Decision making in Merkel cell carcinoma – surgical oncologist point of view

Introduction

In comparison with other skin malignancies, Merkel cell carcinoma (MCC) is a lesser-known form of cancer than melanoma, although it has a higher mortality rate, with one in three diagnosed patients dying. Everyone has heard nowadays of malignant melanoma, but it is only the result of 300 years since the first report, and of sustained efforts to publicize the disease. The survival at 10 years comparing the two types of cancer was previously mentioned by the published studies to be lower in MCC compared to malignant melanoma, 17.7% versus 61.3%, according to the California Cancer Registry⁽¹⁾.

Regarding a recent skin cancers research publication in JAMA Dermatology, there were found higher rates of recurrence for patients treated for Merkel cell carcinoma than for those treated for melanoma and other cutaneous cancers, an approximately 40% recurrence rate^(2,8) at five years. In this cohort study, including more than 600 patients, almost all recurrences were detected in the first three years, making them to conclude about the importance of careful supervision during this period.

The treatment of Merkel’s carcinoma has been completely revolutionized over the past five years by the introduction of targeted molecular therapies that have successfully replaced chemotherapy. The only constant with curative visa remains surgery, and scientific studies considered the wide excision to be the gold standard⁽³⁾.

Not rarely, due to its clinical harmless appearance, the neuroendocrine cutaneous cancer predisposes to local excisions that are not given importance, both by patients and doctors, unfamiliar with such a rare disease^(4,5). Therefore, the diagnosis is made late, in the presence of metastases, and we are losing the start in the fight against a relentless disease.

It is the merit of the acronym AEIOU⁽⁶⁾ that has reached its goal of raising awareness among the population and, at the same time, equally important, among the specialists in the field. As a consequence of it, by increasing the diagnosis, the incidence has also increased.

As we well know, oncological patients rarely fit the rigid criteria of oncological protocols, whose role is only to guide the treatment plan. The responsibility of adapting it to the patient belongs to the multidisciplinary team. The surgeon leads the tumor board, being the one who diagnoses the cancer, with great expertise in clinical surgical scenarios. Furthermore, he is the trigger of this complex process of cancer treatment, because once the biopsy is done, the patient will later be directed to treatment. To know when a biopsy must be taken, from where and how to do this, is not always as obvious as it might seem, especially when the cancer clinically appears to be benign, as in the case of Merkel cell carcinoma.

 In this paper, we propose to recall the role of the surgeon in the treatment of neuroendocrine carcinoma of the skin, as it has been reported a widely increase in incidence among non-Hispanic whites, particularly men, up to 50 years old. We also propose to discuss the key points of diagnosis and the difficulties encountered in the surgical treatment.

Materials and method

Because we have recently faced an increase in the number of patients with Merkel cell carcinoma referred to our clinic, we proposed to deepen our knowledge in the field and draw conclusions regarding the surgical approach of MCC, especially the per primam one.

We conducted a literature review for the last five years, from January 2017 to September 2022, searching for PubMed relevant publications regarding Merkel cell carcinoma, or neuroendocrine cutaneous cancer, or trabecular cancer of the skin, as it is otherwise known in literature, since 1972, when Toker⁽⁷⁾ introduced the term for the first time.

A total of 799 results were identified from the initial PubMed search in this field, so we added another secondary selection criterion by using the terms “treatment” and “surgical excision”. Finally, only 44 articles were included, without classifying them according to a specific criterion, but excluding those not written in English. We also consulted additional appropriate articles selected from the references.

Results

Since all patients with Merkel cell carcinoma who came to our clinic for treatment also needed radical lymphadenectomy, several latest studies in the literature analyzing this specific problem caught our attention.

An important percentage of patients present themselves in an advanced stage, with nodal or metastatic dissemination from the moment of diagnosis, according to the statistics reported by several studies, this percentage reaching 40%^(2,4). And among those who are in an early clinical stage at the onset, through the sentinel lymph node (SLN) technique, a statistically significant group of patients with nodal micrometastases are identified and recruited.

