13-year survival oligometastatic Merkel cell carcinoma: a case report

Abstract

Background

Merkel cell carcinomas are rare, aggressive skin tumors with high metastatic potential and poor prognosis. Their treatment is classically based on surgery with adjuvant external radiotherapy for localized tumors or on immunotherapy or chemotherapy, sometimes associated with radiotherapy, for metastatic stages. Those tumors are highly radiosensitive due to their neuroendocrine and undifferentiated nature, but they usually fail to rapidly respond to treatment.

Case presentation

We report the case of a 65-year-old retired female patient of Caucasian (German) origin with locally advanced Merkel cell carcinoma of the buttock, with pancreatic metastases synchronous at diagnosis, treated with local radiotherapy of the right buttock without regional lymph node irradiation followed by a sequential chemotherapy; 1 year later, the patient developed an isolated pancreatic recurrence treated with exclusive radiotherapy. The patient was still alive at 13 years with complete remission.

Conclusion

External radiotherapy can be an effective alternative to surgery for locally advanced or even oligometastatic Merkel cell carcinomas.

Introduction

Merkel cell carcinomas (MCC) are rare and aggressive cutaneous neuroendocrine tumors [1] caused by sunlight and immunosuppression [2, 3]. In the recent past, incidence rates of MCC have increased in the USA, Australia, and Europe, with an incidence rate of 0.79 per 100,000 in the USA [4]. In France, the incidence rate is approximately 0.25 per 100,000 and is increasing [5]. It occurs preferentially in male subjects over 65 years of age and is associated with Merkel polyomavirus [6,7,8]. The prognosis is directly correlated with the stage of the disease at diagnosis [9]. About one-third of patients present metastatic disease at the time of diagnosis or will develop metastases in the course of their disease. Prognosis is generally poor, with a 10-year survival rate of 50% for all stages [5]. Survival of metastatic disease patients has historically been poor, with a median survival of around 9 months. The natural history of the disease is characterized by rapid invasion of local lymph nodes and the early development of distant metastases. Clinically, the tumor usually enlarges rapidly, within a few months, and one-third of patients with MCC die from the disease. The therapeutic standard relies on initial surgical removal [6], followed by adjuvant external radiotherapy when the disease is local or locoregional [6, 10, 11]. In cases of locally advanced or metastatic disease, standard of care is then based on first-line immunotherapy [4, 12,13,14] or chemotherapy [10, 15, 16], eventually combined with radiotherapy.

We report the case of a patient with locally advanced Merkel cell carcinoma of the right buttock, with pancreatic metastases synchronous at diagnosis, treated with local radiotherapy of the right buttock without regional lymph node irradiation followed by sequential chemotherapy. Surgical removal was not indicated due to the metastatic stage of the disease and the extent of the initial lesion. The patient was still alive at 13 years with complete remission. The patient was treated before the emergence of anti-PDL1 and anti-PD1 immunotherapies, which have since strongly impacted the prognosis of this type of cancers. Their authorization for clinical use for Merkell cell carcinomas was given in 2017 in Europe.

Case presentation

Patient and history: a 65-year-old retired female patient with Caucasian (German) origin, phototype II, had as her only personal history an estimated active smoking habit of 25 pack-years, hypertension treated with hydrochlorothiazide/triamterene, and appendicitis. The patient was not considered to be immunosuppressed. She had no known allergies. At the family level, there was no known history of cancers.

Disease history and diagnosis: following a trauma in early 2011 (Table 1), the patient noticed the apparition of a large erythematous lesion on the right buttock, which grew rapidly and progressively until it reached a diameter of ~ 15 cm (Fig. 1). There was local warmth on palpation of the lesion, which was painless and did not itch. A biopsy of the lesion was then performed on 8 December 2011, and its histological analysis was in favor of cutaneous Merkel cell carcinoma. The patient underwent a staging workup: computed tomography (CT) chest-abdomen-pelvis scan, positron emission tomography (PET) scan, and magnetic resonance imaging (MRI) of the right buttock. Apart from the large tumor mass in the right buttock (Fig. 2), the initial workup revealed a tissue lesion of about 5 cm on the head and isthmus of the pancreas with partial portal thrombosis (Fig. 3). There were also right iliac and inguinal adenopathies and a nodular hypertrophy of the left adrenal gland. The disease was therefore at an advanced locoregional stage with pancreatic oligometastases (stage IV).

Table 1 Summary of disease history

Fig. 1

Indurated, inflammatory, erythematous, purplish skin lesion of the right buttock corresponding to a Merkel cell carcinoma at the diagnosis (2011)

Fig. 2

Initial chemotherapy pelvis scan showing a large necrotic skin lesion on the right buttock (blue arrow)

Fig. 3

Initial chemotherapy abdomen scan showing a mass of the pancreatic head and isthmus (blue arrow)

Therapeutic management: the case was discussed at a multidisciplinary meeting. A local radiotherapy followed by chemotherapy with carboplatin and etoposide were proposed. Surgical removal was not indicated due to the metastatic stage of the disease and the extent of the initial lesion. The patient thus received an external radiotherapy of the right buttock (without pancreatic irradiation) of 45 Gy in 15 fractions, 5 days out of 7, from 27 February 2012 to 20 March 2012, with a bolus of 6 mm thickness, in 3D CRT (conformal radiation therapy), with a usual margin around the GTV (Gross Tumor Volume) of 10–20 mm and around the CTV (Clinical Target Volume) of 5–7 mm, representing an ablative radiation dose in EQD2. Tolerance was acceptable, with a grade 2 radiodermatitis treated by local care. The patient subsequently received three cycles of carboplatin and etoposide chemotherapy, every 21 days, complicated by poor hematological tolerance with febrile neutropenia and Clostridium difficile colitis, which had a favorable outcome.

