Epidemiology and treatment of Merkel cell carcinoma Duprat JP et al. Table 1 - TNM Classification. CLINICS 2011;66(10):1817-1823 T1 T2 T3 T4 cN0 pN0 N1 N1a N1b N2 M0 M1 M1a M1b M1c Tumor (T) #2 cm tumor size .2 cm but no more than 5 cm .5 cm invasion of bone, muscle, fascia or cartilage Nodal (N) node negative by clinical exam (clinical or imaging exam) node negative by pathologic exam metastasis in regional node micrometastasis (sentinel node or elective lymphadenectomy) macrometastasis (clinically detectable, confirmed by surgery or fine-needle aspiration) in-transit metastasis Metastasis (M) no distant metastasis metastasis beyond regional lymph nodes metastasis to skin, subcutaneous tissues or distant lymph nodes metastasis to lung metastasis to all other visceral sites be caused by angiogenic factors produced by these tumors. Furthermore, Kukko et al. analyzed the expression of vascular endothelial growth factor receptor-2 (VEGFR-2) in Merkel tumors and found a strong positive correlation between the presence of VEGFR-2, tumor size and meta- static potential.14 In that study, the authors suggested that antiangiogenic therapy could help control the tumor, but this was not analyzed experimentally. It has been shown in experimental models of MCC that inhibitors of the mTor pathways result in reduced VEGF production and angiogenesis.15 Recently, an interesting study was conducted by Vazmitel et al.16 involving 92 cases of MCC. They found prominent vascular alterations in 18 cases (20%). Pericyte hyperplasia was observed in ten cases (11%) among others six different patterns. In this interesting study, the presence of HHV-8 was analyzed because this virus is known to stimulate angiogenesis. However, HHV-8 was not detected with the polymerase chain reaction. Studies have been conducted on many tumors, including MCC, involving mTor receptors and the AKT/PI3C pathway. mTor (Mammalian Target of Rapamycin) is a protein kinase and a member of the PIKK family that controls cell growth. mTor is regulated by many factors, such as growth factors, hormones (insulin), and the PI3K/Akt pathway. This path- way is initiated by growth factor receptors, such as IGFR (Insulin-like Growth Factor Receptor), PDGFR (Platelet- Derived Growth Factor Receptor), EGFR (Epidermal Growth Factor Receptor), and the HER family.17,18 In this particular pathway, inactivation of PTEN, which commonly occurs in human tumors, is antagonistic to PI3K and results in increases in PIP3. PI3K activation and accumulation of PIP3 causes translocation of Akt to the plasma membrane, where Akt is activated. These steps initiate anti-apoptotic pathways and stimulate the cell cycle via a series of factors, including mTOR. Akt/mTOR can regulate suppression of p53, and Akt can activate mdm2 and promote p53 degrada- tion. In models of MCC, inhibition of Ras causes apoptosis with p53 degradation, so it is very likely that this pathway is involved in MCC.19,20 It is well accepted that Merkel carcinoma commonly occurs in immunocompromised patients, and in this population, changing the immunosuppression regimen from calcineurin inhibitors (azathioprine and cyclosporine) 1818 to serolimus results in better cure rates and regression of tumors.21 Serolimus (rapamycin) acts both via the inhibition of the mTOR pathway and by diminishing angiogenesis.22 It has been tested prospectively after transplants, and there was a significant reduction of skin and non-skin cancers.23 Furthermore, serolimus has been tested for MCC.19 In an experimental model of MCC, the use of imatinib has been tested. It has been suggested that an autocrine and paracrine activation of KIT receptors in MCC cell lines occurs via stem cell factor (SCF) and induces the MAPK pathway and AKT activation. Although MCC cells display some response to imatinib, a high dose is necessary to obtain cell death. However, relapse has been observed and is most likely due to direct activation of MEK1 and AKT, which induces further proliferation and anti-apoptosis effects, respectively. This pathway is promising as a novel therapeutic option for this tumor.24 Diagnosis MCC occurs predominantly in the head and neck (41 to 50%), followed by the extremities (32 to 38%) and trunk (12 to 14%). Typically, this neoplasm presents as a rapidly growing, dome-shaped red or bluish nodule.10,12,25 In addition, the tumor may sometimes have a plaque-like appearance with small satellite lesions.3 Diagnosis is usually established only after biopsy. Similar to other neuroendocrine tumors, small round to ovoid cells with hyperchromatic nuclei and frequent mitosis or apoptosis are commonly observed. The architecture is often variable and includes trabecular, nodular and diffuse patterns. Sometimes, it is difficult to differentiate MCC from other small cell tumors, and in these cases, immuno- histochemical staining and/or electron microscopy must be used. MCC stains positively for neuron-specific enolase, synaptophysin, chromogranin, cytokeratin 20 (in a char- acteristic dot-like pattern) and CAM 5.2 and is negative for S100, desmin and common leukocyte antigens.10 Cytokeratin-20 expression is detected in 89 to 100% of MCC cases as well as in 30% of small-cell lung tumors.26 Stage Classification Yiengpruksawan27 proposed a stage classification for MCC as follows: stage I would be restricted to the skin, stage II would include nodal metastasis, and stage III would be