D

Fig. 1.90 Melanotic neuroectodermal tumour. A Section of maxilla shows tumour infiltration of bone. Note fibrous stroma containing neoplastic cellular infiltrate. B Dual population of neoplastic cells, including smaller blue neuroblastic cells and larger pigmented epithelial cells. C There is a trabecular, tubular, or alveolar arrangement of the biphasic cell population, with the larger pigmented cells surrounding groups of the smaller round, "blue" neuroectodermal cells. The trabeculae are separated by a dense collagenous stroma. D Note spatial relationship of larger pigmented epithelial cells surrounding smaller neuroblastic cells.

Fig. 1.90 Melanotic neuroectodermal tumour. A Section of maxilla shows tumour infiltration of bone. Note fibrous stroma containing neoplastic cellular infiltrate. B Dual population of neoplastic cells, including smaller blue neuroblastic cells and larger pigmented epithelial cells. C There is a trabecular, tubular, or alveolar arrangement of the biphasic cell population, with the larger pigmented cells surrounding groups of the smaller round, "blue" neuroectodermal cells. The trabeculae are separated by a dense collagenous stroma. D Note spatial relationship of larger pigmented epithelial cells surrounding smaller neuroblastic cells.

didymis (4%), skin (3%), uterus (1%), and mediastinum (1%) may be involved {1269,2026}.

Clinical features

Patients present with a rapidly growing pigmented mass, which is usually located in the anterior alveolar ridge of the maxilla. The duration of symptoms ranges from 2 weeks to 5 months (mean 2 months) {1269}. Infrequently, there are elevated levels of vanilmandelic acid, which normalize following adequate therapy.

Macroscopy

The tumours range from 1-10 cm (mean, 3.5 cm), and are smooth, firm to hard, and grey to blue-black {1269}.

Histopathology

This is a nonencapsulated mass composed of a dual population of small neu-roblastic cells and larger melanin-containing epithelial cells in a vascularized dense fibrous stroma {1269,2026}. The epithelial cells show alveolar or tubular arrangement, and often surround nests of smaller neuroblastic cells. The latter possess small, round hyperchromatic nuclei and scant or fibrillary cytoplasm. The epithelial cells have larger, vesicular nuclei and abundant cytoplasm, most containing melanin granules. Mitoses and necrosis are rare or absent.

Immunoprofile

MNTI shows polyphenotypic expression of neural, melanocytic and epithelial markers, but without photoreceptor differentiation. Occasionally glial and rhab-domyoblastic differentiation may be seen. The larger cell (epithelial) component is immunoreactive for cytokeratin, HMB-45, vimentin, and sometimes epithelial membrane antigen {1269,2026}. Neuron-specific enolase, CD57/Leu-7 and dopamine-beta-hydrox-ylase are often positive in both the small neuroblastic cells and large cells. The small cells may express synaptophysin, glial fibrillary acidic protein focally, and desmin focally. The tumour cells are negative for chromogranin, desmin, CEA, retinol-binding protein, neurofilaments, alpha-fetoprotein, and S100 protein.

Electron microscopy

The small cells demonstrate neurosecre-tory granules and neuritic processes, and the large cells contain melanosomes and premelanosomes {517,571,1269}.

Differential diagnosis

The differential diagnoses include alveolar rhabdomyosarcoma, malignant lymphoma, EWS/PNET, metastatic neuroblastoma, immature teratoma and malignant melanoma. Primary melanoma, especially mucosal, is extremely rare in infants, should show S100 protein immunoreactivity, and lacks epithelial markers. Neuroblastomas may rarely be pigmented, but lack the dual cell population and usually show diffuse immunore-activity for neuroendocrine markers.

Histogenesis

A neural crest origin is proposed {145, 517,571,1232,1269,2026}.

Prognosis and predictive factors

The treatment of choice is complete local excision {1269,1657,2092}. Radiotherapy and chemotherapy are to be avoided,

Fig. 1.91 Malignant melanoma. A This macroscopic view of a mucosal malignant melanoma of the septum demonstrates black pigment and the typical polypoid nature of the tumour. Note the well defined border at the base of the tumour. B The vast majority of tumours demonstrate a "Grenz" zone of separation between the surface and the malignant infiltrate (left), although pagetoid spread and surface epithelium involvement is appreciated (right). C Atypical plasmacytoid cells with eccentrically placed nuclei with prominent nucleoli and intranuclear cytoplasmic inclusions. A "Hof" zone is easily identified (left). Rhabdoid cells have abundant opaque eosinophilic cytoplasm arranged eccentrically from the atypical nuclei (right upper). Prominent, magenta nucleoli are common (right lower). D Characteristic peritheliomatous growth with areas of degeneration noted between the vessels (left). A storiform or cartwheel pattern with increased mitotic figures (right).

