View of Merkel cell carcinoma – a challenging situation in a family medicine

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Franc Beigot – general medical practitioner, Selnica ob Dravi, Slovenia Correspondence/

Korespondenca:

Franc Beigot, e: amb.

selnica@siol.net Key words:

excision of skin tumor;

family medicine; Merkel cell cancer

Ključne besede:

izrez kožnega tumorja;

družinska medicina;

karcinom Merklovih celic Received: 7. 3. 2018 Accepted: 10. 11. 2019

10.6016/ZdravVestn.2823 doi

7.3.2018 date-received

10.11.2019 date-accepted

Oncology Onkologija discipline

Short scientific article Klinični primer article-type

Merkel cell carcinoma – a challenging situation

in a family medicine Karcinom Merklovih celic – izziv v ambulanti družinske medicine

article-title

Merkel cell carcinoma Karcinom Merklovih celic alt-title

excision of skin tumor, family medicine, Merkel

cell cancer izrez kožnega tumorja, družinska medicina, karci-

nom Merklovih celic

kwd-group The authors declare that there are no conflicts

of interest present. Avtorji so izjavili, da ne obstajajo nobeni

konkurenčni interesi. conflict

year volume first month last month first page last page

2020 89 1 2 85 91

name surname aff email

Franc Beigot 1 amb.selnica@siol.net

name surname aff

eng slo aff-id

Franc Beigot – general medical practitioner, Selnica ob Dravi, Slovenia

Franc Beigot – dejavnost splošne medicine, Selnica ob Dravi, Slovenija

1

Merkel cell carcinoma – a challenging situation in a family medicine

Karcinom Merklovih celic – izziv v ambulanti družinske medicine

Franc Beigot

Abstract

Background: Merkel cell carcinoma (MCC) is a rare, aggressive, and often lethal neuroendocrine skin cancer. It can clinically resemble a benign skin lesion. Merkel cell carcinoma removal in family medicine practice is not often reported in the literature.

Case report: This report describes the removal of Merkel cell carcinoma less than 1 cm of size on the right wrist of an 80-year-old woman, who was affected by stroke; the initial clinical impression of the lesion was consistent with an inflamed cyst.

Immediately after the incision, it became clear that this was a solid tumour, which was then com- pletely excised and sent to the pathologist. The result showed that this was MCC; however, the edges and the bottom of the tumour had not been radically excised from the healthy surround- ing tissue. The patient was immediately referred to an oncologist for further treatment, but she refused it. Four years and 9 months after the tumour removal, there are no clinical signs of local recurrence or signs of systemic progression.

Conclusion: A family doctor who works in remote rural areas will have to use their surgical skills more often than other doctors at the primary level. In addition, they can encounter rare and aggressive malignant skin tumours. The solution is to confirm the diagnosis by pathohistological examination, followed by interdisciplinary treatment.

Izvleček

Izhodišče: Karcinom Merklovih celic (MCC) je redek, agresiven in pogosto smrten nevroendokri- ni kožni karcinom. Klinično ga zlahka zamenjamo za benigno kožno tvorbo. V strokovni literaturi je zapis o odstranitvi karcinoma Merklovih celic v ambulanti družinske medicine redek.

Prikaz primera: Opisan je primer odstranitve karcinoma Merklovih celic velikosti slabega 1 cm pri 80-letni gospe, prizadeti po možganski kapi, ki je dajal klinični vtis vnete ciste. Takoj po vrezu je bilo jasno, da gre za solidni tumor, ki je bil nato v celoti izluščen in poslan patologu. Izvid je potrdil MCC, robovi in dno pa niso bili odstranjeni v zdravo tkivo. Bolnica je bila takoj poslana na nadaljnjo obravnavo k onkologu, a je tam odklonila vse nadaljnje posege. 4 leta in 9 mesecev po odstranitvi tumorja ni kliničnih znakov za lokalno ponovitev tumorja ali znakov o sistemskem napredovanju bolezni.

Zaključek: Zdravnik družinske medicine, ki dela na oddaljenih podeželskih območjih, mora pogosteje kot drugi zdravniki na primarni ravni uporabljati kirurške veščine. Pri tem lahko naleti celo na redke in agresivne maligne tumorje kože. Rešitev je potrditev diagnoze s patohistološko preiskavo in nato interdisciplinarna obravnava.

