INTRODUCTION

Melanoma is a malignant, potentially fatal neoplasia, that usually arises from the skin, and more rarely from the mucosas. Over 90% of the melanomas are located on the skin (1), its mucosal appearances are less frequent and represent less then 5% of all the tumors of this nature. The latter has special characteristics and biological behavior which is very different then its skin counterpart, in spite of the fact that there are no morphological differences between them (2).

The incidence of head and neck melanomas vary from 0.4 to 4%, and the tumors usually affect individuals between 50 and 70 years of age; there is a subtle preference for males, although neither gender nor age influence prognosis (3). The most common sites of mucosal melanomas in the upper airways are the oral cavity, the nasal cavity and the paranasal sinuses, in this order of frequence (4).

The primary mucosal melanomas of the nose and paranasal sinuses represent 1% of all melanomas. Most of the cases affect the nasal septum, the inferior conchae and the middle conchae, in this order. The clinical manifestations are inespecific, corresponding to the same found in other tumors, that being: nasal obstruction, epistaxis (4) and nasal volume enlargement (5).
One of the most notable characteristics of the mucosal melanomas is its unpredictable clinical course. It is invasive in some cases, having a fast regional and systemic spread; in other cases there may be a fatal recurrence after 5 years of the initial diagnosis (6) or even after 10 years controlling the disease (1).

The last three decades have seen an increase in the incidence of skin melanoma and the identification of some risk factors such as long exposure to sun light in fair skin patients; the number and type of melanocytic nevi and family history of melanoma. There has not been any incidence increase in mucosal melanomas, nor factors that have proven to be predisposing to the disease. The occurrence of mucosal melanomas in peoples of all races and from diverse geographical locations suggests that skin susceptibility and sun light are not risk factors for this type of melanoma (1).

For diagnostic purposes, we should consider that the large metastatic head and neck melanoma (primary from the skin) is very rare (7). Only from 0.6 to 9.3% of patients with skin melanoma have metastasis to the mucosa of the upper aero-digestive tract, and the most frequent metastasis sites are the tongue base and the nasal cavity. These are lesions that appear usually from 2 to 7 years after the initial skin lesion and, when they appear in the head and neck mucosa, usually the patient already has disseminated metastasis (1).
Broad surgery together with radiotherapy offer the best prognosis (1). Immunotherapy has not been useful in the treatment of melanomas of the mucosas. The most frequent treatment failure has been local recurrence of about 40% in the nasal cavity, 32% in the pharynx and 25% in the oral cavity. Survival rates are extremely low, for only 5 to 15% of the patients have a 5 year survival. The high rate of local recurrence, in spite of an apparently properly carried out initial surgery, mandates a more radical resection in initial and localized cases (4).

Both chemo and radiotherapy are considered as options in the palliative approach of head and neck melanomas (4). They are tumors which are considered to be radio-resistants (7), however, with a better understanding of radiology and considering the clinical responses obtained from skin melanomas, its value has been reassessed in mucosal melanomas, and its effectiveness is accepted in some tumor sites (1).

RAVID and ESTEEVES (1960) (8) reported that LUCKE, in 1869, performed surgery to remove a melanocytic sarcoma in the nasal mucosa of a 52 year old man. In the American literature, the first case of nasal melanoma was described by LINCOLN (9) in 1885.

PRASAD et al (2003) (10) assessed 95 patients with a diagnosis of primary mucosal melanoma; of those, 36 were primary of the oral mucosa (stratified epithelium) and 59 of the nasal mucosa (pseudostratified epithelium). They showed that the latter presented a more aggressive histological pattern than the former, being characterized by a larger vascular proliferation and tissue invasion. However, in both cases, the average patient survival was similar (2.8 years for nasal melanoma and 3 years for the oral melanoma).

In a retrospective study, RICHTIG et al (2002) (11) reviewed data from 9 nasal mucosa primary melanoma patients, followed in Osterreich (Germany), from 1985 to 2000, and concluded that this is a highly malignant tumor of unknown cure. The authors stressed that even with surgical treatment and radiotherapy, most of the patients would still present with local recurrence and remote metastasis.

In a similar way, LUND et al (1999) (12) made a retrospective analysis of 58 individuals diagnosed with nasal mucosa melanoma, followed at the Institute of Laryngology and Otology (London, England) from 1963 to 1996. The patients received surgery alone, surgery with radiotherapy, with or without chemotherapy, radiotherapy or chemotherapy alone. The authors did not see any improvement as far as survival rates are concerned, regardless of the therapy method employed, being single or combined.

