Amelanotic melanoma with tonsillar and thyroidal metastases and no primaries detected.
Amelanotic Melanoma is a rare entity (2-8% of melanomas), its diagnosis is difficult, due to its pleomorphism and to the impossibility to make use of dermoscopy. These features imply a delay in diagnosis so that often these lesions are detected already in a metastatic stage. This delay leads to worse prognosis.
In our report we describe the case of a patient affected by a metastatic amelanotic melanoma without evidence of a primary lesion (Tx). The metastatic tumor was first diagnosed in 2003 after a parotidectomy and a concomitant lymphadenectomy. The patient underwent a bilateral neck dissection, hepatectomy, extended lymphadenectomy and thyroidectomy.
The prognostic factors in melanoma are: stage, presence of ulceration, type of surgical intervention, depth of invasion and the localization of the primary tumor. Our patient presented a bad prognosis for all these features. In addition, the metastatic lesions found in our patient were localized in uncommon sites such as palatine tonsil, thyroid and parotid. The other localizations were quite common (bowel, liver).
Although the characteristics of the melanoma case in our patient indicated bad prognosis, the patient had a long survival (7 years).
Keywords: amelanotic melanoma, neoplasm metastasis, lymphatic metastasis, tonsillar neoplasms, neoplasms/unknown primary.
de Vincentiis, Marco
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The term amelanotic melanoma is often misused to describe both a melanocytic lesion with minimal residual component or a true amelanotic lesion. (1) Incidence reported in the literature for amelanotic melanoma is 2-8% of all melanomas, but this statistic includes also partially pigmented lesions. (2) Superficial spreading amelanotic melanomas are very rare and difficult to diagnose, especially if it appears in plate form, very similar to a scurfy process. This implies that, at the moment of diagnosis, that the majority of these lesions are already in a metastatic form. Although dermatoscope can help in the diagnosis of pigmented lesions (3) there is no evidence for its effectiveness in the diagnosis of amelanotic melanoma, although it can detect areas of amended skin. (4) Diagnosis can be made if the lesion is positive for antigens of melanosome, such as protein S-100 and HMB45. (5)
As a consequence of difficulty in diagnosis, melanoma lesions may be wrongly treated. According to the work of Charles and De Giorgi, only the 72% of melanomas are reported correctly to surgeons. (6)
The treatment of melanoma depends on its thickness. It can be studied either with the Breslow or the Clark scale. Usually the treatment is based on surgery but laser and cryotherapy can be used for particular body regions. (7)
The rarity of our case is the presence of amelanotic melanoma in palatine tonsil. This localization has never been reported in literature for amelanotic melanomas and only four cases were found for pigmented melanomas. (8-11)
The patient is a 65 years old Caucasian man, brought to our attention in March 2009 for an expansive neoformation of 20x15 cm in the right tonsillar region, detected with MRI (Magnetic Resonance Imaging). The patient's clinical history began on July 2003 when he underwent a right parotidectomy and removal of a chin lymph node. The histological report indicated the presence of a metastatic melanoma. One month later, the patient underwent a bilateral radical neck dissection but the histological analysis was negative for melanoma. The patient was clinically free of disease for three subsequent years. During that period the patient was subjected to periodic control with [T.sub.c] Pet imaging (every 6 months); the imaging results led to the diagnosis of various metastases that were subsequently removed.
On January 2007 the patient underwent multiple segmental bowel resections (the total length of the resected segments was recorded in cm and was 35 cm of small intestine). The histological analysis was compatible with the diagnosis of melanoma. On the June of the same year, the patient underwent an excision of the left parotid gland, which was free of metastatic infiltration. On July of 2007, new metastases in the right liver lobe were found and a liver metastasectomy followed.
On March 2008, a bilateral axillary lymphadenectomy revealed new metastases of the tumor. On July 2008, the patient was thyroidectomised with positivity in the presence of metastatic melanoma. On the September of the same year, an excision of a lesion in the right brachial region was made (positive for metastatic melanoma).
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Brought to the Department of Otorhinolaryngology on March 2009, the removal of the right tonsil and of a portion of tongue's base was decided as part of a right lateral cervical discharge. The histological examination showed a neoplasm, infiltrating the epithelium and negative for melanin pigments; the immunohistochemical study however highlighted positivity for the S-100 protein and HMB-45, and negativity for cytokeratin staining. The framework then allowed the immunohistochemical diagnosis of metastatic amelanotic melanoma. On April 2009 the patient underwent further excision of four nodes of which only one had metastases. On August 2009, we diagnosed the paratracheal lymph node neoplasmatic involvement. On October, the patient underwent a left lateral cervical discharge for the presence of lymph node enhancing contrast at CT examination. The histological examination was positive for metastatic amelanotic melanoma. Currently, the patient still had some lymph nodes in the left groin, with the use of enhancing contrast.
