Malignant melanoma of unknown primary site. To make the long story short. A systematic review of the literature
Introduction
Malignant melanoma is a potentially lethal neoplasm and a major public health concern. The incidence of cutaneous melanoma has increased significantly in the last three decades [1] while the lifetime risk for cutaneous melanoma development is one in 40 males and one in 60 females [2]. In 2008 more than 64,000 new cases and more than 8000 deaths from malignant melanoma were estimated to occur in the US [2].
Although more than 90% of melanomas have a cutaneous origin, occasionally it is discovered first as a secondary deposit, lymph node or visceral, without evident primary site. This entity of melanoma of unknown primary (MUP) was initially characterized by Das Gupta in 1963 who was the first to describe the criteria for MUP [3]. Indeed, Das Gupta excluded patients from his study fulfilling any of the followed described criteria: (1) patients with metastatic melanoma with evidence of previous orbital exenteration or enucleation; (2) patients with metastatic melanoma with history of excision, electrodesiccation or cauterisation of a mole, birthmark, freckle, chronic paronychia or skin blemish; (3) patients with metastatic melanoma in one of the node-bearing areas who presented a scar of previous local treatment in the skin area drained by this lymphatic basin; and finally (4) patients with metastatic melanoma who did not have a thorough physical examination including ophthalmoscopy and adequate examination of the anus and the genitalia. Nevertheless, the first reports of MUP come from registries dated as far back as 1917 [4]. To explain the phenomenon of MUP various theories have been developed such as the spontaneous regression of the primary site due to involvement of immunological mechanisms [5], [6].
The incidence of MUP varies considerably between the different studies, ranging from 1.2% [7] to 18% [8] or even 31% in special settings [9]. Moreover, there are conflicting results concerning survival differences between MUP and melanoma of known primary (MKP), therapeutic interventions and prognostic issues.
Although various reports exist concerning MUP, a comprehensive review on this field is missing. Herein we describe the characteristics of patients with melanoma of unknown primary as was revealed from the search of literature expanding in a period of more than 80 years. The demographics, therapeutic methods, survival differences and prognostic factors are presented.
Section snippets
Materials and methods
We searched MEDLINE (last search, February 2010) using combinations of terms such as Melanom*, unknown origin, unknown primary, indolent, occult. We set no geographical restrictions. Reference lists in these trials were checked to identify any other published or unpublished data. We hand searched the references of review articles and evaluated symposia proceedings, poster presentations, and abstracts from major cancer meetings (including American Society of Clinical Oncology Annual Meetings,
Results
The PubMed/Medline search revealed 1183 hits. The eligible articles were 133 from which 9 were not from English literature. The search from the congresses revealed three eligible abstracts. Altogether, 41 peer reviewed articles [3], [4], [7], [8], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46] and one abstract were analyzed [47].
Therapeutic interventions (Table 2)
Data were retrieved from 32 studies on the therapeutic modalities used for the treatment of MUP. Lymph node dissection either radical or modified was the gold standard of treatment for nodal disease. This was combined with parotidectomy whenever the parotid gland was involved [9], [22], [23], [32]. Further medical treatment is depicted in Table 2, according to the treatment setting (adjuvant or palliative). 474 patients were managed with an immunotherapeutic or chemotherapeutic regimen. Drugs
Survival/recurrence
Outcome and relapse data are summarized in Table 3a, Table 3b. For optimal comparison of the survival data two big groups were created; one with nodal involvement and one with visceral disease. Twenty-three studies gave information about survival from MUP with nodal disease and 16 from visceral disease. Considering nodal disease (Table 5a) the median overall survival varied between 24 and 127 months reaching up to 165 months in the matched control population of the John Wayne cancer institute
Prognostic factors
The various prognostic factors of significant importance are tabulated in Table 4. Tumour regression is a well recognised factor with the involvement of immune system to describe this correlation. A low number of involved lymph nodes was a favourable factor [15], [19], [26], [42], [44], [45], [47] but could not be confirmed in all studies [25], [32]. Females seem to have better survival in various studies [26], [42], [44], [45] but the opposite result could also be noticed [28], [40]. There was
Discussion
The aim of our study was to bring together the information of almost 90 years of clinical practice and to analyse all the potential information given. The first one to portray criteria for the definition of MUP was Das Gupta in 1963. The fact that in only seven studies these criteria were used and 13 used a different combination of clinical and imaging definition criteria suggests that the MUP population studied is heterogeneous. With this drawback in mind, an attractive information that came
Conclusions
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The incidence of MUP is 3.2%, it is twice as common in males and the peak age of presentation is the 4th and 5th decades.
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MUP patients with nodal disease probably have similar or better prognosis than stage-matched MKP patients. MUP patients with visceral disease are not that well studied although the better prognosis than disseminated MKP setting has been demonstrated.
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There is no consensus on the prognostic factors of MUP patients. The most commonly cited prognosticators are MUP itself (as
Conflict of interest
None declared.
Reviewers
Maurice Matter, MD, Centre Hospitalier Universitaire Vaudois (CHUV), Department of Visceral Surgery, Rue du Bugnon 21, CH-1011 Lausanne, Switzerland.
Piotr Rutakowski, MD, PhD, M. Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Dept of Soft Tissue/Bone Sarcoma and Melanoma, Warsaw, Poland.
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