The 5 year survival rate in head and neck mucosal melanoma diagnosed patients was estimated to be 14% according to a retrospective study carried out by MANOLIDIS et al (1997) (13), who assessed 14 sick patients who were followed at the School of Medicine of Massachusetts (United States of America). The authors reported that the 5 year survival rate mentioned in the literature is of 31%, if one considers the primary lesions of the nasal mucosa and it may drop down to zero in cases of primary tumors of the paranasal sinuses.

STAMMBERGER et al (1999) (14) evaluated the possibilities and limitations of the endoscopic nasal surgery in the treatment of malignant lesions. In the case of nose and nasal sinuses melanomas, 5 patients underwent endonasal surgery and 2 died between 5 and 14 months after surgery (patients in advanced stage and remote metastasis - T4), and the most survival was of 34 months in one patient with local recurrence.

Few years ago, a new therapy was described as yielding benefits in the treatment of nasal mucosa melanomas. SEO et al (1997) (15) reported 3 cases of this neoplasm in which hormonal chemotherapy led to a favorable clinical outcome. They used Tamoxifen, an anti-estrogen chemotherapeutic agent that competes for the estrogen receptor. Although its action mechanism in mucosal melanomas has not yet been ascertainned, the authors believe that this may prove to be one future option in the therapeutic approach to these lesions.

CALDERÓN-GARCIDUEÑAS et al (2000) (16), assessed 256 cases of nasal and paranasal cavities neoplasms in Mexico City and in Monterrey, considering the idea that these tumors etiology may be related to the air pollution in large cities, which would damage the DNA of the nasal respiratory epithelium, although epidemiological studies have failed to prove this association.
PERALES et al (1992) (4) reported that epidemiological studies in the black African population have frequently shown pigmentation zones in areas of the nasal mucosa that match exactly the most common origin sites of melanomas.

Studies have recently shown a relationship between nasal melanosis and mucus melanomas. HOFBAUER et al (2002) (17) showed that in nasal melanosis areas and in tumoral areas there may be atypical melanocytes, immune-reactants to anti S-100, gp100, tirosinase and Melan A protein, p 16 gene alterations may be common, and this is involved in the tumor development. Besides, genetic studies have shown alterations in the chromosomes 1 and 6 in naso and sinus mucosal melanomas (18).

New monoclonal antibodies for the differentiation of melanocytical antigens have been broadly studied in the diagnosis of skin melanomas and metastasis. However, very little is known about monoclonal antibodies as markers for mucosal melanomas. PRASAD et al (2001) (19) investigated 79 mucosal tumors (44 nasosinuses and 35 of the oral mucosa), which were studied under immunohistochemistry for anti S-100, T311 (anti-tirosinase), A103 (anti-Mart-1/Melan A), D5 (transcription factor related to anti-microphthalmia) and HMB-45 (anti-gp 100) proteins. The authors showed that T311 is the most sensitive marker for the diagnosis of nasosinuses melanomas, and the anti S-100 protein for the oral mucosa melanomas.

CASE REPORT

A 57 year old white female, housewife, born and living in Garça, São Paulo state, came to the otolaryngology ward of the Medical School of Marília (FAMEMA), complaining of nasal obstruction and right side epistaxis for about 90 days. Se said the nasal obstruction had started 3 months before and it had progressed causing complete obstruction of the right nostril at about 60 days prior to this visit, with mild epistaxis on this side. She had no pain, however, she complained of ipsilateral visual blurring. She had been to the Basic Health Unit (BHU) in her city, 60 days prior to this visit, and was seen by a general practitioner who ordered a simple X-Ray of the nasal sinuses in which he saw signs of sinusitis. At the time she received a prescription for cephalexin (500 mg PO 4qd) for 21 days and prednisone (20 mg PO for 10 days), she used the medication regularly, without improvement. She returned to the BHU after she had taken the medication and a new X-Ray was ordered, and this new one kept the same radiographic pattern as before. The previous prescription was kept in the same dosage. She was then referred to the Otolaryngology Department of the University Hospital of the Medical School of Marília for further evaluation.