Melanoma arises from malignant transformation of melanocytes and has an aggressive course once the tumor has spread beyond the superficial skin. However, like all tumor types there is considerable heterogeneity in outcome and molecular pathogenesis. (12)
Factors that most influence the prognosis of melanoma are:
1) Stage (p = 0.0014).
2) Presence of ulceration (p = 0.006).
3) Type of surgical treatment (p = 0.024).
4) Depth of invasion (p = 0.032).
5) Primary localization (p = 0.038). (13)
6) According to Wong and Ghaferi (14) another important prognostic information is given by biopsy of the lymph nodes draining the lesion's area.
Our report presents the case of a patient with amelanotic melanoma; this type of melanoma has worse prognosis than other melanomas, due to difficulty in its diagnosis and its multiform presentation. This tumor may appear as erythematous, scurfy, and macular, it can arise taking the form of nodules or plaques with irregular borders. Amelanotic melanoma is considered as a great mimic, it can appear as a Bowen neoplasm, an actinic keratosis, lupus erythematosus (as reported by Sbano and Nami15). It can also simulate vascular lesions such as hemangioma or pyogenic granuloma. The amelanotic subtype presents worse prognosis itself regardless other characteristics.
As far as evaluation is concerned:
a) Melanoma should be evaluated for its prognosis according two different scales, the Breslow scale and the Clark's scale. (16,17) The first takes into account merely the depth of lesion. The second is divided into 4 levels depending on the characteristics of diffusion and metastasis of melanomas, first class includes melanoma in situ, second class radial growth melanoma, third class vertical growing melanomas that have acquired skills to penetrate surrounding tissues. Fourth class is characterized by the ability to metastasize. Our patient presents a fourth class case.
b) Presence of ulceration is a negative point in melanoma prognosis. Our patient did not present any skin lesions.
c) The gold-standard treatment for melanoma in situ and lentigo maligna is surgical excision with the Mohs technique (18), because these kinds of lesions have no potential for metastatic spread (19). In more advanced cases, the excision margins depend on the Breslow thickness (varies from 2 to 4 cm). (20-23) In some cases, such as conjuntival melanoma, other treatments can be used, instead of surgery, such as cryotherapy, radiotherapy and laser. (7) A particularly promising therapy is that with Imiquimod, a drug primarily used for the treatment of genital warts. (24) This drug, is administered as a cream and works by stimulating an antitumor cytokine response (inducing the activation of TLR-7 and up-regulation of nuclear factor-jb). (25) Since this therapy alone is not sufficient for a complete treatment of the tumor, some authors highlight the possible use--in combination- of CD40L (see index). (26)
d) Depth of invasion was not evaluated in our case because of visceral metastasis that implies staging in fourth Clark's scale.
e) No primary tumors were diagnosed and the first clinical features were due to metastatic dissemination. This characteristic implied worse prognosis for our patient.
f) A large number of nodes were all sites of metastasis.
Although the location of metastases may involve many organs and tissues, as is evident in our case; the presence of tonsillar metastases is an uncommon event. Only four cases of pigmented melanoma are reported worldwide and no cases of amelanotic melanoma have been diagnosed so far. (8-11) Another rare localization for melanoma metastases is thyroid; quite rare is also parotid melanoma, already described in literature from Mesa and Quesada. (27) Bowel and hepatic metastases are common in melanomas. (28-30)
Although all characteristics were evaluated according to Charles's (13) scheme (modified by Ghaferi (14)) and an unfavourable prognosis was expected for our patient, his 7-year survival proved that curative resections may lead to long-term beneficial results.
Our case report presents a large number of particular features, even for a melanoma that is typically a pleomorphic disease. This is an amelanotic melanoma (2-8% of all melanomas) and there is no an evident primary localization. Metastases were present in uncommon sites, such as thyroid, palatine tonsil and parotid. Our recording of palatine tonsil as metastatic lesion of amelanotic melanoma is the first worldwide. Considering these characteristics, all clearly negative for the prognosis, the long survival of the patient (seven years) should be regarded as a rare event.
CD40L = Recombinant Human soluble CD40 (CD154) Ligand
Recombinant Human CD40L produced in E. coli is a non-glycosylated, Polypeptide chain containing 149 amino acids and having a molecular mass of 16308 Dalton.
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Mario Tombolini , Emanuele Cigna , Valentina Sorvillo , Fabio Socciarelli , Nicolo Scuderi , Marco de Vincentiis 
 Department of Otorhinolaryngology, Audiology and Phoniatrics, University "La Sapienza", Rome, Italy
 Department of Plastic Surgery and Dermatology, University "La Sapienza", Rome, Italy
 Department of Experimental Medicine and Pathology, University "La Sapienza", Rome, Italy
Corresponding author: Mario Tombolini MD, Via Arenula, 41, 00186, Rome-Italy E-mail: firstname.lastname@example.org
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