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

Case Presentation

A 62-year-old woman of Norwegian ethnicity, previously healthy, presented in September 2012 with a large fast-growing nodal mass in her left groin; a computed tomography (CT) scan showed a 62 mm tumor infiltrating the subcutis. A clinical examination did not reveal any other pathological glands or any skin lesions. An magnetic resonance imaging (MRI) of her pelvis showed a solitary tumor, and subsequent CT of her thorax and abdomen, mammography, and endoscopy could not reveal or indicate the primary location of the tumor; in addition, the tumor markers we use in our screening were all within normal range: carcinoembryonic antigen (CEA), CA125, CA15-3, CA19-9, neuron-specific enolase (NSE), and chromogranin A (CgA). In November 2012 the tumor was still regarded as operable and surgery was performed. On macroscopic examination, the tumor was a 57 mm solid tumor. Histopathological examination revealed a tumor composed of malignant epithelioid cells, which on immunohistochemical examination stained positive for cytokeratin (CK) AE1/AE3 (diffuse), CK7 (focally), CD10, vimentin, and epithelial membrane antigen (EMA; scattered tumor cells). S100 was positive in scattered cells with dendritic features and possibly in a few scattered tumor cells. Nearly 100 % of the tumor cells were positive for Ki67/MIB1. The cells were negative for BerEP4, CK20, CK5/6, p63, thyroid transcription factor 1 (TTF1), synaptophysin, chromogranin, estrogen and progesterone receptors, human melanoma black 45 (HMB45), melan A, leukocyte common antigen (LCA), desmin, myogenin, smooth muscle actin (SMA), and CD30 (Fig. 1). We screened for actionable targets and molecular genetic analysis was negative for KRAS and synovial sarcoma marker, translocation t(X;18), but revealed BRAF V600E mutation. In the final pathology report, the tumor was classified as a metastasis from an undifferentiated carcinoma.

Figure 1.

Tumor resected in 2012. The resection revealed malignant epithelioid cells with pale eosinophilic cytoplasm and pleomorphic nuclei with vesicular chromatin; hematoxylin, eosin and saffron staining (a). The resection revealed a positive reaction for cytokeratin AE1/AE3 (b). Scattered cells stained positive for S100 (c) and CD68 (d), representing tumor-associated macrophages, but tumor cells were S100 negative

Our patient had postoperative complications with infection and lymphatic leakage, subsequent CT scanning and positron emission tomography (PET)-CT showed masses to be growing deeper in her pelvis, which could not be removed (Fig. 2).

Figure 2.

The patient had postoperative complications with infection and lymphatic leakage. Subsequent positron emission tomography-computed tomography (a) showed masses to be growing deeper in the pelvis, which could not be removed surgically (white arrow). Computed tomography scanning (b) showed complete remission after four courses of paclitaxel and carboplatin (white arrow)

We decided to give paclitaxel with carboplatin (AUC5) every 3 weeks, which is a standard treatment for CUP and after four courses the masses went into complete remission. Consolidation radiotherapy was performed April to May 2013, 2×(25 to 50) Gy. Our patient was in very good general condition during all the treatment period: World Health Organization (WHO) performance status (PS) grade 0. The remission lasted for 18 months to July 2014, when multiple, fast-growing subcutaneous nodules evolved within and near the surgical wound and radiation field and distally on her left thigh. Moreover, multiple small metastases were seen in both her lungs. One subcutaneous nodule was extirpated for histopathological analysis, which revealed a tumor with a cellular morphology and cellular growth pattern similar to the tumor resected 18 months earlier. The tumor cells were, as previously, negative for BerEP4, CK20, CK5/6, P63, HMB45 and melan A, but surprisingly CK AE1/AE3 was now negative and S100 strongly positive in all tumor cells (Fig. 3). The tumor cells were closely studied, both initially when the first report was made and on reevaluation, and conspicuous pigment was not detected.

Figure 3.

Several subcutaneous recurrent tumors developed after 18 months. A biopsy showed cells with a growth pattern, cellular features, and nuclear features similar to the tumor resected in 2012 seen by hematoxylin, eosin and saffron staining (a), but a change to negative staining for cytokeratin AE1/AE3 (b) and now positive staining for S100 (c)

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.

Due to the previous good results with chemotherapy, one course of paclitaxel and carboplatin was tried. However, the nodules grew more aggressively, and chemotherapy was discontinued in favor of a BRAF inhibitor, dabrafenib, that showed a brief response of 2 months, and subsequently vemurafenib was administered resulting in progressive disease. Combined treatment with a mitogen-activated protein kinase (MEK) inhibitor was not introduced in Norway at that time point. In the meantime, ipilimumab was approved for use in melanomas in Norway and in December 2014 she was offered this treatment. After four cycles of ipilimumab there was a complete response in her skin and her lungs, with no reported side effects (Fig. 4).

Figure 4.

At recurrence the patient had multiple small metastases in both lungs (red arrows) and multiple subcutaneous nodules in her left groin and thigh (white arrows). There was no effect of chemotherapy and only 2 months' effect of dabrafenib. Panels a and b show before treatment with ipilimumab and c and d after two cycles where a significant remission was seen. After four cycles she was completely tumor free, and still is with virtually no side effects

Today, 4 years and 4 months after primary diagnosis of aggressive CUP and 2 years and 6 months after metastatic melanoma was diagnosed in the re-biopsy, she is radiologically and clinically cancer-free (Fig. 5).

Figure 5.

Timeline of the key events