Slovenian Medical

Journal

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1 Introduction

Merkel cell carcinoma (MCC) is a rare, aggressive and often lethal neuroendocrine skin carcinoma (1,2,3). Merkel cells are neuroendocrine and mechanosensitive cells which participate in the transfer and modulation of gentle touch sensations as a cellular-neural complex. Transforming mechanical energy into electrical signals is the first step towards mechanotrans- duction in the peripheral sensory nervous system (4,5). The cells are located in the basal layer of the epithelium. Carcinoma of these cells were described by Torker in 1972 (6).

Merkel cell carcinoma is manifested as a fast growing, asymptomatic, red-blue dermal papule or nodule. It develops over weeks or months, and Merkel cell carcinoma is rarely suspected before a biopsy is completed. It can easily be mistaken for an epidermal cyst, an abscess or other benign skin tumours (Figure 1) (1,7,8,9,10).

Mortality with MCC is higher than with a malign melanoma (11). Tumour has a high risk of local reoccurrence. Me- dina-Franko et al., after a review of 1,024 MCC cases (after excluding patients with stage III distant metastases), found that with 30.1% of patients, a local relapse occurred during the monitoring period, and that in 55%, metastases in regional lymph nodes were already present at the examination or occurred during monitoring. The free interval of relapse was 4–10 months (2). More than 20% of patients already had stage II at the examination (tumour size between 2 and 5 cm) (2). 80–90% of re- lapses of the Merkel cell carcinoma occur during two years (3).

Figure 1: A Merkel cell carcinoma arising on the lower leg.

(Photo provided with permission from www.

merkelcell.org and dr. Paul Nghiem). Cite as/Citirajte kot: Beigot F. Merkel cell carcinoma – an unpleasant situation in a family medicine. Zdrav

Vestn. 2020;89(1–2):85–91.

DOI: https://doi.org/10.6016/ZdravVestn.2823

Merkel cell carcinoma occurs on the head and neck in 41–50% of cases, followed by the limbs (32–38%) and the tor- so (12–14%) (12). It most frequently occurs on parts of the skin that are exposed to the sun, with Caucasians, aged above 65 years (3). It is assumed that ultraviolet radiation which generates the DNA dam- age, and Merkel cell polyomavirus (MCV or MCPyV), are responsible for malignant cell transformation (13). On the northern hemisphere, 80% of malignant transfor- mations are believed to be the result of the Merkel cell polyomavirus, while the dam- age resulting from ultraviolet radiation is also a factor in MCV-negative tumours (13,14).

Merkel cell carcinoma requires a com- bination of therapies. It is treated surgically, with radiation and chemotherapy (1,3,10,15).

The core therapy of local MCC is a full surgical excision with adjuvant radiation therapy of this area (3,15). The scope of the excision depends on the size of the primary tumour. For tumours of up to 2 cm it is recommended that the excision edge should be at least 1 cm, while with those larger than 2 cm, it should be 2 cm (12,16).

Strub et al. recommend a secure resection edge on the face of at least 1,5 cm, and 3 cm for limbs (17).

Approximately 25–30% of patients without a clinically detected change in lymph nodes will have histologically positive lymph nodes (18,19). Clinical guidelines of the National Comprehensive Cancer Network (NCCN) recommend a biopsy of the sentinel lymph node, and,

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1 Introduction

Merkel cell carcinoma (MCC) is a rare, aggressive and often lethal neuroendocrine skin carcinoma (1,2,3). Merkel cells are neuroendocrine and mechanosensitive cells which participate in the transfer and modulation of gentle touch sensations as a cellular-neural complex. Transforming mechanical energy into electrical signals is the first step towards mechanotrans- duction in the peripheral sensory nervous system (4,5). The cells are located in the basal layer of the epithelium. Carcinoma of these cells were described by Torker in 1972 (6).

Merkel cell carcinoma is manifested as a fast growing, asymptomatic, red-blue dermal papule or nodule. It develops over weeks or months, and Merkel cell carcinoma is rarely suspected before a biopsy is completed. It can easily be mistaken for an epidermal cyst, an abscess or other benign skin tumours (Figure 1) (1,7,8,9,10).

Mortality with MCC is higher than with a malign melanoma (11). Tumour has a high risk of local reoccurrence. Me- dina-Franko et al., after a review of 1,024 MCC cases (after excluding patients with stage III distant metastases), found that with 30.1% of patients, a local relapse occurred during the monitoring period, and that in 55%, metastases in regional lymph nodes were already present at the examination or occurred during monitoring. The free interval of relapse was 4–10 months (2). More than 20% of patients already had stage II at the examination (tumour size between 2 and 5 cm) (2). 80–90% of re- lapses of the Merkel cell carcinoma occur during two years (3).