In the first study, Cramer et al.⁽⁹⁾ analyzed 447 positive sentinel lymph node patients who underwent four different therapeutic approaches after excision of the positive SLN: 71 patients went for surveillance, 64 underwent complete lymph node dissection (CLND), 216 received adjuvant radiotherapy, and in 96 of the patients both complete lymph node dissection and subsequent adjuvant radiotherapy (RT) were performed. The results showed that complete lymphadenectomy alone without the addition of radiotherapy did not improve overall survival, but had better outcomes than the choice of surveillance after positive sentinel node identification. 

The second study, of Perez et al.⁽¹⁰⁾, evaluated 71 patients with positive sentinel lymph node biopsy (SLNB), where 11 patients (15.5%) underwent CLND, 40 (56.3%) received radiation, and 20 patients (28.2%) underwent CLND plus postoperative radiation. The outcomes were favorable in all types of treatment, with low morbidity and also with a low regional failure. Other risk factors may be taken into consideration for a more refined differentiation. In the third article, Lee et al.⁽¹¹⁾ also compared 163 positive SLN patients who underwent CLND (n=137) or RT (n=26). Median follow-up was 1.9 years. In patients in whom complete lymph node dissection was performed, after the identification and excision of the sentinel lymph node, an increase in survival at 5 years was observed, this being 71% compared to 64% in those who received only adjuvant radiotherapy after the identification of the sentinel lymph node, but without statistical significance (p=1.0). Also similar results for DFS (52% versus 61%; p=0.8), NRFS (76% versus 91%; p=0.3), or DRFS (65% versus 75%; p=0.3) were mentioned.

The fourth study, of Sims et al.⁽¹²⁾, revealed that adjuvant radiotherapy succeeded in canceling the risk given by positive SLNB, giving patients equal chances of survival compared with those SLNB negative. The research conducted by Cheraghlou et al.⁽¹³⁾ revealed better outcomes when surgery and adjuvant chemoradiation therapy were associated, with improved survival than with surgery or adjuvant radiation therapy alone. For lymph node-positive MCC, a new prognostic factor was measured, called Lymph Node Ratio (LNR)⁽¹³⁾, in order to give a potential prognostic. This demonstrated to be an usefully treatment planning and follow-up after surgery. The last study, of Lamberti et al.⁽¹⁴⁾, observed that adjuvant radiotherapy seems to have no benefit in T4 patients and in those with positive lymph node (Table 1)^(9-14).

Regarding the aggressiveness of Merkel cell carcinoma, which relies on its ability to metastasize early in almost any organ, the liver and the lungs are the preferred sites for metastasis in solid organs, as many authors observed⁽⁴⁾.

Overall, it was observed that MCC has a poorer prognosis due to the fact that patients initially present at a more advanced stage, with metastases, in a higher percentage than those with malignant melanoma⁽⁸⁾. In terms of body distribution, in statistic reports it appears more frequently on the head and neck, and on extremities, while malignant melanoma has a predilection for the trunk⁽¹⁾. Only a few data in literature are discussing rare locations of Merkel cell carcinoma. In supporting the data from literature, we aim to address several aspects of one of the our most challenging cases of Merkel cell carcinoma, both regarding treatment and diagnosis, with aggressive behavior but with good response in maximal multimodal therapy (Figures 1, 2, 3, 4 and 5 illustrate tomography and intraoperative images from an unusual case of groin Merkel cell carcinoma).

Postoperatively, the pathologic result was pT4N1, with intravascular lymphatic invasion present, Ki-67 positive 98%.

From the point of view of the surgical approach, we have two therapeutic options: Mohs micrographic surgery^(15,16) and radical surgery of the wide local excision⁽²²⁾ type, both in circumference and in depth, excising the fascia.

In both cases, the results are good, and safety margins not invaded by tumor are obtained. The decision to perform one in favor of the other must be carefully planned according to the anatomical site distribution, and could require multidisciplinary approach, both general and plastic surgery^(16,17).

Mohs micrographic surgery⁽¹⁵⁾ is preferable in the case of tumor locations on the head where the cosmetic factor is extremely important and saves the skin, with the inconvenience that the sentinel ganglion technique must be performed first by a surgeon with oncological surgery skills, which complicates the patient’s path.