Fig. 1.91 Malignant melanoma. A This macroscopic view of a mucosal malignant melanoma of the septum demonstrates black pigment and the typical polypoid nature of the tumour. Note the well defined border at the base of the tumour. B The vast majority of tumours demonstrate a "Grenz" zone of separation between the surface and the malignant infiltrate (left), although pagetoid spread and surface epithelium involvement is appreciated (right). C Atypical plasmacytoid cells with eccentrically placed nuclei with prominent nucleoli and intranuclear cytoplasmic inclusions. A "Hof" zone is easily identified (left). Rhabdoid cells have abundant opaque eosinophilic cytoplasm arranged eccentrically from the atypical nuclei (right upper). Prominent, magenta nucleoli are common (right lower). D Characteristic peritheliomatous growth with areas of degeneration noted between the vessels (left). A storiform or cartwheel pattern with increased mitotic figures (right).

unless there Is evidence of metastasis. Despite its rapid growth and tendency to destroy bone, MNTI pursues a benign clinical course in most cases {1269,2026}. However, if not totally excised, local recurrences occur frequently. About 7% of cases develop metastases to sites such as the lymph nodes, liver, bone, adrenal glands or soft tissue {2026}. The potential for recurrence or metastasis, however, cannot be predicted from the clinical or pathologic features.

Mucosal malignant melanoma

Definition

A malignant neoplasm derived from the melanocytes in the mucosa.

Epidemiology

Sinonasal mucosal malignant melanomas are rare, accounting for less than 1% of all melanomas {112,165}, and <5% of all sinonasal tract neoplasms {205,2603}. Both genders are equally affected, without a race predilection, although an increased incidence has been suggested in Japanese patients. Malignant melanomas typically affect older individuals in the 5-8th decade with a peak incidence in the 7th decade {165,260,273,386,484,500,560,807,930, 1076,2603}.

Etiology

Formaldehyde exposure and tobacco smoking have been suggested as possible etiologic factors {260,273,1318, 2603}.

paranasal sinuses and present as extensive skull base tumours {260,273,386, 484,500,560,807,930,1324,2603}.

Clinical features

Symptoms include nasal obstruction, epistaxis, nasal polyp, pain, nasal discharge of variable duration, and melan-orrhoea ("coal flecked" or brown nasal discharge) {273,386,930,1076,2603}.

Macroscopy

The lesions are large, bulky and polypoid tumours with a mean size of 2-3 cm, but may be larger with involvement of multiple paranasal sinuses. The vast majority are ulcerated. The cut surface varies from black and brown to light tan, depending upon the amount of melanin production {273,386,930,2603}.

ICD-O code

8720/3

Synonyms

Melanosarcoma; melanoma

Localization

The nasal cavity is affected most frequently, followed by a combination of the nasal cavity and paranasal sinuses. Large tumours may involve multiple

Tumour spread and staging

At presentation, 70-80% of cases are localized, 10-20% have regional lymph node and <10% have distant metastasis {112,273,386,1324,2603}. However, dur-

Sit-

faste faste

Fig. 1.92 Malignant melanoma. A Interlacing fascicles (left) and an undifferentiated to epithelioid pattern (right) can be seen in melanoma. B Focal melanin pigment noted in an epithelioid mucosal malignant melanoma (left) while an S-100 protein immunohistochemical study stains both the nucleus and cytoplasm.

ing the course of disease, an additional 20% may develop nodal metastasis and 40-50% may develop distant metastasis to lungs, brain, bone and/or liver {273,386,484,500,1324,2603}. There is currently no universally accepted staging system. However, the most common and prognostically significant staging system in use is: stage I- localized tumours, stage II- tumours with lymph node metastases, and stage III-tumours with distant metastasis {1076}. Tumour thickness or depth of invasion cannot be accurately assessed due to the lack of a well-defined reference point for the surface in the respiratory mucosa, frequent ulceration, tissue fragmentation and poorly oriented specimen {273,386,2603}.

