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The undifferentiated carcinoma that became a melanoma: Re-biopsy of a cancer of an unknown primary site: a case report
© The Author(s). 2017
Received: 21 July 2016
Accepted: 7 February 2017
Published: 27 March 2017
Cancer of unknown primary site is still a demanding condition as it is per definition metastatic, with heterogeneous biological behavior, and it is often resistant to therapy. Cancer of unknown primary site accounts for approximately 1 to 5 % of all cancers, but is currently among the top six causes of cancer deaths in Western countries. To correctly identify the biological origin of the tumor, a large spectrum of differential diagnoses must be considered and scrutinized. At progression, re-biopsy might be necessary to reveal the true origin of the tumor or actionable targets.
A 62-year-old Norwegian woman, with a fast growing lump in her left groin, was primarily diagnosed as having undifferentiated carcinoma that was BRAF V600 positive. There was complete response with paclitaxel-carboplatin and she was recurrence-free for 18 months. She had recurrence in both lungs and subcutaneously in her left groin and thigh; a re-biopsy revealed transformation to a malignant melanoma. She was resistant to BRAF inhibitors, then treated with ipilimumab and is currently a long-term survivor of 4 years and 4 months since the first diagnosis, with no clinical or radiological evidence of recurrence.
A biopsy from patients with metastasis of unknown primary should be analyzed thoroughly to identify organ of origin, molecular make-up, and possible molecular targets. Re-biopsy of cancer of unknown primary site at progression can reveal the true cellular origin of the tumor as well as provide novel therapeutic opportunities, including immunotherapy.
Cancer of unknown primary site (CUP) accounts for approximately 1 to 5 % of all cancers but has a dismal prognosis of approximately 10 to 20 % 1-year survival and in Australia is the sixth cause of cancer death [1–4]. Depending on the patient series, up to 40 % of patients with CUP are diagnosed as having metastasis in their lymph nodes, while the remaining patients present with metastasis in their internal organs [5, 6]. In a large series of CUP in various anatomical regions, patients with an affected lymph node showed a wide survival span; patients presenting with affected inguinal lymph nodes had a median survival of 18 months and patients affected intra-abdominally had a median survival of only 4 months . Thus CUP is a very heterogenous entity, where histopathological examination, immunohistochemical profiling, and molecular profiling of the tumor are necessary to improve treatment and survival of patients with these tumors.
The complexity and unusual features of the history of this 62-year-old woman with a fast-growing mass in her left inguinal area, has taught us a lesson that may be important to share with oncologists treating this patient population.
The BRAF V600E mutation persisted, strongly indicating that the tumor was of the same origin but probably another clone, or a transformation from the primary tumor after chemoradiation with an unusual or aberrant expression profile for a melanoma.
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  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 . 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.
Currently, with the advent of targeted treatment and immunotherapy, identifying molecular subtypes may be of benefit for several cancer types. Immunotherapy, by ipilimumab, a fourth-line treatment, induced a complete and durable response after recurrence and progression on chemoradiotherapy and two BRAF inhibitors. Moreover this patient had clinical benefit with paclitaxel-carboplatin on what was perceived as an undifferentiated carcinoma, which became resistant when transformed to a S100-positive melanoma.
In conclusion, molecular screening in the primary biopsy and re-biopsy of the recurrence may be of clinical value in CUP, where evaluations with a broad spectrum of immunohistochemical and molecular analyses are necessary.
We thank the patient who generously provided consent to publish her medical history to help other patients.
There was no funding for writing this article.
Availability of data and materials
All data are available in the electronic medical records of our hospital, accessible to the treating medical doctors.
ODR was the clinician that has treated the patient, collected the clinical and radiological data, and wrote the paper. SW carried out the immunohistochemistry and analyzed the pathology and molecular data, interpreted the results and wrote the pathology section. Both authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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