The physical exam revealed facial asymetry, right side proptosis and important conjunctival hyperemia ipsilaterally. The otolaryngological exam showed:
• Mouth inspection: moderate quantity of a yellowish secretion in the retropharynx without detectable macroscopic alterations.
• Anterior rhinoscopy: pinkish polypoid-like mass, elastic, painless, filling up all the right nostril (fig. 1); moderate deviation of the nasal septum to the left side, moderate quantity of yellowish secretion in both nostrils and fetid nasal odor.

• Otoscopy: bulging of the right auditory canal medial wall; intact ear drums.
• Nasofibroscopy: optic fiber passed through the left nostril (the right side was totally occluded by the mass), showed large amount of sero-purulent secretion, filling up the entire nasal cavity.

The lesion was taken to biopsy and a CT scan of the nasal sinuses and skull was ordered. The biopsy revealed it to be a malignant melanoma and the CT showed an extensive mass in the right nasal cavity extending itself to the maxilla and ethmoid sinuses bilaterally, having invaded and destroyed the nasal septum posteriorly, and also involvement of the right orbit; there was also extensive involvement of the skull base (Figures 2 - A and B).
This case was discussed with the Oncology team who did tumor metastasis tracking (they diagnosed extensive loco-regional involvement, without evidence of distant metastasis). Radiotherapy was chosen as treatment mode due to the impossibility of surgical resection.

The patient was followed by both the otolaryngology and the oncology/radiotherapy teams for 8 months, and then se died because of cachexia and generalized metastasis. We highlight the fact that the preferred location of the metastasis were in the gastrointestinal tract mucosas (esophagus, stomach and intestines).

DISCUSSION

The primary malignant melanomas of the nasal mucosa are but rare entities. The few reports in the literature are but isolated instances, without the existence of any large number of cases reported that could point towards epidemiology or treatment experience. Notwithstanding, these reports are important sources in an attempt to better understand this type of tumor, because we can not consider the mucosal melanoma as a skin melanoma, due to the differences in biology and prognosis aforementioned.

The case reported shows initial inespecific symptoms for this disease and the difficulties in obtaining an early diagnosis that would allow better cure possibilities.

These are tumors of uncertain etiology and they have no established risk factors or prophylactic measures (4). These are lesions which are hardly diagnosed in their initial stage because of their intracavitary location, and this allows for obvious and unnoticeable expansion for a considerable period of time. The initial nasal obstruction is subjective and the assessment by the general practitioner is difficult, often times based exclusively on the simple facial X-ray, that only depicts a blurring in the nasal sinuses. This leads the physician to treat the patient as if he/she were having sinusitis, as we have seen also in other nasal diseases such as nasal polyps.

The progress in specialized radiology, most specific with the CT-Scan and MRI and the nasal endoscopy methods have greatly enhanced nasal disorder diagnosis. Notwithstanding, rare entities such as the nasal mucosa melanoma are usually diagnosed already in advanced stages because they grow inside a cavity or because they were insistently treated based on exams such as the facial X-Ray, considered to be too simple in the investigation of nasal obstruction and epistaxis.

It is necessary to consider that mucosal melanomas have a distinct behavior when compared to its skin counterpart; those are considered more malignant and of worse prognosis. Radical surgery with broad safety margins (20,21) makes up the treatment pillar, and it should be indicated whenever the tumors may be resected, together with radio and chemotherapy that, in most cases are only palliative.

Immunotherapy has not proven efficient in this tumor type. Despite all efforts, the attempts to control this neoplasm have not proven successful.
Despite promising genetic research progress, the rareness, high malignancy trait and difficulty in diagnosis put the nasal mucosa melanoma at the top of disease severities list; therapeutic frustrations generate generalized pessimism when such disease is diagnosed.

CONCLUSIONS

Primary malignant nasal mucosa melanomas are very rare tumors and, due to their specific location, are of hard diagnosis in its initial stages. Of uncertain etiology and risk factors, these are highly recurrent tumors, both locally as well as remotely, and it spreads in the mucosa compromising total and effective surgical resection. Thus, it bears bad prognosis, and cure possibilities are based on the surgical treatment of early diagnosed cases.

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Figure 1. Anterior rhinoscopy showing pinkish polypoid-like mass in the right nostril (arrow). Notice the periocular tumoral invasion in this side.
Figure 2-A. CT-Scan in coronal view depicting large mass in the right nasal cavity, projecting itself towards the skull base.
Figure 2-B. CT-Scan in axial view depicting extensive tumoral mass in the right nasosinus cavity.