The Undifferentiated Carcinoma That Became a Melanoma: Re-biopsy of a Cancer of an Unknown Primary Site

A Case Report

Oluf Dimitri Røe; Sissel Gyrid Freim Wahl


J Med Case Reports. 2017;11(82) 

In This Article


Diagnosis is often difficult in CUP. On microscopic examination of the first resected left groin tumor that was a lymph node metastasis, malignant melanoma was excluded due to the immune profile with CK AE1/AE3 positivity and negative reaction for three melanoma markers. Due to this finding we re-stained the primary biopsy with S100, as well as HMB45 and melan A. All three markers were negative. Of interest, the few scattered S100 positive cells with dendritic features were also positive for CD68, and thus believed to represent tumor-associated macrophages.

Malignant melanomas, especially metastases, are known for aberrant immunohistochemical features in some cases. Expression of various non-melanoma markers, including intermediate filaments and loss of classical melanoma markers is not unusual[8,9] and awareness of the possibility of unusual immunophenotypes is crucial for the right diagnosis. BRAF mutations are most commonly associated with malignant melanomas, colorectal adenocarcinomas, and papillary thyroid carcinoma and could therefore be helpful in identifying the origin of the tumor.[10,11] Neither the clinical picture nor the histopathological examination supported the two last diagnoses. Moreover, the metastasis localized in the surgical field where the primary lymph nodes had infiltrated the skin, also indicated that this was the same tumor. In hindsight, the simultaneous finding of a BRAF mutation, combined with the localization and morphology of the tumor, should have aroused our suspicion of an aberrant malignant melanoma. Thus we conclude that in our case, the undifferentiated CUP probably was transformed to, or at least acquired the molecular characteristics of, a melanoma at recurrence, and was successfully treated with immune checkpoint therapy.

Metastatic melanoma was treated with chemotherapy in general until recently when the use of BRAF, MEK, CTL-4, and PD-1 inhibitors showed increased survival for patients, even beyond 5 years in a subset of patients.[12,13] A predictive marker for BRAF inhibitors in melanoma is the BRAF V600E mutation, where positive tumors have a high response rate with increased progression-free survival for patients and when combined with a MEK inhibitor there is increased overall survival.[14,15] Positive predictive markers for PD-1 inhibition in melanoma appear to be positive PD-L1 expression in a tumor[16] and low expression is predictive for combined PD-L1/CTL-4 inhibition. Moreover, checkpoint inhibitors seem to be very effective in several types of tumors with a high mutational burden as well as in tumors with microsatellite instability and/or mismatch repair deficiency.[17] In our patient, neither PD-L1 expression nor microsatellite status was evaluated. However, in the future, given the possible therapeutic implications, this may well become part of a future biomarker panel in both CUP and melanoma.

From the patient's perspective, the decision to re-biopsy this recurrent CUP turned out to become a life-saving procedure that changed her future.