Merkel Cell Tumour:Multifaceted Presentation

Abstract

Merkel Cell Tumour  is a very rare tumour. Just over 300  cases have been described in literature. The author have come across nine such cases in the two years one of which is the first reported on  Afro-Carribean.. Usually it is a mistaken diagnosis onlyto be confirmed by histology. The authors here describe  the nine  cases delving into the discussion about the tumour including its high agressive nature. Its varied presentation sometimes results in mistaken or late diagnosis and therby delay in appropriate treatment

Introduction

Merkel cell tumour (MCT), considered by some as the most malig­nant primary skin tumour, is a neuroendocrine neoplasm found in the dermis and extremely aggressive if not treated early. There are just over 300 cases reported since first described in 1972 as trabecular carcinoma. Its diagnosis has been difficult, usually reported as a poorly differentiated or anaplastic carci­noma but electron microscopy and immunohistochemistry have made it easier to identify.

MCT affects mainly elderly Caucasians in the head and neck region as well as in the limbs. We have reviewed the literature on this tumour and present 9 cases, one of which is the first reported on an Afro-Caribbean.

MethodologyThis study involves cases presented to Nottingham Group of Hospitals, i.e City Hospital and Queens Medical Centre between 1990 and early 1994.
 

Case Reports

Case 1:

An 88 year old female presented to the Dermatologists in July 1990 with a two year history of a small fleshy lesion on the anterior chest wall which occasionally bled. An excision biopsy revealed MCT. She was referred to us three months later with a local recurrence. On examination, a lump was felt at the previous excision site but there were no palpable regional lymph glands. A wide excision and split skin graft were performed. A further three months later she presented with two local recurrences and palpable bilateral axillary lymph nodes. Wide excisions and bilateral axillary dissections were performed followed by radio­therapy. Five months later she developed a tumour at the angle of her left jaw. In view of the aggressive nature of the disease a decision against further surgery was made. The patient died six months later.

Case 2:

An 82 year old female presented to her General Practitioner (GP) in July 1991 with a fleshy lesion on the left shin which she noticed a few months before following an injury to her leg. A curette biopsy carried out by the GP was reported as malignant melanoma and the patient was referred to the Plastic surgery department. On examination no palpable inguinal lymph nodes were felt. A wide excision with a 3 cm clearance margin was performed. The histology of this specimen along with review of the previous biopsy revealed a final diagnosis of MCT. Postoperative radio­therapy was administered. She was recently reviewed in clinic and remains free of recurrence.

Case 3 :

 A 78 year old female was referred to the Plastic Surgery team from the Accident & Emergency (A&E) Department in December 1992 with a lesion on the right side of her neck. It had appeared two years before but had grown rapidly and fungated in the past days. Examination revealed a firm fleshy lesion measuring 4 cms in diameter with surface ulceration. On palpation, a cervical and a preparotid lymph nodes were felt. An incisional biopsy performed revealed a highly anaplastic Merkel cell tumour. This proved to be very aggressive and within days multiple metastatic lesions appeared on the same side of her face,  deforming it and paraly­sing the right facial nerve. In view of the rapid progression of the disease and in consultation with the Oncologist it was decid­ed that the condition was beyond radiotherapy. The patient was commenced on palliative oral chemotherapy, but she continued to deteriorate rapidly dying five weeks after admission.

Case 4:

A 63 year old male of Afro-Caribbean origin initially present­ed to the A&E Department in August 1992 with a small lump on the left anterior thigh of one year duration. A biopsy performed revealed a highly malignant anaplastic small cell carcinoma of Merkel cell origin. He was referred to the Plastic Surgery team. On examination, a large lump on the previous biopsy site and palpable left inguinal nodes were noted. Wide excision with 3cm clearance margin and a left inguinal block dissection were carried out. The patient received postoperative radical radio­therapy and seen recently in clinic remains free of recurrence.

Case 5:

 A 77 year old female was seen by the Dermatologists in Febru­ary 1985 with a 6 week old rapidly growing  purple nodule on her right forehead. Biopsy-excision confirmed it to be MCT, invading subcutaneous tissues. Despite excision being incomplete (deep margin) no further action was taken. She presented 18 months later to the ENT department with a palpable mass in her right parotid area. A superficial parotidectomy was performed and the  histolo­gy showed it to be a metastasis of the initial MCT but she received no additional treatment. She remained asymptomatic until her death in 1989 of unrelated causes.

Case 6:

A 76 year old male in July 1990, during a routine follow-up after vascular surgery, was noted to have a 2x3 cm purple pedun­culated nodule on his right calf and a 4x5 cm firm lump in the ipsilateral groin. He admitted to have discovered them 3 months and 2 weeks before, respectively. He underwent excision of both tumours and grafting of the calf. Merkel cell tumour was the final diagnosis but no further treatment was administered. He has been seen recently in clinic with no sign of recurrence or metas­tasis.

Case 7:

A 75 year old gentleman was referred in March 1988 to the dermatologist with a cherry-like, non-tender smooth nodule firmly attached to his lower lip. It had grown rapidly in the previous 3 months. An incisional biopsy confirmed it to be MCT and he under­went radiotherapy with resolution of the tumour. He was unfortu­nately  admitted  6 months later with disseminated metastasis dying within days.

