Clinically misinterpreted melanoma metastases can correctly be diagnosed by ultrasound-guided fine needle aspiration cytology

ARTICLE

ejd.2011.1275

Auteur(s) : Gregor SCHAEFER-HESTERBERG¹, Alexander J.C.Van AKKOOI², Anne LETSCH³, Joachim ROEWERT¹, Ulrike BLUME-PEYTAVI¹, Ulrich KEILHOLZ³, Christiane VOIT¹ christiane.voit@t-online.de

¹ Department of Dermatology, Venerology and Allergology, Charité – Universitlsquätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany

² Department of Surgical Oncology, Erasmus University Medical Center – Daniel den Hoed Cancer Center, the Netherlands

³ Dept. of Hematology and Medical Oncology, Charité – Universitlsquätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany

Reprints: C. VOIT

A 64-year old, male patient was first diagnosed for cutaneous amelanotic melanoma on his right elbow in January 2003. The tumor thickness of the primary melanoma was 3.3 mm, Clark level III, with no ulceration or regression signs. A single sentinel node excised in the lower right axilla proved to be negative. The patient's history and clinical documentation did not report any lesion proximal to the primary at the time of surgery. B-scans of the regional lymph nodes and the abdomen showed no pathological findings. Consecutively, he received adjuvant interferon treatment and clinical follow-up.

The patient presented to our US and FNAC-based diagnostic unit for the first time in September 2004 (20 months later). As the clinical examination had reported axillary lymph node enlargement, suspicious for metastasis, an axillary lymph node ultrasound, if necessary followed by a fine needle puncture, was scheduled. During the clinical examination, a palpable tumor on the right elbow with the macroscopic aspect of a lipoma, though well known to the patient and to all his treating doctors, drew our attention. This lesion was well defined, extremely smooth and perfectly mobile in all directions, as shown (figure 1).

The patient reported that it had appeared shortly after the excision of the primary amelanotic melanoma, with no further sign of growth since then. Interestingly, he had had a serious car crash soon after the surgery of his primary lesion. Possibly, he therefore did not pay any particular attention to this new mass. Although this lesion raised significant suspicion from all his treating physicians, the explanation that this mass was induced by trauma and had not changed or grown afterwards was believed, and no further attention was paid to this lesion. Up to this time the lesion had been considered as a lipoma or another benign adnexal lesion.

Examining the patients’ regional lymph nodes is part of the regular staging procedures in Germany. We especially also always check the in-transit region by ultrasound. Fine-needle aspiration (FNA) is a procedure that has been approved in our institution by the local ethics committee and patients’ informed consent is provided prior to FNA (Ethical standards of the Helsinki Declaration).

The patient's chart up to this time did not yet mention the abovementioned lesion. Regular chest x-ray, computed tomography and ultrasound of the abdomen had been performed and all were considered to be without any signs of disease recurrence. We conducted an ultrasound of both axillae and we did not detect any suspicious lymph nodes by this examination. The above-mentioned mass on the elbow, however, clearly did not reveal any sonographic features consistent with a lipoma or an epidermoid cyst compared to the examples presented here, with typical features and moreover with a lack of any perfusion (figures A-C).

The lesion in our patient was depicted as a predominantly echo-poor, balloon-shaped space-occupying lesion, with significant irregular perfusion in the center as well as in the periphery, separated from the surrounding structures by a thick, echo-rich pseudo-capsule. All these features, except for the thick echo-rich pseudo-capsule can be considered as suspicious for melanoma recurrence (figure 2C). Subsequent fine needle aspiration guided by ultrasound confirmed the suspicion of melanoma metastasis of epithelial subtype within 1 hour and therefore the lesion was completely excised at once and confirmed by histopathology (H&E staining) (figure 3A) including immunohistochemistry (S100, HMB45 and Melan-A) (figure 3B). The metastasis was located in the subcutaneous layer, had an unusual and thick capsule of 0.2 mm, in part, a lot thicker by being mixed with fatty tissue, which is maybe responsible for the smooth aspect. The whole capsule extended itself into the centre of the node in the form of multiple fibers (figure 3A). Towards the rim of the node, a rich infiltration with plasma cells and lymphohistiocytary cells could be seen.