Histopathology

The tumours are comprised of epithelioid, spindled, plasmacytoid, rhabdoid, and/or multinucleated tumour cells. The cells are generally medium to large-sized {260,273,386,484,1472,2603}. They have a high nuclear to cytoplasmic ratio with pleomorphic nuclei containing prominent eosinophilic nucleoli and intranuclear cytoplasmic inclusions. Nuclear molding can be present. The cytoplasm is usually densely eosinophilic, and variably contains melanin pigment. Mitoses, including atypical forms, are frequent and easily identifiable. Vascular invasion and neurotropism may be identified in up to 40% of cases. An inflammatory infiltrate admixed with pigment-laden histiocytes is commonly identified within or adjacent to the tumour. Tumour cell necrosis is common, particularly in tumours displaying a peritheliomatous or pseudopapil-lary growth pattern. Other growth patterns include solid, alveolar or sarcoma-toid.

Intraepithelial melanocytic atypia (melanoma in-situ) is sometimes seen in the overlying epithelium {260,273,386,

1472,1624,2603}. The tumours usually invade the subepithelial tissue and frequently extend into the bone, cartilage or skeletal muscle.

Immunoprofile

Malignant melanoma expresses S100 protein and vimentin {1472,1661}, and variably HMB45, tyrosinase, melan-A and microphthalmia transcription factor. Neuron specific enolase, CD117, CD99, synaptophysin, CD56, and CD57 have been reported to be occasionally positive, but epithelial membrane antigen, cytokeratins, and muscle markers are not expressed {260,273,484,1472,1661, 2603}.

Differential diagnosis

Sinonasal mucosal malignant melanoma may morphologically masquerade as a variety of benign and malignant neoplasms, such as "small blue round cell" neoplasms, pleomorphic neoplasms

Fig. 1.93 Melanoma in situ, associated with primary mucosal melanoma of the maxillary sinus. A A portion of the respiratory epithelium is replaced by melanoma in situ and shows melanophages in the superficial lamina propria. B Anti-tyrosinase antibody (T311) strongly decorates the invasives tumour cells (bottom) as well as melanoma cells in the sinonasal respiratory epithelium.

Melanosis Bronchial Mucosa

Fig. 1.94 Heterotopic central nervous system tissue. A Mucosal glands are subtended by reactive glial tissue composed of neuropil separated by dense, more brightly eosinophilic fibrous connective tissue. Astrocytes are not seen. B S-100 positivity in nuclei and cytoplasm of subepithelial glial cells. C The left side demonstrates a number of "gemistocytic-type" astrocytes within glial tissue, the right image shows classic neuroglial tissue without significant fibrosis or inflammatory cells. D Trichrome stain highlights the neural tissue red, while the reactive background fibrosis is blue (left). GFAP immunoreactivity is present in glial tissue, but not in the surrounding soft tissues (right).

Fig. 1.94 Heterotopic central nervous system tissue. A Mucosal glands are subtended by reactive glial tissue composed of neuropil separated by dense, more brightly eosinophilic fibrous connective tissue. Astrocytes are not seen. B S-100 positivity in nuclei and cytoplasm of subepithelial glial cells. C The left side demonstrates a number of "gemistocytic-type" astrocytes within glial tissue, the right image shows classic neuroglial tissue without significant fibrosis or inflammatory cells. D Trichrome stain highlights the neural tissue red, while the reactive background fibrosis is blue (left). GFAP immunoreactivity is present in glial tissue, but not in the surrounding soft tissues (right).

(sinonasal undifferentiated carcinoma, anaplastic large cell lymphoma, angiosarcoma), or various sarcomas {260,273,386,1 472,1 661,2603}. Metastatic melanoma to the sinonasal tract, although highly uncommon, must always be excluded, as the prognosis is even poorer. Presence of intraepithelial atypical melanocytes favours primary melanoma {386,1624,2603}.

Histogenesis

Melanocytes, distributed throughout the upper respiratory tract are considered the progenitor of primary sinonasal mucosal malignant melanoma.

Genetic susceptibility

Patients with sinonasal mucosal malignant melanoma do not seem to be part of dysplastic nevus syndrome or xeroderma pigmentosum kindreds {273,2603}.

