Somatostatin receptor expression in Merkel cell carcinoma as target for molecular imaging

Merkel cell carcinoma (MCC) is a rare, highly aggressive, viral associated cutaneous neoplasm with neuroendocrine characteristics [1, 2]. Indeed, it is characterized by expression of neuroendocrine markers including somatostatin receptors (SSTR) [3, 4]. Five-year survival rates are as low as 66% for stage I, 51% for stage II, 39% and 18% for stage III and IV, respectively [5]. While a standardized staging system has been introduced with the 7^th edition of the AJCC staging manual [6, 7], the definite staging algorithm for MCC remains to be established. Current imaging procedures for patients with clinical stage I/II disease include ultrasonography of regional lymph nodes and the abdomen as well as a chest X-ray. A sentinel lymph node biopsy (SLNB) is recommended for all patients with no evidence of lymph node or distant metastasis [8‐11]. Contrast-enhanced computed tomography (CT) is generally performed in patients with clinical stage III/IV disease. Functional or molecular imaging modalities such as ¹⁸ F-fluorodeoxyglucose positron emission tomography (FDG-PET) are increasingly used [12‐17].

In analogy to neuroendocrine tumors (NET), SSTR expression may be used for staging [18]. ⁶⁸Ga-labeled 1,4,7,10-tetraazacyclo-dodecane-N,N’,N”,N”-tetraaceticacid D-Phe¹-Tyr³-octreotide (⁶⁸Ga-DOTATOC) and Tyr³-octreotate (⁶⁸Ga-DOTATATE) are somatostatin analogs with high affinity to SSTR subtype 2 suitable for PET imaging, thereby offering superior spatial resolution [19]. Radiotracer uptake has been shown to correlate with expression of SSTR 2 in NET and MCC [3, 20, 21]. SSTR-PET is more sensitive and accurate for tumor detection than respective scintigraphic techniques [22]. SSTR-PET has been claimed to be beneficial compared to conventional imaging and FDG-PET in selected patients with MCC [23, 24].

The aim of this study was to assess the impact of non-invasive characterization of SSTR expression in MCC on tumor staging, as compared to conventional staging by CT and to explore its suitability as molecular target for treatment of metastatic MCC.

In this retrospective study, we have demonstrated that tumor staging using specific imaging of SSTR expression by PET is feasible and provides additional diagnostic information. All primary tumors were visualized with focal uptake of the radiotracer, indicating that SSTR-PET could be used for tumor localization in patients with unknown primary.

SSTR-PET showed higher sensitivity for detection of bone metastases as compared to CT, which is consistent with findings in other neuroendocrine cancers [28]. Notably, diagnosis of bone metastases provided a rationale for initiation of bisphosphonate treatment in those three patients. Interestingly, two patients of our cohort were diagnosed with cerebral metastases based on SSTR-PET. A rate of 8% in the total cohort, i.e. 20% in stage IV patients, is much higher than expected from previous observations that reported central nervous system involvement to be a very rare event in MCC. Thus, SSTR-PET appears as a highly sensitive means to detect cerebral metastases of MCC that may have been under-diagnosed previously [29] and SSTR-PET is superior to FDG-PET in this regard [14]. SSTR-PET was superior to CT regarding detection of soft tissue metastases which could also have further impact on the therapeutic decision making process. Overall, patient management was directly changed in 13% of cases.

In contrast, SSTR-PET turned out to be significantly inferior to CT in terms of imaging liver and lung metastases. This is likely due to physiologically high uptake in the liver. With respect to the lung, pulmonary metastases from MCC are generally small and motion artifacts due to breathing negatively interfere with lesion detection by PET. Detection of cutaneous metastases depends on lesion size. In the present series, lesions had to be at least 5 mm to be visualized with SSTR-PET. However, several skin metastases did not show increased tracer uptake despite a size > 15 mm. A similar result has been recently described for gamma camera-based imaging using ¹¹¹In-octreotide. With this imaging approach none of 14 cutaneous metastases were visualized in 2 patients [30].