The sentinel ganglion technique must be performed before the wide excision of the tumor, when the lymphatic drainage channels have not been sectioned yet⁽¹²⁾. Most of the time, it is followed by adjuvant radiotherapy on the regional lymph nodes. By that, sentinel lymph node dissection (SLND) leads to the diagnosis of some cases in the early stages and increases the overall survival (OS).

Nodal metastases are the most common, depending on the location, raising difficulties in the surgical approach, but once addressed and excised, improve the patient’s prognosis^(18,19).

Even in the case of small tumors where Mohs surgery solves the excision of the primary tumor, a systematic evaluation of all ganglion groups must be done, starting with the neighboring ones, of course, and with the clinical examination through a careful palpation⁽²⁰⁾.

Later, ultrasonography completes the evaluation. More importantly, in the absence of palpable or imaging-detected regional lymphadenopathy, the sentinel lymph node technique will be used, the studies performed demonstrating the effectiveness of the technique in detecting lymph node occult micrometastases⁽²¹⁾. Both radiotherapy and radical lymph node dissection have proven useful in increasing survival and local and distant nodal recurrences, after SLNB was performed⁽²²⁾. Depending on the skin tumor location, lymph node dissection involves the risks of vascular, nerve or ureters damage⁽²³⁾. In such circumstances, there is required an increase expertise, and patients must be referred to a specialized center or to an experienced dedicated surgeon.

Severe preexisting conditions of the patient may pose challenges for both postoperative evolution and oncological outcome^(23,24).

There were surgeons who also considered the laparoscopic or the robotic approach regarding inguinal and ilio-obturatory lymphadenectomy. This was taken into account for a faster postoperative recovery and for smal­ler incisions in an area with a high risk of contamination.

The largest first single institutional experience in treating MCC is from Memorial Sloan Kettering in which the specialists treated 250 patients over 30 years. They performed radical lymphadenectomy or sentinel lymph nodes in patients who clinically had no evidence of lymph node invasion, and found a high percentage of positive nodes in 16 out of 70 patients, which represented 23%, thus demonstrating the ease with which MCC can be substaged⁽²⁵⁾.

Discussion

Regarding pathogenesis, two major pathways are known in the oncogenesis of Merkel cell carcinoma: one is exposure to ultraviolet radiation, the other one, which represents 80%, involving the Merkel cell polyomavirus^(26-28). Although the Merkel cell polyomavirus carcinoma seems to be part of the skin microbiota, the colonization occurs in children from the first months of life, especially after they are no longer protected by the mother’s antibodies⁽²⁷⁾. The promoter factor of tumor genesis is not yet known, and a vaccine for this has not yet been developed. Being a ubiquitous virus, cancer recurrence prophylaxis is rather aimed at improving immunocompetence and at avoiding exposure to ultraviolet rays, and also at educating the population to see a doctor when they notice suggestive skin changes⁽²⁹⁾.

Even in the case of small tumors where Mohs surgery solves the excision of the primary tumor, we must be prepared to do skin flaps because the location involves most of the time the areas with inextensible skin, such as the leg⁽³⁰⁾ or the front arm. Also, because of the tumor size and after a wide excision, surgical closure may need a skin graft, and this may later influence the adjuvant layering.

Thus, if there is agreement for adjuvant radiother­apy^(30,31) treatment to be done within eight weeks after surgery, we have to consider that a skin flap may delay the radiation therapy.

The key to therapeutic success is an early diagnosis that allows radical surgery. The laparoscopic approach may represent an alternative and decreases the risk of dehiscence, related to persistent lymphorrhea, especially in the inguinal fold.

The high costs and the low incidence of cases do not allow for the refinement of the technique, nor the learning curve, perhaps only for surgeons who are already familiar with lymphadenectomy in urogenital, vulvar^(30,32) or penian cancers. Particularly the comorbidities of elderly patients and biological parameters are some of the contraindications of general anesthesia. That’s what makes the technique rather suitable for early cases with micrometastases or for diagnostic, prophylactic purposes⁽³³⁾.