Histology of this metastatic lesion revealed a subcapsular T cell infiltrate, which we tried to characterize. Unfortunately we could not establish an autologous melanoma cell line in order to perform a precise T cell analysis, since the cells did not grow in vitro. We therefore decided to look at the T cell response against the HLA-A*0201 binding epitopes of tyrosinase, MAGE and GnTV, which are antigens frequently expressed on melanoma cells by intracellular IFN-γ cytometry (ICC). Unfortunately, none of the tests analyzing higher frequencies of peptide-specific CD3+CD8+ IFN-γ secreting T cells against certain peptides which exceed the spontaneous IFN-γ secretion against the HIV control peptide, were positive [1] (data not shown). Additionally, a tyrosinase PCR of the fresh node, as well as of the peripheral blood, was performed but they were both negative.

The serum Melanoma Inhibitory Activity tests (MIA, cut-off 8.8 ng/mL), which were controlled regularly according to clinic standard, had always remained negative in this patient: 7.3 ng/mL at time of diagnosis of his primary tumor on January 2003 and 7.6 ng/mL at the time of the excision of the metastasis in October 2004. During follow-up, the results have constantly been below the cut-off to date. Thus none of these tests demonstrated disease activity or immune response in this patient.

After the excision of the lesion, the patient is still free of disease until today (11/2010; follow-up of 94 months) and comes in for regular ultrasound examinations of the regional lymph node basins and the in transit regions, every 6 months.

Discussion

Unfortunately this was obviously NOT a very suspicious cutaneous mass at the edge of the wide excision margin and it was therefore clinically misdiagnosed.

First, apart from any other considerations, this lesion, due to its topography, should have been removed or a FNAC should have been performed to determine if it was truly benign, as it was judged clinically, or malignant. Unfortunately, this had not been done and therefore a possibly hazardous delay in diagnosis was introduced, due to diagnostic failure on the behalf of the treating physicians.

Routine ultrasound of the regional lymph node basins is performed by a specialist in ultrasound diagnostics, as recommended [2]. In our department, this ultrasound examination not only checks the lymph node basins, but also the in-transit distance [3].

On first presentation to us, the lesion was considered quite morphologically uncommon for melanoma/in-transit metastases, yet the topography did raise our suspicion. Thus we swiftly and easily performed an ultrasound of the lesion, which suggested a tumoral process. Subsequently, a FNAC of the lesion and of possible areas of interest was performed under ultrasound guidance. In our department we were provided with a cytology report of this lesion within a few hours, confirming our suspicion. Consequently the lesion was excised the same day.

It remains unclear why some melanoma patients, as in our case, relapse but keep their disease restricted locally – even in shape of a capsule – and why others (even though they have the same known risk factors as the ones mentioned previously) progress and have shorter long-term survival. It is postulated that this reflects the individual tumor biology, but further risk factors must be identified. Our hypothesis that the tumor metastasis remained restricted in our patient because of a spontaneous cytotoxic T cell response could unfortunately not be confirmed with the laboratory means we disposed of.

However, there is a completely different lesson to be learned by a case such as the one we present. As shown here, in a patient with a metastatic lesion of atypical appearance where the regular follow-up procedures (clinical examination, blood tests etc.) failed to correctly diagnose a relapse, ultrasound can be of added value. Palpable masses appearing in melanoma patients, despite a “normal” clinical impression or despite a harmless explanation on behalf of the patient, should systematically undergo ultrasound examination, even out of schedule when there is no regular follow-up examination planned. A study in 2008 by Calvo Lopez et al. [4] demonstrated the high yield of soft tissue metastases detected by ultrasound.

By combining ultrasound with the method of fine-needle aspiration cytology we are able, at a level of minimal invasion, to diagnose accurately and in a timely manner, suspicious lesions in patients with a high-risk of loco-regional recurrences [5, 6].

Furthermore, in our opinion, all patients at high risk for loco-regional recurrence should undergo regular follow-up examinations with ultrasound. Ultrasound examination of lymph node regions and in transit areas of melanoma patients is an easy and valuable tool. In the hands of a skilled physician it has high identification rates of suspicious lesions in the skin and the soft tissue [6]. This method can be rapidly performed and has no side effects, with the added benefit of a low cost. Taking into account that currently the first choice among technical procedures in the follow-up of melanoma patients outside of Europe is still CT or the combination of PET and CT, which both still have false positive results and are at the same time more expensive, the authors want to emphasize the cost-effectiveness and the good feasibility of this method in different situations with melanoma patients [7, 8].

Disclosure

Financial support: none. Conflict of interest: none.

References

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