Author: Aamenah Al-Ani, Medical Student, University of Auckland, New Zealand. DermNet NZ Editor in Chief: Dr Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by: Gus Mitchell. March 2018.
Metastatic melanoma with unknown primary (MUP) refers to metastatic melanoma in either lymph nodes, subcutaneous tissue or visceral sites in the absence of a detectable primary tumour despite detailed examination . Metastatic melanoma should be considered in the differential diagnosis for any patient presenting with a malignancy of unknown origin.
Melanoma commonly metastasises to regional lymph nodes, liver, lungs, bone or brain, spreading through lymphatic and haematogenous routes . It can also metastasise to the skin, either locally or to distant sites .
For classification purposes, MUP can be separated into subcutaneous, nodal and visceral disease, with nodal MUP being the most common.
MUP accounts for approximately 2–9% of cases of metastatic melanoma . The mean age of patients presenting with MUP is in the 5th and 6th decades of life . It more commonly presents in males than in females. This gender bias is currently unexplained.
The origin of MUP is not fully understood. Possible explanations follow.
Genotyping of MUP shows a mutational pattern similar to cutaneous melanoma and not the pattern seen in primary melanoma arising in other sites, such as mucosa or central nervous system. MUP mutations include BRAF (particularly the V600E subtype) and NRAS . This lends support to the theory that MUP represents metastases from an original primary cutaneous melanoma that may or may not have regressed.
As the primary site of the melanoma is unknown, the presentation of MUP is atypical, in that there is no clinically apparent primary cutaneous lesion.
Rarely, the primary melanoma is later found at an extracutaneous site, such as in the eye, or in a sinonasal, vulvovaginal or gastrointestinal area. In most cases, the primary melanoma cannot be found .
The most common clinical presentation of MUP is lymph node disease without clinical or radiological evidence of visceral involvement. Lymph node metastases commonly arise in axillary (50%), neck (26%) and groin (20%) lymph nodes .
In cases of MUP spreading to visceral sites, initial symptoms are site-specific.
Advanced MUP that has spread to distant sites may also present with systemic features related to cytokine production, such as fever, weight loss and anaemia .
Diagnosis of MUP is usually made based on clinical signs and symptoms consistent with metastatic disease along with histopathology of a tissue specimen that confirms the presence of malignant melanocytes, such as excisional biopsy of lymph node or needle core biopsy of a solid organ metastasis .
Histological features of MUP on a tissue specimen include:
It is currently not possible to predict the primary site of MUP from histology, immunohistochemistry or genetics .
The requirement of an extensive physical examination to search for the primary lesion has been questioned. Examinations such as ophthalmoscopy, otoscopy, rhinopharyngoscopy, laryngoscopy, sigmoidoscopy and in women, gynaecological examination, have traditionally been undertaken, yet the yield in finding a primary lesion is not high. These examinations may be costly, time-consuming and uncomfortable for patients. Special physical examinations are undertaken using clinical judgement in an individual case .
Other recommended investigations for MUP include CT imaging of the head, neck, brain (preferably by MRI), chest, abdomen and pelvis to detect any visceral involvement. CT-PET scanning may also aid in staging the disease.
Studies have shown that lymph node and subcutaneous MUP have a better prognosis than stage III melanoma of a known primary site. The American Joint Committee on Cancer (AJCC) recommends:
For nodal MUP, radical lymph node dissection of the affected region is generally undertaken. Patients that undergo surgery are less likely to have recurrence of the malignancy and have improved survival compared to other treatments. Some patients with stage III MUP may benefit from adjuvant systemic and radiation therapy with identical criteria to patients with a known primary melanoma [1,10].
Subcutaneous MUP behaves more like thick primary melanoma and is generally treated by wide local excision and sentinel lymph node biopsy, if indicated. An epidermal component is sometimes identified in the wide local excision specimen, establishing it as primary cutaneous melanoma rather than MUP .
A full metastatic work up is undertaken for MUP that develops in a visceral site, including cross sectional imaging. Management involves resection of any isolated lesion where possible.
Unlike the established role of adjuvant therapy for stage III MUP, its role is unclear in stage IV MUP .
Results from studies comparing MUP with matched groups of patients with cutaneous melanoma have shown that MUP has similar or better overall survival rates than patients with cutaneous melanoma.
A 2015 systematic review and meta-analysis by Bae et al showed that compared with melanoma of known primary, MUP has a better overall survival with a hazard ratio of 0.83 for stage III disease and a hazard ratio of 0.85 for stage IV disease .
Favourable prognostic factors include:
MUP patients may have improved survival because there may be a more active tumour-directed immune response against the malignant cells (supporting the idea that MUP may be a result of tumour regression) .
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