Figure 1: A Merkel cell carcinoma arising on the lower leg.

(Photo provided with permission from www.

merkelcell.org and dr. Paul Nghiem).

considering the results, a potential removal of regional lymph nodes and/or radiation therapy of regional lymph nodes.

Chemotherapy as an adjuvant therapy with a broad type of MCC has not prov- en to improve the survival rates of these persons. In the metastatic stadium of Merkel cell, the response to therapy is not long-lasting, only 3–8 months, with a relapse in 90% of patients within 10 months (20,21). Chemotherapy in the metastasis phase of the disease has the role of palli- ative therapy (3). Bergant, Hočevar and Čufer reported a good response of the therapy of a locally and regionally advanc- ing MCC in stage II with chemotherapy before the operation and an operation. In the regional hospital, MCC was mistaken- ly identified as a gluteal tumour. 2 and a half years after the first therapy, the patient showed no sign of MCC (10).

Merkel cell carcinoma is highly sensitive to radiation therapy (22,23,24). As a monotherapy, radiation therapy is an al- ternative method of treating the primary changes of MCC, especially in those cases where a surgical procedure is not possible, is declined by the patient or is

undesired (co-morbidity, non-functional MCC, in those cases where a bigger cos- metic or functional deficit can be expect- ed) (3,15,21,22). In their comparative and retrospective study (25 patients treated exclusively with radiotherapy) Pepe et al.

did not find a statistically significant dif- ference between patients who were treated conventionally (surgical procedure with adjuvant radiotherapy) and the patients who were treated only with radiotherapy, neither in the 5-year free interval, nor in the total rate of survival (23). Harrington and Kwan ascertained similar in their study of 179 MCC patients, 57 of whom were treated only with radical radiotherapy, while the others received radical surgical treatment (24).

The results of immunotherapy of virus-positive and virus-negative Merkel carcinoma are promising (MCPyV positive tumours express viral oncoproteins), as well as trials with monoclonal antibod- ies and studies following targeted molecu- lar therapy (somatostatin analogues, tyro- sine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors) (3).

Between 1994 and 2011, the Ljubljana Institute of Oncology treated 45 patients with Merkel cell carcinoma. Outside the Institute of Oncology 15 patients were op- erated on for the first time, and only with two of them the cut was wide enough, with resection edges into the healthy tissue (1).

The trend of non-melanoma cancers has been growing in Slovenia as well, by approximately 5.0% per year (25).

Merkel cell carcinoma is a very rare tumour, and even rarer are descriptions in professional literature of biopsy and removal of this tumour in family medical practices. In 2008, Zucchi, a family doctor in a remote French town, conducted a biopsy of the tumour and after receiving histological results, cut out the Merkel cell carcinoma. He mentions that this was probably the first case of discovering and treating MCC at the primary level in France (26).

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2 Case study

In December 2013, an 80-year old woman came by the outpatient clinic because of a “outgrowth” on the back of her right arm, which she noticed 14 days earli- er. She said that the skin anomaly is growing fast but does not open. The woman was in a wheelchair because of left hemi- plegia and contractions following a stroke 16 years prior. She wished to have the procedure conducted in the outpatient clinic.

The examination showed that the dor- sal side of her right wrist had a round, soft, non-painful papule, in the size of just un- der one centimetre, pinkish-red in colour.

The working diagnosis was cystis inflam- mata carpi dex susp., and we prepared the patient for the surgical procedure. Imme- diately after the incision into the tissue, it became clear that it was not an inflamed cyst, but a solid, soft tissue, which differs from a lipoma in colour and consistency.

We decided to fully remove the tumour.

We surgically closed the wound with su- tures and sent the excised material to the

Department of Pathology of the Universi- ty Medical Centre Maribor (UKC MB).

On the eight day, we removed the su- tures. On the thirteenth day after the excision of the tumour, we received the pathology results, which described an oval-shaped piece of skin, 1.5 × 1 cm in size, with the opinion that it was a Merkel cell carcinoma. There was no description whether the excision was also made into the healthy tissue. We immediately in- formed the patient of the tumour’s nature and referred her to a surgeon for plastic surgery at UKC MB. He decided to inform the woman about further therapy once the histology report was revised. Three weeks later, she was examined at the Ljubljana Institute of Oncology, where they advised her to have another excision and a biopsy of the sentinel lymph node, considering the histology report. In the meantime, we received an addendum to the histology results, establishing that the edges and the bottom of the excision did not include healthy edges. The woman was summoned to the agreed-upon surgical procedure two weeks after the examination; however, she rejected it, as well as all other measures and controls.