Lymphatic metastases are frequent in MCC and severely impact prognosis [5]. However, MCC affects the elderly and is frequently localized in the head-and-neck region, thus both SLNB and possible radical lymphadenectomy are associated with an increased surgery risk. In our series, SSTR-PET was true negative in 6 SLN-negative patients and true positive in one SLN-positive patient but failed to demonstrate a 5 mm iliac lymph node metastasis in a patient who underwent complete lymph node dissection. Moreover, since neither SSTR- nor FDG-PET/CT consistently detects nodal MCC micro-metastases, these techniques are not intended to replace the sentinel lymph node biopsy [8, 13, 15]. However, if SSTR-PET detects unapparent lymph node metastases, as e.g. in patient no. 15, the patient can directly undergo complete lymphadenectomy, i.e. SLNB can be spared. SSTR-PET may have higher diagnostic performance than FDG-PET in MCC as pointed out in a recent case report [24]. In a retrospective analysis, FDG-PET/(CT) has been shown to be a useful tool in management of MCC and may lead to upstaging of 16% of patients [14]. A head-to-head comparison of both imaging approaches (SSTR expression vs. FDG metabolism) warrants an interesting tool for further research to gain deeper knowledge of tumor biology. However, SSTR-PET is superior to FDG-PET for detection of cerebral metastases of MCC and only SSTR-PET harbors the possibility of a theranostic approach towards the disease by combining diagnostic and therapeutic properties. Based on these notions, we propose a staging algorithm, which includes SSTR-PET/CT (Figure 4). Current therapy regimens for metastatic MCC have a limited impact on the overall survival [31]. Recently, treatment with somatostatin analogs has been reported for both MCC and NET [32‐36]. In NETs, retention of DOTATOC, as measured by calculation of SUV_mean or SUV_max, is usually at least 2-fold higher as compared to a reference segment in the liver. MCC lesions in our cohort showed markedly lower tracer retention of DOTATOC/-TATE. This fact indicates that response rates to targeted radionuclide therapy (i.e., ⁹⁰Y-DOTATOC or ¹⁷⁷Lu-DOTATATE) may be inferior, however, MCC is a very radiosensitive tumor and therefore, therapy with radio-labeled somatostatin analogs might nevertheless be considered in an otherwise limited therapeutic scenario.

One of the limitations of our study is immanent to the orphan disease status of MCC: it comprises a limited number of patients; nevertheless, to the best of our knowledge, this is the largest cohort of MCC patients imaged by SSTR-PET to date. Other limitations are also related to the low incidence of MCC: The SSTR-PETs were carried out over a period of 3 years; over this period substantial improvements of SSTR-PET technologies were introduced. Thus, the majority of patients were examined using a dedicated PET scanner and only 5 patients were imaged by PET/CT. Thus, it can be assumed that implementation of integrated PET/CT scanners providing enhanced image quality will facilitate detection of smaller lesions. An example demonstrating improved image quality and sensitivity of PET/CT devices as compared to a PET only device is shown in the Additional file 1: Figure S1. Similarly, the possible benefits of ⁶⁸Ga-DOTATATE over ⁶⁸Ga-DOTATOC had been realized. However, since we could demonstrate the advantage of SSTR-PET in combination with contrast-enhanced CT using older technologies for correct staging of MCC, it can be envisaged that these benefits are even better with improved SSTR-PET techniques.

This study highlights the role of molecular imaging of SSTR expression in MCC. The advantage of SSTR-PET is based on an improved visualization of bone, soft tissue and brain metastases, whereas limitations relate to an insufficient detection of lung and liver metastases. Therefore, in MCC, SSTR-PET should be always performed in combination with contrast-enhanced CT; indeed, such an approach resulted in a change of patient management in 13% of cases. Furthermore, focally increased tracer uptake suggests treatment of MCC using β-emitter-labeled SSTR analogs such as ⁹⁰Y- or ¹⁷⁷Lu-DOTATATE as a therapeutic option.

Initials: Kristina Buder (KB), Constantin Lapa (CL), Andreas Schirbel (AS), Ken Herrmann (KH), Michael C. Kreissl (MCK), Alexander Schnack (AlS), Eva Bettina Bröcker (EBB), Matthias Goebeler (MG), Andreas K. Buck (AKB), Jürgen C. Becker (JCB).