Otherwise, for advanced stages with voluminous lymph nodes adhering to the vessels, it becomes risky and the choice is not justified.

Merkel carcinoma surgery is a surgery of the lymphatic territory, therefore for the head and neck locations a modified laterocervical lymphadenectomy must be performed, a three-level axillary lymphadenectomy for upper arms located tumors and inguinal iliac and obturator lymphadenectomy for those located in the lower limbs^(31,33).

The surgeon’s role in the treatment of Merkel cell carcinoma is essential, from diagnosis to palliative care⁽³³⁾.

A high risk of relapse is reported, as well as metastasis, usually happening in the first two years after diagnosis^(34-37).

Although immunotherapy has encouraging results, there are studies that observed a weak response to immunotherapy for specific locations of metastases, namely a resistance to those metastases disseminated at the cerebral and testicular level, because they become inaccessible to the host’s immune defense system or to systemic therapy. Some authors believe there are being protected in the so-called “sanctuary”⁽³⁸⁾ locations, by the blood-encephalic barrier and, respectively, the blood testicular network.

Lately, great strides have been made in the field of immunotherapy⁽³⁹⁾, and the use of anti-PD-(L)1 inhibitors registered a high therapeutic success in the metastatic stages of Merkel carcinoma, but a significant number of patients still develop resistance or do not effectively respond to therapy. Since it is known that 80% of Merkel cell cancer cases in the USA are positive for the Merkel cell polyomavirus, the use of vaccines in the fight against the disease, especially after the therapeutic success obtained in other cancers, such as cervical cancer, led to research in the field.

The small number of cases worldwide does not justify the costs of research and the production of a vaccine in this regard. Thus, a preventive vaccine for MCPyV is likely not cost-effective, but a therapeutic vaccine could be very useful for the population affected by the disease and especially in the prevention of recurrence which is quite high, between 25% and 75% in the USA⁽³⁸⁾.

Both CT and PET-CT are used as staging tools. It’s already been five years since chemotherapy is no longer the first line of treatment in metastatic Merkel cell carcinoma, being the backup solution for cases that do not respond to immunotherapy, or when the patients do not tolerate it and have adverse reactions. Other contraindications to immunotherapy are the personal history of solid organ transplantation and the autoimmune diseases.

Regarding the etiology of cancer, two forms are described: virus positive (VP-MCC) and virus-negative (VNMCC), with a more favorable prognosis for the first category in terms of response to treatment⁽³⁷⁾.

Initially introduced in the second line of treatment, avelumab increased the overall survival which doubled from six to approximately 12 months, being relati­vely well tolerated by patients, without major adverse reactions⁽³⁹⁾.

Also, a better response was observed in naive patients, who had not previously received chemotherapy, an effect explained by the immunosuppressive action of chemotherapy drugs. However, approximately half of the patients do not respond to immunotherapy, regardless of the presence of the polyomavirus⁽²⁾. In single fractionated doses (SFRT), radiotherapy can be used as an immunostimulant. There are studies supporting the titers of T oncoprotein and MCPyV oncoprotein for monitoring patients after treatment, elevated levels of these biomarkers suggesting relapse and requiring an earlier clinical imaging evaluation^(40,41).

Conclusions

Surgery is basic and the earlier it is applied for the first curative intention, the better the rest of the multimodal treatments manage to keep the disease under control. Radiotherapy alone did not give good results, even though Merkel cell carcinoma is highly radiosensitive, but must come in addition to surgery.

The resectability should be assessed by experienced surgeons, taking into account the risks versus the benefits, the patient’s desire and consent, always reminding the segment of affected patients – elderly or immunocompromised.

Salvage surgery with excision of single metastases followed by immunotherapy significantly prolongs survival in advanced stages for well selected patients.

Efforts should be directed towards primary diagnosis, this being the only one capable of ensuring the long-term survival.

New instruments of predicting the response to adjuvant therapy after positive SNLD are ongoing to be developed in further research. Until then, lymph node ratio (LNR) will prove its usefulness. 
 

Conflict of interest: none declared

Financial support: none declared

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