Malignant Melanoma

ICD-O:8720/3

Sinonasal melanomas represent between 0.5 and 1.5% of all melanomas [25, 82, 157] and between 3 and 20% of sinonasal malignant neoplasms [25, 74]. They most frequently develop after the fifth decade of life [25, 42, 250] and seem to originate from melanocytes present in the mucosa of the respiratory tract [25, 58, 275]. In our experience, it is not uncommon to see melanomas arising in an area of squamous metaplasia . In contrast to Caucasians, black Africans often show visible pigmentation at sites corresponding with the common locations of intranasal melanomas, of which they have a higher incidence [148]. Although there is not a significant sex predilection, men seem to be affected more than women [25, 29, 42]. The signs and symptoms of presentation of sinonasal melanomas are not specific. Epistaxis and nasal obstruction are frequent when located in the nasal cavity.

Grossly sinonasal malignant melanomas are either pigmented (black-brown) or non-pigmented (pink-tan) lesions. In the nasal cavity, they commonly arise in the anterior portion (Fig. 2.11a) of the septum and present as tan-brown polypoid formations, with occasional ulcerated and hemorrhagic areas. When arising within sinuses, they present as extensive and widely infiltra-tive tumours. The development of an intranasal malignant melanoma in an inverted papilloma has been reported [99].

The histological features of sinonasal melanomas may be as polymorphic as in their cutaneous counterpart. Metastatic disease needs to be ruled out, before they are labelled as primary tumours. Primary melanomas may be recognised by the presence of junctional activity (Fig. 2.11c) or by the finding of an intraepithelial component in the adjacent mucosa; nevertheless, these features are usually lost in advanced stages of the disease. Histologically, melanomas are composed of medium to large cells that may be polyhedral, round, fusiform (Fig. 2.11b), pleomorphic, microcytic, or a mixture of them. Usually, they have finely granular cytoplasm and nuclei with one or more eosinophilic nucleoli. Mi-totic activity is prominent. A rare balloon cell variant with clear cytoplasm may mimic various types of clear cell tumours (see Chap. 5). Osteocartilaginous differentiation has also been observed [244]. The cells of sinona-sal melanoma grow in solid, loosely cohesive, storiform, pseudo-alveolar or organoid patterns [25]. Two-thirds of sinonasal melanomas contain some intracytoplasmic brown pigment (Fig. 2.11d) [25], which has to be confirmed as melanin by Masson-Fontana or Grimelius silver stains. However, in the sinonasal tract non-pigment-ed melanomas are not uncommon; in our Barcelona series up to 40% of the sinonasal melanomas are amela-notic. When melanin is scarce or is not found, diagnosis may be difficult, and special techniques are mandatory. Immunohistochemically, the cells of amelanotic melanomas are negative for cytokeratin and positive for vimen-tin, S-100 protein and HMB-45 [65, 82, 209], as well as anti-tyrosinase and other newly reported markers [207]. Electron microscopy reveals the presence of pre-mela-nosomes and/or melanosomes.

Fig. 2.11. Sinonasal malignant melanoma. a Darkly pigmented cytes with storiform pattern. c Nests of non-pigmented, invasive polypoid lesion of the anterior nasal cavity in contiguity with a malignant melanocytes arising from metaplastic squamous epi-

pigmented lesion of nasal skin. Courtesy of Prof. J. Traserra, Bar- thelium showing junctional activity. d Pigmented malignant me-

celona, Spain. b Spindle cell non-pigmented malignant melano- lanocytes underneath ciliated respiratory epithelium c d

Fig. 2.11. Sinonasal malignant melanoma. a Darkly pigmented cytes with storiform pattern. c Nests of non-pigmented, invasive polypoid lesion of the anterior nasal cavity in contiguity with a malignant melanocytes arising from metaplastic squamous epi-

pigmented lesion of nasal skin. Courtesy of Prof. J. Traserra, Bar- thelium showing junctional activity. d Pigmented malignant me-

celona, Spain. b Spindle cell non-pigmented malignant melano- lanocytes underneath ciliated respiratory epithelium

The differential diagnosis of amelanotic malignant melanoma of the sinonasal tract comprises a long list of entities. Epithelioid melanomas mainly have to be distinguished from non-keratinising squamous cell carcinomas, but also from other large cell carcinomas as well as from epithelioid malignant schwannomas [76] and from metastases. Microcytic melanoma may mimic SNUC and other small round cell tumours (Table 2.2).

Spindle-cell melanoma may be mistaken for a variety of spindle-cell sarcomas (see Sects. 2.11.13 to 2.11.17).

The prognosis and management is related to the peculiar biology of the tumour. The prognostic significance of the level of local invasion, as established for cutaneous melanomas, does not apply to mucosal melanomas because of the absence of histological landmarks analogous to the papillary and reticular dermis; nevertheless, inva sion deeper than 0.5 mm is associated with decreased survival [25].

