Merkel cell carcinoma overlapping Bowen’s disease: two cases report and literature review

Merkel cell carcinoma (MCC) is a rare and highly aggressive primary cutaneous neuroendocrine carcinoma, which predominantly affects individuals of Caucasian descent. Risk factors include advanced age, exposure to ultraviolet radiation, male gender, immunosuppression, hematologic malignancies or posttransplant status, and infection with Merkel cell polyomavirus (MCPyV) (Harms et al. 2018). It is characterized by high invasiveness, frequent local recurrence, a tendency for regional lymph node and distant metastases, with high mortality rates of 33–46% (Harms 2017; Garcia-Carbonero et al. 2019).

MCC often occurs in sunexposed sites, typically presenting as solitary nodules or patches with skin-colored, red or purple hues. Reportedly, it occured concomitantly with or in the setting of pre-existing cutaneous neoplasms, including actinic keratosis, Bowen’s disease (BD), squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and miscellaneous adnexal tumors (Kervarrec et al. 2022). Only a small percentage of MCC presented combined with other tumors, for which, current data have suggested a more aggressive course than pure MCC (Tono et al. 2015; Chattopadhyay et al. 2020). Clinically, its association with BD is exceedingly uncommon. Its unspecific manifestations often lead to delayed diagnosis clinically, which is necessary for dermatologists and oncologists to familiarize themselves with and recognize it (Swain et al. 2022).

Few cases in the literature have been described and the management is not well defined. In our paper, we reviewed the literature and reported two additional cases to summarize the epidemiology, clinical and histopathological characteristics and management of it.

We first reported two cases with MCC overlapping BD. Then, we searched different databases, including PubMed, ResearchGate and Google Scholar by the combination MeSh of “Merkel cell carcinoma” and “Bowen’s disease, “Bowen disease” or “squamous cell carcinoma in situ” from January 2013 to December 2023. Total 15 papers were identified. Inclusion criteria were systematic review or meta-analysis of randomized controlled trials, review, retrospective comparative reviews/studies and case series. Exclusion criteria were laboratory studies and non-English translated articles. A wide review of the bibliography of each of the selected articles was performed. In total, 10 papers met our inclusion criteria, including 11 case reports and case series.

We reviewed and analyzed all of the cases with MCC overlapping BD and summarized the demographic information, such as the age, sex and the medical history, clinical and histopathological characteristics and the treatment and prognosis of them.

MCC is a primary cutaneous neuroendocrine carcinoma, predominantly diagnosed in fair-skinned elderly populations. Characterized by its aggressive nature, MCC is particularly notorious for its tendency towards local recurrences and distant metastases (Siqueira et al. 2023). Interestingly, MCC lesions may coexist with, or be found in close proximity to, a variety of other neoplasms, including actinic keratosis, BD, invasive SCC, BCC and sweat gland tumors (Kervarrec et al. 2022; Hobbs et al. 2020). Clinically, cases of MCC coexisting with BD are very rare. This comprehensive review of the literature spanning the past decade has revealed a notably rare occurrence, identifying only 11 cases of MCC overlapping BD. At the same time, we reported another two cases with MCC overlapping BD in the paper.

The annual incidence rate of MCC is approximately 0.24 cases per 100,000 individuals, showing a trend of exponential increase. This rising incidence can be attributed to a confluence of factors, including demographic shifts towards an aging population, heightened use of immunosuppressive agents, significant improvements in diagnostic technologies facilitating earlier and more accurate detection, and a general enhancement in clinical vigilance and awareness regarding this malignancy (Mistry et al. 2023; Mohsen et al. 2023). Our retrospective examination has disclosed that incidences of MCC overlapping BD present a gender distribution, with a male-to-female ratio of 1:1.6. Notably, a higher prevalence is observed in females, a finding potentially attributable to the limited scope of the sample size. The pathological manifestations of MCC predominantly arise in individuals aged over 70, though a sporadic occurrence in middle-aged adults has been noted (Swain et al. 2022). Owing to the absence of a conclusive diagnosis in MCC patients before undergoing histopathological examination, recent research has offered valuable insights into the clinical presentation of MCC, coalescing into the AEIOU mnemonic for ease of recall. “A” stands for asymptomatic lesions, often presenting without pain or tenderness. “E” denotes rapid expansion, with lesions demonstrating notable enlargement over a period of just three months. “I” represents immunosuppression, a key risk factor, encompassing conditions such as HIV infection, post-solid organ transplantation, or chronic lymphocytic leukemia. “O” refers to individuals over the age of 50, a demographic showing increased susceptibility. Finally, “U” highlights ultraviolet exposure in fair-skinned individuals as a significant risk factor. In the context of MCC overlapping BD, we propose the “AEIOUN” guideline, wherein “N” signifies the rapid emergence of nodules on the foundation of erythematous patches, expanding upon the initial AEIOU criteria.The presence of three or more of these features warrants a heightened clinical suspicion of MCC or MCC overlapping BD, guiding the clinician towards appropriate diagnostic and therapeutic interventions (Siqueira et al. 2023; Brusasco et al. 2022; Mistry et al. 2023).

