Introduction
Merkel cell carcinoma (MCC) is a rare and aggressive endocrine-differentiated skin cancer that commonly presents as a painless erythematous nodule with or without ulceration. Dermoscopic features include linear, irregular, and polymorphous vessels, poorly focused vessels, and milky-pink areas [1]. It is often confused with basal cell carcinoma. It is more common in elderly Caucasians in sun-exposed areas such as the head and neck [2].
The exact pathogenesis of MCC is poorly understood. Increased ultraviolet radiation is associated with MCC incidence rates [3], and immunosuppression has also been associated with it. In 2008, Merkel cell polyomavirus was found to be associated with this tumour. However, its prevalence varies depending on the region (8% in North America and 80% in Asia) [4].
Prognostic factors in MCC are scarce. Tumour budding (TB) has shown a prophetic role in different cancers but has not been explored in MCC. A unique and fundamental characteristic of malignant neoplastic cells is the ability to invade and metastasize; the first step in this process is the dissociation of some of these cells from the invading front of the tumour; various researchers have highlighted the histopathological representation of this phenomenon using multiple terms; the most accepted and, until relatively recently, agreed, is the term TB. Tumour budding has taken on great relevance in recent years, given its relationship with vascular invasion, metastasis, and prognosis in terms of recurrence and survival. In addition, it has been closely associated with the phenomenon called epithelial-mesenchymal transition.
The definition of TB has been a controversial issue throughout its development, even today, when there is a consensus on the matter [5]. The most widely used definition refers to an isolated tumour cell or groups of up to 4 cells separated from the glands of the invading front of the tumour [6].
Our objective is to determine if TB is a factor that impacts the survival of patients with MCC.
Material and methods
Population
Patients with pathologically confirmed MCC were identified in 2005–2018, and their medical records were reviewed. We recorded the following characteristics: age, sex, primary location, staging, treatment, and oncological outcomes. Patients with MCC were staged according to the 8th American Joint Committee on Cancer system [7]. Tumour budding was evaluated in the same way that was described in colorectal cancer [6] by 2 pathologists with consensus in the case of discordant cases.
The research committee of our institution approved this study (ICAN/18/20).
Treatments
Patients with locoregional MCC underwent wide local excision of the primary tumour with or without lymph node management. Adjuvant chemotherapy or radiation therapy was selected and performed at the physicians’ discretion based on the pathology reports. Palliative chemotherapy (cisplatin and etoposide) and immunotherapy were chosen for patients with inoperable MCC.
Statistical analysis
Continuous variables are presented as median with minimum and maximum, while categorical data are presented as count and percentage. Overall survival was defined as the time from diagnosis to death from any cause or to the last follow-up. Survival curves were plotted using the Kaplan-Meier method, and survival analysis was performed by comparing survival curves with the log-rank test. Statistical analyses were performed using SPSS version 22.0 software.
Results
We identified 45 cases of MCC. The average follow-up was 31.11 months; to date, 68.9% of patients are alive. The minimum age was 40 years, and the maximum age was 91 years; the mean was 69 years, with a higher frequency of presentation in women (25 versus 20 men). The most frequently affected anatomical regions were those not photo- exposed (55.6%); histologically, an infiltrative invasive front was found, primarily present in 68.9% of cases, with an average Breslow of 11.36 mm, and the average mitotic rate was 31.93 mitoses/mm2. The diagnosis was made in early clinical stages (EC I and II) in 40% of cases, 22.2% in locally advanced stage (ECIII), and 37.8% in metastatic clinical stage, most of whom received adjuvant treatment (55.6%), which consisted of chemotherapy and radiotherapy.
Tumour budding in most cases was low (< 5 buds/ 0.785 mm2, 44.4% of cases) compared to 24.4% of those with a high budding rate (> 10 buds/ 0.785 mm2). As shown in Table I, no clinical or pathological features were associated with high TB.
Among the prognostic factors for 5-year survival, we found that tumour size and therefore clinical stage were statistically significant (p = 0.031 and 0.021, respectively), whereas TB was not associated with survival (Table II).
Discussion
In our study of 45 cases of MCC, we did not identify clinical or pathological characteristics associated with the various degrees of TB. Likewise, TB did not influence survival.
Tumour budding on the invasive front has recently been suggested as a potential index of aggressiveness and poor prognosis for various types of cancer [1–5]. An essential advantage of this index is its simplicity and reproducible measurement. It is easily adapted to routine histopathological examination based on haematoxylin and eosin staining without the need for additional expensive techniques. This feature is essential and may have therapeutic implications for patients with MCC. In this study, consistent with previous reports in other cancers, good reproducibility was achieved for the assessment of TB based on intra- and interobserver agreement studies (k = 0.880 and 0.717).
To date, the prognostic implication of TB in MCC has not been investigated. In our study, there is no evidence that tumour budding has a prognostic significance in overall survival. We are aware that there are several limitations to our report. First, there are potential biases due to the retrospective nature of our study. Second, the findings could even be biased because, in a concentration and national reference hospital, the percentage of tumours with a poor prognosis could be higher due to referral than in daily outpatient practice.
Conclusions
No clinical or pathological characteristics of MCC are associated with any degree of TB. Tumour budding is not related to overall survival in MCC.
The authors declare no conflict of interest.
References
1. Jalilian C, Chamberlain AJ, Haskett M, et al. Clinical and dermoscopic characteristics of Merkel cell carcinoma. Br J Dermatol 2013; 169: 294-297.
2.
Girschik J, Thorn K, Beer TW, et al. Merkel cell carcinoma in Western Australia: a population-based study of incidence and survival. Br J Dermatol 2011; 165: 1051-1057.
3.
Youlden DR, Soyer HP, Youl PH, et al. Incidence and survival for Merkel cell carcinoma in Queensland, Australia, 1993–2010. JAMA Dermatol 2014; 150: 864-872.
4.
Feng H, Shuda M, Chang Y, et al. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008; 319: 1096-1100
5.
Lugli A, Kirsch R, Ajioka Y, et al. Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol 2017; 30: 1299-1311.
6.
Lugli A, Karamitopoulou E, Panayiotides I, et al. CD8+ lymphocytes/tumour-budding index: an independent prognostic factor representing a ‘pro-/anti-tumour’ approach to tumour host interaction in colorectal cancer. Br J Cancer 2009; 101: 1382-1392.
7.
Harms KL, Healy MA, Nghiem P, et al. Analysis of prognostic factors from 9387 Merkel cell carcinoma cases forms the basis for the new 8th Edition AJCC Staging System. Ann Surg Oncol 2016; 23: 3564-3571.
