Malignant melanoma of unknown primary site. To make the long story short. A systematic review of the literature

https://doi.org/10.1016/j.critrevonc.2010.04.007Get rights and content

Abstract

Introduction

Although more than 90% of melanomas have a cutaneous origin, occasionally it is discovered as a secondary deposit without evident primary site. The aim of this study was to systematically review published literature and analyse data on incidence, presentation, therapeutic interventions, survival and prognostic factors.

Methods

We searched MEDLINE, (search terms Melanom*, unknown origin, unknown primary, indolent, occult) and the abstracts from major congresses of the last 4 years and perused the references of the retrieved relevant articles.

Results

4348 patients with MUP were reported along with 132,643 patients with Melanoma of Known Primary (MKP). The incidence of MUP was 3.2%. The male to female ratio was 2:1 while the age peak was in the 4th and 5th decades. MUP patients harbouring nodal disease had a median overall survival ranging between 24 and 127 months, 5-year survival rate between 28.6% and 75.6% and 10-year survival rate between 18.8% and 62.9%. MUP patients with visceral disease had median survival times between 3 and 16 months, and 5-year survival rates between 5.9% and 18%. Presence of tumour regression in metastatic sites and low nodal burden were associated with favourable outcome. Potentially curative surgical treatment offered survival advantage in comparison to patients with residual metastatic foci. MUP patients who received adjuvant chemotherapy or radiotherapy paradoxically seemed to fare worse compared to patients observed.

Conclusions

This is the first review to bring together the information of 89 years and to analyze all the potential information accumulated. Although a well know entity no consensus is reached in order to describe MUP presentation, management or prognosis.

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

  • 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.

  • 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.

  • 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.

References (67)

  • G.T. Pack et al.

    End results in the treatment of malignant melanoma; a report of 1190 cases

    Ann Surg.

    (1952)
  • F.H. Saleh et al.

    Primary melanoma tumour regression associated with an immune response to the tumour-associated antigen melanA/MART-1

    Int J Cancer

    (2001)
  • E. Zorn et al.

    A MAGE-6-encoded peptide is recognized by expanded lymphocytes infiltrating a spontaneously regressing human primary melanoma lesion

    Eur J Immunol

    (1999)
  • C.M. Sutherland et al.

    Patient characteristics, treatment, and outcome of unknown primary melanoma in the United States for the years 1981 and 1987

    Am Surg

    (1996)
  • C.C. Lee et al.

    Improved survival for stage IV melanoma from an unknown primary site

    J Clin Oncol

    (2009)
  • B.Y. Wang et al.

    Malignant melanomas of the parotid: comparison of survival for patients with metastases from known vs unknown primary tumor sites

    Arch Otolaryngol Head Neck Surg

    (1999)
  • S. Hopewell et al.

    A comparison of hand searching versus MEDLINE searching to identify reports of randomized controlled trials

    Stat Med

    (2002)
  • B. McSwain et al.

    Malignant melanoma: report of 203 patients

    Ann Surg

    (1964)
  • L.H. Einhorn et al.

    Prognostic correlations and response to treatment in advanced metastatic malignant melanoma

    Cancer Res

    (1974)
  • G.H. Baab et al.

    Malignant melanoma: the patient with an unknown site of primary origin

    Arch Surg

    (1975)
  • J. Conley et al.

    Melanoma of the head and neck

    Laryngoscope

    (1977)
  • G.W. Milton et al.

    Occult primary malignant melanoma: factors influencing survival

    Br J Surg

    (1977)
  • A.E. Giuliano et al.

    Clinical aspects of unknown primary melanoma

    Ann Surg

    (1981)
  • R. Lopez et al.

    Malignant melanoma with unknown primary site

    J Surg Oncol

    (1982)
  • P. Chang et al.

    Metastatic melanoma of unknown primary

    Cancer

    (1982)
  • D.S. Reintgen et al.

    Metastatic malignant melanoma with an unknown primary

    Surg Gynecol Obstet

    (1983)
  • E. Panagopoulos et al.

    Metastatic malignant melanoma of unknown primary origin: a study of 30 cases

    J Surg Oncol

    (1983)
  • J.M. Klausner et al.

    Unknown primary melanoma

    J Surg Oncol

    (1983)
  • J.H. Muchmore et al.

    Isolated perfusion of extremities for metastatic melanoma from an unknown primary lesion

    South Med J

    (1986)
  • J.H. Wong et al.

    Surgical treatment of lymph nodes with metastatic melanoma from unknown primary site

    Arch Surg

    (1987)
  • A. Jonk et al.

    Lymph node metastasis from melanoma with an unknown primary site

    Br J Surg

    (1990)
  • D.G. Coit et al.

    Prognostic factors in patients with melanoma metastatic to axillary or inguinal lymph nodes. A multivariate analysis

    Ann Surg

    (1991)
  • A. Velez et al.

    Treatment of unknown primary melanoma

    Cancer

    (1991)
  • Cited by (0)

    View full text