Follow-up: the imaging follow-up, performed in May 2012, showed a complete response with complete local regression and regression of the pancreatic tumor mass. Clinical surveillance was validated by a multidisciplinary meeting, and 3 months later a progressive recurrence of the pancreatic lesion, hypermetabolic on morpho PET scan, was observed.

New therapeutic management: an exclusive pancreatic radiotherapy was validated, delivering 30 Gy in 10 fractions, 4 days out of 7, in RT3D technique, from 26 September 2012 to 10 October 2012. A reduced-dose radiation was chosen to decrease the risk of digestive toxicity and was based on the metastatic nature of the disease. No systemic treatment (either chemotherapy or immunotherapy) was associated. Tolerance of treatment was mediocre with acute grade 2 gastrointestinal toxicities (nausea, vomiting), requiring the use of an intravenous antiemetic treatment and corticosteroids.

Continued follow-up: a complete response of the pancreatic tumor was observed following the radiation therapy. Since the end of treatment in 2012, no progression has been observed, neither clinically, nor on follow-up PET scans, both at the cutaneous and visceral levels. There was no recurrence of pancreatic metastases. Given the initial aggressiveness of the disease, monitoring continued on an annual basis for up to 10 years with annual PET scans. On local clinical examination, the patient presented a skin fibrosis with post-radiation telangiectasias and depigmentation of the right buttock, with no functional impact.

Discussion

This patient’s history is very remarkable, with a prolonged survival of 13 years after the initial diagnosis of the disease at an oligometastatic stage. Surgery was declined and treatment consisted of an initial locoregional radiotherapy initially followed by as sequential chemotherapy, which had to be stopped early because of hematological toxicities and poor clinical tolerance. Pancreatic radiotherapy was performed at a second time, after the discovery of pancreatic metastatic recurrences. Merkel cell carcinomas tend to quickly spread to lymph nodes and metastasize. Approximately 30% of patients have lymph node involvement and 10% have metastatic stages at the time of diagnosis [9, 17]. Median survival of patients with a metastatic disease is poor; ~ 9 months [2, 16, 18]. The standard treatment is an initial surgery for localized stages. However, those tumors present a radio- and chemosensitivity due to their neuroendocrine and undifferentiated nature [19]. This reported case highlights the effectiveness of an external radiotherapy since chemotherapy had to be stopped early. The patient first received an appropriate radiation dose of 45 Gy in 15 fractions in the right buttock, which is a curative dose, and then a dose of 30 Gy in 10 fractions in the pancreas, which is a reduce dose of radiotherapy. These two irradiation therapies allowed for an effective control of the disease, with complete remission. Some studies, cited in national and international recommendations, also indicated the efficiency and the benefit in terms of progression-free survival and overall survival rates of exclusive radiotherapy for advanced tumors or when a systematic treatment is not feasible due to poor general conditions and/or comorbidities [10, 15, 20]. However, dedicated trials are still lacking to formally recommend external radiation therapy for the treatment of oligometastatic Merkel cell carcinomas.

The hypothesis of a potential abscopal effect can be discussed in this case. This phenomenon, which is very rare in clinical practice, is described as the antitumor effect caused by radiotherapy outside the field of irradiation. The term abscopal was defined by Mole in 1953 as a tumor event occurring “at a distance from the irradiated volume but in the same organism” [21]. The mechanism is not completely understood. Radiotherapy is thought to induce an antitumor immune response. Radiation dose destroys local tumor cells, releasing tumor antigens that stimulate a systemic immune response capable of attacking tumors located elsewhere in the body. The radiotherapy would thus operate as a systemic chemotherapy or immunotherapy. In this case, we first observed a regression of non-irradiated metastatic pancreatic lesion at a distance from the primary site of irradiation, which was the right buttock. Although the abscopal effect is rare, there have been documented cases, particularly in patients with melanoma, lymphoma, and renal cell carcinoma, which are the disease entities traditionally considered immunogenic [21]. Studies are exploring the molecular and cellular mechanisms underpinning the abscopal effect. Insights into how different radiation doses, fractionation schedules, and combinations with immune modulators influence this effect are critical for optimizing therapeutic strategies [21].

In recent years, the development of anti-PDL1 (avelumab) [13, 22] and anti-PD1 (pembrolizumab) [23] immunotherapies has led to a significant improvement in the prognosis and survival of patients with metastatic Merkel cell carcinomas. It is currently recommended as the first-line therapy in metastatic diseases.

Conclusion

This case report highlights a remarkable 13-year survival of a patient with Merkel cell carcinoma following radiotherapy to both the primary site and a pancreatic metastasis. Exclusive external beam radiation therapy may be an effective alternative treatment to surgery for advanced or oligometastatic Merkel cell tumors, but further studies are still needed. Indeed, to date, there are no high-powered studies recommending an exclusive external beam radiation therapy for the treatment of oligometastatic Merkel cell carcinoma. The abscopal effect represents a fascinating intersection between radiotherapy and immunotherapy, highlighting the potential for systemic cancer control through localized treatment. Continued research is essential to harness this effect more consistently and effectively, potentially transforming the therapeutic landscape for metastatic cancers.