Our patient developed an eyelid MCC 7 months after the diagnosis of lung cancer. Available data in literature shows that, overall, there is no statistically significant risk to develop an MCC following a diagnosis of primary lung cancer (i.e. standardized significant rate (SIR) 0.88; 95% CI 0.32–1.92), as well as to develop an MCC within 1 year from the diagnosis of lung cancer ((SIR) 0.63; 95% CI 0.13–1.85) [17].
The development of MCC occurred during a treatment with nivolumab for a lung adenocarcinoma. Nivolumab is a fully human IgG4 immune checkpoint inhibitor antibody targeting PD-1 that has been approved for the treatment of advanced or metastatic non-squamous non-small-cell lung cancer (NSCLC) according to positive results of the phase III, open label study CheckMate 057 [18].
An analysis of the literature was performed to know whether any MCC occurrences in the course of a nivolumab treatment had been reported. The research did not identify any publications related to the occurrence of MMC during nivolumab treatments. Based on post-marketing reports of the nivolumab producer, one case of neuroendocrine carcinoma during the treatment with this drug for lung adenocarcinoma has been described. However, since this type of event is reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate the frequency or to establish a causal relationship to the drug exposure.
MCC represents a checkpoint inhibitor responsive cancer. Factors that have been suggested to contribute to an immunotherapy response are represented by a high tumor mutational burden due to the ultraviolet rays exposure [19] and the integration of MCPyV DNA sequence. In fact, high expression levels of inhibitory receptors such as PD-1 and Tim-3 have been found on MCC infiltrating lymphocytes and T CD8-specific MCPyV cells [5]. These factors offer a rationale for treating patients with anti PD-1/anti PD-L1 monoclonal antibodies.
Avelumab is indicated in the treatment of MCC based on an open-label, single-arm, multi-center clinical trial (JAVELIN Merkel 200 trial). It induced an objective response (OR) in 33% of treated patients [11]. Responses to avelumab were observed irrespective of PD-L1 expression on tumor cells or Merkel cell polyomavirus status [12].
In a multicentre phase 2 noncontrolled trial including 26 patients with an advanced MCC pembrolizumab induced an OR in 56% of patients. PD-L1 expression was more frequent in MCPyV-positive cancers than in MCPyV-negative cancers (71% vs 25%). Responses were observed in both virus-positive and virus-negative. No significant correlation of PD-L1 expression on tumor cells or infiltrating immune cells with drug response was observed [13].
A significant and durable response in a patient with metastatic MCC following nivolumab therapy was reported [14]. Preliminary results of an ongoing non-comparative, multiple cohort, open-label, phase 1/2 study (CheckMate 358) of nivolumab in patients (n = 50 MCC) with virus-positive and virus-negative solid tumors show an OR in 64% of advanced MCC cases and pathologic tumor regressions in 65% of resectable MCC cases [15, 16]. Moreover, a phase 2 clinical trial evaluating nivolumab + ipilimumab +/− stereotactic body radiation therapy (SBRT) for metastatic MCC is ongoing (NCT03071406).
Four main factors are implicated in the development of MCC: immunosuppression [20,21,22,23,24,25], ultraviolet radiation [3], age [26], and MCPyV [4, 5]. Overall, our patient presented three out of four MCC risk factors, whereas the MCPyV positivity status was unknown.
As far as immunosuppression is concerned, it is known that immunosuppressed patients have a poor prognosis with a reduced MCC-specific survival [20]. Immunosuppressive conditions determining an increased risk of developing an MCC are: patients with haematological malignancies, especially chronic lymphocytic leukaemia [21, 22], acquired immunodeficiency syndrome (AIDS) [23], patients undergoing organ transplantation [24] or patients in chronic treatment for autoimmune diseases [25]. Our patient did not have an immunosuppressive state such as those described above, but he had a lung cancer and he previously had received chemotherapy with vinorelbine.
It is also well known that there is a strong association between MCC and a history of sun exposure [3]. Ultraviolet-associated mutations in RB1, TP53, NOTCH1 and FAT1 genes have been reported in MCPyV-negative cancers [19]. In our patient, the MCC developed in one of the most sun-exposed anatomical sites, so prolonged exposure to ultraviolet light may have been a relevant causal factor of the MCC. On the basis of the information gained by the anamnestic collection, a history of high sun exposure both before and during the treatments was highlighted.
Regarding age, it has been shown that H&N MCCs have a higher incidence in elderly patients. It is known that MCPyV seroprevalence increases according to age achieving 73% in subjects older than 70 years [26].
Our patient had two cancers in which MCPyV has been proposed to be related with the pathogenesis. In fact, several studies have reported the presence of MCPyV-DNA integrated into tumor cells in about 80% of MCC cases [4, 5] and in a range from 9 to 18% in NSCLCs [27,28,29]. Thus, although the underlying tumorigenic mechanisms are unknown, in a subset of patients MCPyV could play an important role also in the pathogenesis of NSCLC, through the expression of two putagenic oncoproteins (i.e. large T and small T antigens) [29, 30]. Unfortunately, we were not able to determine the presence of MCPyV DNA due to the unavailability of biological material. However, it must be noted that although MCC is a rare cancer, MCPyV is ubiquitous in human populations (i.e. from 60 to 80% of the general population is infected with MCPyV) [30].
In conclusion, we described a case of eyelid MCC occurring in a patient with recent diagnosis of NSCLC during second-line treatment with nivolumab. Cases of co-occurrence of MCC and NSCLC have rarely been reported. Interestingly, common risk factors may be postulated for both cancers. Considering the rarity of this adverse event, its short-term temporal relation with the administration of the drug, which makes a relation improbable, and the coexistence of other risk factors, which may provide plausible explanations, it is possible to conclude according to the WHO Adverse Reaction Terminology [31] that a causal relation between the occurrence of this serious adverse event and the exposure to the drug is unlikely. However, the case deserves to be reported in the literature.