The patient is monitored at her home.

Today, 4 years and 9 months after the tumour removal, there are no clinical signs of a local resurgence of the carcinoma, nor any signs of increased regional lymph nodes or other signs that would point to a potential progression of the disease (Fig- ure 2).

3 Discussion

There is no reliable data on how many family medicine doctors in Slovenia also perform minor surgical procedures. Ac- cording to my estimates, there are very few in urban areas, but more can be found in rural areas.

This includes surgical procedures that family medicine doctors can perform with basic surgical skills, as well as minor surgical procedures listed in Table 1, as defined Figure 2: 4 years and 9 months after removal

of the skin tumour.

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by the Association of Surgeons in Primary Care (Table 1) (27).

It is clear that doctors of family medicine decide to remove skin anomalies only in cases where their clinical assessment makes it certain that the formations are benign. However, the Merkel cell carcinoma is an exception, as even a very expe- rienced clinical doctor can mistake it for an inflamed cyst or another benign skin tumour.

Heat et al. established, based on a sam- Table 1: Procedures suitable for community surgery (Dhumale R, 2016, personal

communication, cit. Marsden J, Lipp A, Kumar V) (27).

Layer 1: Surgical procedures that family medicine doctors can complete with basic surgical skills, as minor surgical procedure or in the room for procedures.

• sebaceous cyst

• lipoma, smaller than 2 cm

• ingrown toenail

• excision of small solid lumps

• chalazions

• injections into joints and bursas

• cryotherapy

• cys aspiration

Layer 2: Surgical procedures that specialists or family medicine doctors can complete with special surgical skills, in an adapted room for procedures, or an operating room.

• vasectomy

• carpal canal decompression

• ganglion of the wrist (dorsum)

• Zadek’s procedure for full toenail ablation

• varicose vein ligation

• haemorrhoid injection

• sigmoidoscopy

• gastroscopy

• cystoscopy

• caudal blockade

ple of 195 patients with Merkel cell carcinoma, that the clinical impression of the tumour is very diverse when the biopsy is made: 32% defined it as a cyst or an acne, 6% as a lipoma, 4% as a dermatofibroma, 4% as a vascular change, 3% as an insect bite, and 7% as a different kind of benign change or similar. 19% defined it as skin carcinoma, and 6% for lymphoma. Only in 1% of cases, the suspicion of Merkel cell carcinoma was given before the biopsy (8).

Additional danger is hidden in the fact that family medicine clinics only send samples that are assessed as suspicious for histology examination.

Buis et al. estimate that only approximately 60% of skin tumours removed by family medicine doctors in The Nether- lands are sent for a pathology examination. And that is not all. From all the samples, they selected 90 that did not include the skin, but only the subcutaneous tis- sues, and it turned out that two were malign: the first was Merkel cell carcinoma, clinically submitted as a lipoma, and the second one a dermatofibrosarcoma protu- berans, submitted as sebaceous cyst. Both required another excision. Both malignant tumours were unexpected (positive fore- cast value of 0). However, according to the findings from Buis at al., family medicine doctors are not the only ones to make this mistake. Dermatologists, plastic surgeons, and other doctors face the exact same is- sues.

I believe that the share of removed skin tumours in family medicine clinics sent for a histology examination is even smaller than what Buis et al. estimate for The Netherlands. This is partially also because costs of a histology examination are covered directly from the clinic’s material costs, and not as separately chargeable material or as costs for laboratory services.

The price of this histology examination was EUR 569.72 in December 2013. On- ly at a later date did the Health Insurance of the Republic of Slovenia (ZZZS) add histology examinations among separately chargeable material.

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4 Conclusion

Family medicine doctors who work in remote rural areas know how to use their surgical skills, and also use them more frequently than their colleagues in family medicine. This brings forth the risk of finding rare and malignant tumours.

It should be emphasized that a histopa- thology examination of removed tissue in a family medicine doctor’s clinic is always required for papules and tumour skin el- evations, especially when they change in shape, size and colour. If the histopathol- ogy examination detects a malignant tumour, the patient is immediately referred

for interdisciplinary treatment, and in the case of Merkel cell carcinoma, also to an oncologist to plan the therapy and provide guidance.

A family medicine doctor will be the first to encounter Merkel cell carcinoma, so they should keep it in their minds. In all unclear cases, the patient should be referred to a dermatologist.

5 Acknowledgment

I hereby thank the patient for her writ- ten approval of publishing this case, in- cluding the images.

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