+ sustentacular cells wrapping around the tumour islands.

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