The etiology of MCC is multifactorial. Current research posits that infection with MCPyV and genetic mutations triggered by ultraviolet (UV) radiation are primary contributors to the pathogenesis of MCC (Yang et al. 2022). Specifically, UV radiation plays a critical role in the development of MCPyV-negative MCC cases. Intriguingly, MCC cases that present concurrently with SCC or BD predominantly lack MCPyV. Among the 13 cases of MCC overlapping BD that were reviewed, only three patients underwent testing for MCPyV, and all 3 cases were negative for MCPyV. This observation suggests a distinct oncogenic mechanism in composite MCC, diverging from the pathways observed in solitary MCC (Kervarrec et al. 2022). The simultaneous manifestation of MCC overlapping BD might be attributed to a confluence of various factors, including immune regulation and the intricacies of the tumor microenvironment (Chattopadhyay et al. 2020). Genetic predisposition also appears to play a significant role in this context. Moreover, the pathogenesis of these conditions may be exacerbated by immunosuppression, immune deficiency or immune system dysregulation. The interplay and communication among cells within the tumor microenvironment, particularly through the release of cytokines, are believed to significantly influence the coexistence of MCC overlapping BD. Furthermore, lifestyle choices and environmental exposures, such as to chemicals, ultraviolet radiation, or toxins, are potential contributory elements in the concurrent development of these dermatological conditions (Casari et al. 2018).

MCC is unequivocally diagnosed through histopathological examination, recognized as the definitive gold standard. This is often supplemented by immunohistochemical profiling to accurately distinguish MCC from other poorly differentiated neoplasms. A significant majority of MCC cases demonstrate cytokeratin expression, with approximately 95% exhibiting perinuclear and/or cytoplasmic positivity for CK20 or CAM5.2. Additionally, these carcinomas frequently express neuroendocrine markers, most notably Syn, CgA, CD56 and NF. In contrast, TTF-1 and CDX-2 are typically negative in MCC (Khanna et al. 2020). Emerging studies suggest that around 60% of MCC cases express the protein p63, which is potentially correlating with a decreased overall survival rate and a lower disease-specific survival rate of patients. CK7 expression is generally absent in MCC, while there are noteworthy instances of CK7 positivity. A notable aspect in the immunohistochemical landscape of MCC is positive for MCV, observed in about 55% to 90% of cases. Interestingly, MCV-negative cases frequently demonstrated a lack of NF expression, and they distinctively exhibit markers of follicular stem cells along with a higher incidence of p53 positivity, which are predominant in CK20-negative MCCs. In patients with MCC overlapping BD, a distinctive dual pathology is often revealed through marker expression. The immunohistochemical signature of MCC is characterized by the concurrent expression of epithelial markers, including AE/1AE3, CAM5.2 and a broad spectrum of cytokeratins, alongside neuroendocrine markers such as neurofilaments and neuron-specific enolase. In contrast, BD typically demonstrates positive immunoreactivity for markers like CK7 and p16. Notably, an uncommon immunophenotype has been documented in a case merging MCC overlapping BD. In some cases, the MCC cells exhibited an absence of CK20 expression while maintaining positivity for CK7.

This diagnostic approach assumes critical importance in instances where MCC coexists with other tumors derived from epidermal origins. In conducting histological evaluations, it is imperative to scrutinize for the co-occurrence of other tumor types, such as SCC (observed in up to 15% of cases) or BCC. A critical aspect of the assessment is determining the extent of epithelial involvement by the tumor, whether the tumor cells are situated within the epidermis or affect the cutaneous adnexa. Furthermore, a detailed examination of the tumor's morphological attributes is essential, including discerning whether the tumor presents as infiltrative or manifests as well-defined nodular formations, alongside evaluating the dimensions (ranging from small to large) and the particular morphology of the cells, which can determine the appropriate treatment strategies and the prognosis of the tumors. The extent of invasion, growth patterns, and overall prognosis of MCC tumors exhibit significant interrelations (Gonzalez et al. 2022). Notably, patients exhibiting sentinel lymph node involvement typically will face a more challenging prognosis. Similarly, individuals suffering from active hematologic malignancies or under immunosuppression are also likely to experience adverse outcomes. Research on the differential prognosis or metastasis rates between MCC and MCC overlapping BD remains scarce. However, the co-occurrence of MCC overlapping BD may signal a broader spectrum of skin damage and an elevated risk of recurrence or metastasis.

The treatment of MCC overlapping BD adheres to the principles established for MCC treatment (Green et al. 2022; Harvey et al. 2022). In the management of MCC, surgical excision is often considered the primary modality of treatment. This involves employing techniques such as Mohs micrographic surgery or its modified forms, ensuring a margin of 1–2 cm extending to the fascia or periosteum (Uitentuis et al. 2022). For metastatic, post-surgical residual, or recurrent MCC, a combination of radiotherapy and chemotherapy serves as effective adjunctive treatment modalities. In recent advancements, immunotherapies targeting various anti-tumor immune mechanisms, particularly therapies focused on the PD-1 and PD-L1 pathways, have emerged as frontline treatments for metastatic MCC (Harms et al. 2018; Becker et al. 2018). Agents such as Avelumab, Pembrolizumab, and Nivolumab have been instrumental in significantly prolonging patient survival in these cases (Fojnica et al. 2023; Topalian et al. 2020).

The coexistence of MCC overlapping BD represents an exceedingly rare condition, necessitating further research and accumulation of cases to better comprehend its clinical characteristics and determine the optimal therapeutic regimen. It is a lesion with nonspecific features and dermoscopy evaluation can be helpful for improving the clinical suspicion. We introduce the concept of “AEIOUN” as a pioneering approach for the early identification of clinically suspicious lesions indicative of MCC overlapping BD. The excision of doubtful nodular lesions is mandatory especially in the elderly, because MCC overlapping BD has not only a tendency to recur locally, but it can also metastasize. However, due to its rarity, there are no well-defined guidelines for the management. Complete surgical excision with clear margins stands as the optimal therapeutic choice, complemented by adjuvant radiotherapy, chemotherapy, immunotherapy, or their combination. Regular follow-ups are strongly recommended to monitor the condition. These two case reports and the review of the literature can provide better awareness and management of this rare tumor.