Magnetic resonance imaging was performed, revealing compression fractures at T12 and L2, as well as mottled sclerosis seen throughout L4 (Figure). A verbal report by the radiologist recommended urgent oncology referral, as these fractures appeared to be metastatic lytic lesions as opposed to simple compression fractures.

The patient was referred to a medical oncologist who ordered a 24-hour urine examination for kappa total light chain, lambda total light chain, and monoclonal antibody protein. A dual-energy X-ray absorptiometry scan revealed a T- score of -1.2 in the vertebrae and -1.4 in the hip, confirming a diagnosis of osteopenia, and ruled out a diagnosis of multiple myeloma. With no presence of soft tissue mass as well as a normal mammogram, colonoscopy, and chest radiograph, the patient was told that she had nonpathologic compression fractures. The patient was advised to undergo positron emission tomographic (PET) imaging, but her insurance company refused the approve payment for the scan, even following specialist peer-to-peer review. 

The patient returned to the primary care office 5 weeks later with complaint of a 2.5 x 2.2 cm nontender, moveable, right-sided submandibular mass. Ultrasound was performed, revealing luminal atypia. The patient was referred to an otolaryngologist for fine needle biopsy. The stain is mildly positive for melanoma markers SOX10 and MART-1 but was read as inconclusive for melanoma due to a lack of additional biomarkers including a more reliable S100 stain.

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The patient was then referred to a dermatologist who reports finding no abnormal nevus or primary melanoma lesions; however, the patient is found to have a high burden of small, dark nevi covering her trunk and extremities. Biopsy of multiple nevi was performed, but all were found to be benign. PET scan was ordered and approved by her insurance company based on the presence of the soft tissue mass. The fluorodeoxyglucose PET scan revealed significantly increased uptake in her right submandibular and supraclavicular nodes, a left lower fissural nodule, and a high level of activity in T12 and L2.


The patient was referred to an oncologist specializing in melanoma. During the visit, 4 tissue samples were collected via fine needle biopsy from the submandibular lymph node. Each sample showed tissue consistent with a “metastatic process,” but there were no definitive tissue markers to make an official diagnosis. The surgical oncologist opted to perform a wide excisional biopsy with immunostaining of the submandibular node. The biopsy results were significant for epithelioid histiocytes and a SOX10 biomarker. Comprehensive molecular profiling 26 was submitted and revealed the presence of mutations in the following genes: NRAS, TP53 and MAP2K1. The patient was diagnosed with stage 4 metastatic melanoma of unknown primary (MUP).

Melanoma of Unknown Primary

Carcinomas of unknown primary (CUP) comprise approximately 2% to 5% of all cancers and include epithelial cell line malignancies such as melanoma, sarcoma, lymphoma, and germ cell cancers.1 It is important for clinicians to be aware of an unknown primary tumor diagnosis in patients who have metastatic lesions but no identifiable tumor.2 Melanoma must be included in the differential diagnosis for any suspected cancer of unknown primary, as well as for head and neck cancers such as tonsillar, mucosal, and salivary.

The incidence of CUP associated with head and neck cancers has been increasing, especially in individuals infected with HPV.3 In most cases of CUP, a tumor is never identified due to partial or complete regression of the original lesion via immune-mediated responses.1 If biopsy of a lymph node is performed and a definitive cell line determined, the diagnosis is that particular cancer plus unknown primary but not CUP alone.2

MUP can be diagnosed with fine needle aspiration or wide excisional biopsy of a metastatic lymph node, or with biopsy of a visible soft tissue metastasis. The original tumor of MUP, however, is usually not found because it has either regressed or is hidden, as in mucosal melanoma (vulvovaginal, gastrointestinal, or sinonasal) or choroidal/ uveal melanoma.2 Some lesions present as brain, lung, bone, and soft tissue metastases. Diagnosis is typically made by tissue staining for biologic markers and/or molecular tissue evaluation to identify any obvious genetic mutation(s) consistent with melanoma.2,4 

Several genetic melanoma mutations of clinical importance currently exist that are used to guide first-line treatment options; these include mutations of BRAF V600e, NRAS, NF1, and KIT.4 Melanomas arising from intermittently sun-exposed skin frequently have mutations in BRAF V600e, which is seen in 50% of affected patients, and in NRAS, which isseen in approximately 20% of affected patients.4 Melanoma is referred to as wild-type in the absence of these mutations.5

This article originally appeared on Clinical Advisor