Prognosis and predictive factors

Surgery is the cornerstone of therapy, although wide free margins of resection are difficult to achieve. Radiation therapy has a palliative role {500,2078,2603}.

Local recurrence is frequent (67%-92%), may be repeated, and is a harbinger of adverse prognosis {273,386,560,1324, 2603}. Most tumours progress to regional and distant metastasis resulting in poor 5-year disease-specific survival that may range from 17- 47% {165,260,273, 386,560,1076,1324,2310,2603}. Other poor prognostic factors include advanced age, obstructive symptoms, tumour size >3 cm, location in paranasal sinuses and nasopharynx, vascular invasion into skeletal muscle and bone, high mitotic count, marked cellular pleomorphism and distant metastasis {165,273, 500,1324,2081,2310,2603}.

Heterotopic central nervous system tissue (nasal glioma)

Definition

A mass of heterotopic neuroglial tissue presenting in and around the nose.

Synonyms

Nasal glioma, nasal glial heterotopia

Epidemiology

Most patients present at birth, and 90% of cases are diagnosed by age of 2 years. There is no gender predilection.

Localization

The lesion is situated externally on or near the bridge of the nose in 60% of cases, within the nasal cavity in 30% of cases, and in both sites in 10% of cases. In the latter cases, communication of the intra- and extranasal components is through a defect in the nasal bone.

Clinical features

Extranasal heterotopic CNS tissue presents as a smooth noncompressible subcutaneous mass over the dorsum of the nose. The intranasal lesions usually present with nasal obstruction or nasal deformity. Heterotopic CNS tissue may occur at other sites, such as the paranasal sinuses, nasopharynx {2289}, pharynx, tongue, palate, tonsil and orbit, and may be referred to as "facial glioma". One-third of pharyngeal heterotopic CNS tissues are associated with cleft palate or choanal stenosis.

A helpful clinical sign is the absence of expansion or pulsation of the mass following compression of the ipsilateral jugular vein (negative Furstenberg test), due to lack of connection of the mass with the CSF pathway. Importantly, radiographic imaging scans (CT and MRI) reveal a soft tissue mass without an intracranial component or bony defect in the floor of the anterior cranial fossa.

Macroscopy

The lesion appears as a polypoid, smooth, soft, grey tan, non-translucent mass with encephaloid features. It usually measures 1-3 cm.

Histopathology

The lesion is non-encapsulated, composed of large or small islands of glial tissue with evenly spaced astrocytes and interlacing bands of vascularized fibrous connective tissue. The glial tissue merges with the collagen of the stroma or dermis. Mitoses are absent. At times, the astrocyte nuclei may appear enlarged or multinucleated. Long-standing or recurrent lesions tend to contain a considerable amount of fibrous tissue. Neurons are rare or absent. Rarely, choroid plexus, ependyma-lined clefts and pig-mented retinal epithelium are seen, especially those of the palate and nasopharynx.

The glial tissue can be confirmed by immunoreactivity for glial fibrillary acidic protein (GFAP) or S100 protein {607,1273,1323,1991,2851}.

Differential diagnosis

The histologic differential diagnoses mainly include nasal encephalocele and, less frequently, a fibrosed nasal polyp. In contrast to heterotopic CNS tissue, encephaloceles are herniations of meningeal lined brain tissue that communicate with the intracranial ventricular system and subarachnoid space through a bony defect in the skull {1134}. Nasal encephalocele is composed of CNS tissue with easily found neurons. However, in nasal encephalocele of long-standing and in recurrences, the excessive fibrous tissue relative to the amount of glial cells and absence of neurons may make it impossible to distinguish from hetero-topic CNS tissue.

Long-standing heterotopic CNS tissue may be mistaken for a fibrosed nasal polyp {1258}. The absence of glial tissue differentiates the latter from the former.

Histogenesis

It is a congenital malformation in which there is anterior displacement of mature cerebral tissue that has lost connection with the intracranial contents.

Prognosis and predictive factors

Adequate excision offers a cure in most cases, but incomplete excision can be accompanied by recurrence (15-30%). There is no local aggressive behaviour or malignant potential.

Ectopic pituitary adenoma

This lesion is described in Chapter 2 on tumours of the nasopharynx.

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