Although many of the patients do not show initial lymph node involvement or disseminated metastases [25, 83, 107] and have stage I disease at the time of initial diagnosis, the prognosis is bad due to a high recurrence rate [250]. This recurrence appears to be related to the multicentricity of the tumours and to the anatomic characteristics of the region that preclude adequate resection, which is the treatment of choice [29, 256]. The utility of radiotherapy is controversial, but it can be of use in unresect-able cases or to control recurrences [29, 95]. Immunotherapy and chemotherapy are also used for metastatic disease [256]. Five-year survival of sinonasal melanoma is reportedly under 35% [29, 250, 256]. The mean survival has not improved during the past 15 years [32]. In our Barcelona series, the 5-year survival rate of 35% is similar to that of sinonasal squamous cell carcinoma. Patients with primary nasal melanomas had a significantly better 5-year survival rate than patients with melanomas from other head and neck sites [154].

ICD-O:9522/3

Olfactory neuroblastoma (ONB) is defined as a malignant tumour composed of neuroblasts derived from the olfactory membrane [14, 175, 246, 257]. Synonyms include early terminology such as esthesioneuroepitheli-oma, esthesioneurocytoma and esthesioneuroblastoma. The site of origin of ONB is confined to the olfactory mucosa that lines the upper part of the nasal cavity [181]. On rare occasions ONB predominantly involves the superior aspect of the cribiform plate and grow as intra-cranial masses [15, 186]. Before establishing a diagnosis of the extremely rare entity known as "ectopic" olfactory neuroblastoma, which implies absence of involvement of the olfactory membrane, other sinonasal small round cell tumours have to be carefully ruled out (Table 2.2).

Olfactory neuroblastoma has a bimodal age distribution with peaks in the 2nd and 6th decades [70]. This clearly differs from adrenal neuroblastoma, with most cases arising in children under 4 years of age. Both sexes are equally affected. Nasal obstruction, rhinorrhoea and epistaxis are the most common presenting symptoms.

Grossly, the tumours are often unilateral, presenting as smooth polypoid or fungating masses of fleshy consistency and yellow to pink colour (Fig. 2.12a).

At low magnification, ONB exhibits one of two main patterns of growth [176]. Most often, it presents a lobular arrangement with well-defined groups of tumour cells separated by abundant oedematous stroma. Less frequently, the tumour grows as diffuse sheets of cells with scanty, but highly vascular stroma. The neoplastic neu-roblasts are typically small, showing round to oval nu clei with stippled chromatin, absent or small nucleoli, and minimal cytoplasm. They are commonly separated by a neurofibrillary matrix formed by neuronal cell processes in which axons may be demonstrable by conventional silver stains. This background, seen in about 85% of ONBs, is the most helpful diagnostic feature (Fig. 2.12b). The Homer-Wright type of rosettes is quite characteristic of ONB; however, they are less commonly seen. They form when the tumour cells surround the neurofibril-lary matrix in collar-like arrangements. Even more rare are the true olfactory Flexner-Wintersteiner type of rosettes, which depict well-defined lumina lined by columnar cells resembling olfactory epithelium. These cells generally have basally located nuclei and merge with the adjacent neuroblasts without any intervening basal lamina. Perivascular pseudorosettes, formed by tumour cells arranged around capillaries, are of no diagnostic value, for they may be found in several types of neoplasms.

The scheme proposed by Hyams [122] to grade ONB into four groups carries diagnostic and prognostic implications (Table 2.3). The differential diagnosis of ONB includes a wide variety of small round cell tumours arising in the sinonasal region (Table 2.2). Immunohisto-chemically, ONB shows diffuse positivity for NSE and synaptophysin, but is less often positive for chromo-granin. In tumours with a nesting pattern, sustentacu-lar cells are positive for S-100 protein, but generally negative for cytokeratin, although in ONB with a nesting pattern a few tumours may exhibit focal staining for low molecular weight cytokeratins. They are negative for EMA. Neurofilament protein and other markers of neural differentiation are more often expressed in tumours with diffuse, sheet-like patterns [53, 87, 246, 268]. Electron microscopy shows evidence of neuroblastic differentiation, demonstrating neuritic processes, neurotu-bules and membrane-bound dense-core granules [131, 159, 247]. The human analogue of achaete-scute gene (HASH1), expressed in immature olfactory neurons, is also expressed in ONB [45]. Conversely, the olfactory marker protein [182], expressed exclusively in mature olfactory neurons, is not. ONB lacks CD 99 (MIC-2) expression, as well as the t(11;22) translocation characteristic of primary neuroectodermal tumour (PNET) [13, 263]. It also lacks the molecular genetic changes of sympathetic neuroblastoma, which, in children, may be metastatic to the sinonasal region.

Staging of ONB is based on the Kadish system [129], in which stage A disease is confined to the nasal cavity, stage B to the nasal cavity and paranasal sinuses, and stage C shows local or distant spread beyond the nasal cavity or sinuses. This correlates with prognosis [70]. Necrosis is the single histological feature that seems to correlate with poor survival [175]. About two-thirds of recurrences are in the form of local disease, whereas locoregional recurrences, with intracranial extension or involvement of cervical lymph nodes, represent about 20%, and distant

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