Case 8:

A 69 year old female in July 1990 underwent excision and direct closure of a small lesion on her right upper cheek. No other symptoms nor signs were noted. The lesion had grown slowly during the previous 9 months. Histology confirmed it to be an MCT, completely excised. No further action was taken. She has been seen by her GP recently and remains free of recurrence.

Case 9:

A 67 year old male in April 1992 was seen by the Dermatolo­gists with a gradually increasing 4 month old 3.5cm in diameter lesion on his right forearm. An initial diagnosis of haemangio­sarcoma was made. He was referred to our team and subsequently underwent excision of the tumour one month later. Histology confirmed it to be MCT, but complete excision of the deep margin could not be assured. No further action was taken but in a regu­lar follow-up 6 months later he presented with a right axillary mass. Block dissection in January 1993 confirmed it as metastasis of the first tumour. Treated with radiotherapy in March 1993, he remains free of recurrence when last seen in July 1993.

Discussion

In 1875, experimenting with osmium tetroxide staining on the skin of the nose of  a mole,  Merkel described epidermal  cells that functioned as an end organ for touch sensation. These were later discovered in human skin and are now regarded as slowly adapting type 1 mechanoreceptors23. Histologically, they are clear cells of the basal layer of the epidermis (dermal cells have also been described) closely related to processes of nerve fibres. They are distributed all around the body including gingiva and palate, being the richest source being the skin in the neck and abdomen 21.

Merkel cell tumour, considered by some as the most malignant primary skin tumour 2, invades subcutaneous tissue and spreads via both permeation of cutaneous as well as deep lymphatics. Hence its high rate of recurrence 1,2 and capability of distant metastases.

It is an uncommon tumour, first described by Toker 20 in 1972 as  trabecular carcinoma, because of its histological appearance.  Less than 300 cases had been reported by 1990, when Shaw and Rumball 15 established a database after reviewing 30 reports on MCT in order to define the biology, prognostic factors and opti­mal management of this tumour. Since then, few more cases have been reported, but based upon our experience we wonder how many have been misdiagnosed or not considered worthy of publication.

MCT frequently presents as a 6-24 month old small (1-3cm) pain­less subcutaneous lump, with intact epithelium but ulcerated in advanced cases; brown, blue or red-purple in colour, sited on the face mainly but also affecting  the neck or extremities. Fifty per cent of patients may have positive nodes at presentation 13. Although most cases have been described in Caucasians in their 7th decade of life, it can affect younger patients 2, other sites and rarely other races. One Polynesian 15, four East- Asiatics 12  and our 4th case in an Afro-Caribbean are the only reported exceptions we are aware of. Fewer MCTs have been found in the trunk and buttocks 15,16,20,21 mounting up to a total of 17 including our 1st case in the chest. Ten per cent of MCTs, ac­cording to some studies, take place in the eyelid 22.

MCT may rarely mimic benign conditions like a chalazion 22, but it is mainly other neoplasms it has been confused with such as basal cell carcinoma 11, squamous cell carcinoma 12, malig­nant melanoma, lymphoid infiltrates (particularly if fixation is poor)5,18,  sweat gland tumours, neuroblastoma, Ewing's sarcoma and metastatic small cell (oat cell) carcinoma 16,21. Indeed the latter cannot be reliably distinguished from MCT on histolog­ical, ultra structural or immunohistochemical grounds and can only be excluded on clinical examination. An association between MCT and squamous cell carcinoma has been reported and Gómez et al. record 11 of 32 patients with MCT who had previous or concomitant squamous cell carcinoma 6.

None of the tumours presented here were recognised at primary clinical examination and in all cases the diagnosis was made histologically. The histological characterestics are described with reference to Case 2 described before in the figure legends. A variety of histological features may be seen in MCT including a trabecular pattern, pseudo rosettes, sheets or solid nests of cells (Figure 1).  A mixture of larger pale-staining vesicular nuclei and smaller hyperchromatic nuclei of tumour cells with nuclear moulding is often seen. Mitoses are prominent. Electron microscopy and immunohistochemistry is required to make a defi­nite diagnosis. Electron microscopy shows peripherally situated, membrane bound dense core neurosecretory granules (Figure 2), complex intercellular junctions, prominent Golgi apparatus, varying num­bers of mitochondria and rough endoplasmic reticulum; appearances similar to those seen in normal Merkel cells 3,10,16,18. Posi­tive labelling with neuron specific enolase (NSE) and antibodies to neurofilaments may be present and paranuclear clumps of posi­tivity with antibodies to cytokeratins are also seen 3,9,17,24,25  (Figure 3). Neuroendocrine markers as synaptophysin 27 and chromatogranin A  26,27,28 have superseded now the the NES.

Many Merkel cell tumours have been seen to be radioresponsive as well as chemosensitive 24. The treatment advocated by most comprises wide surgical excision combined with block dissection of the local lymph nodes if necessary followed by post-operative radiotherapy, especially in these node positive patients 2,7. However, cases of dramatic response to radical radiotherapy alone as treatment or palliation have been described 4,7,11,13. The role of chemotherapy has yet to be established. Few cases have proven to be effective as first-line treatment, but success has been reported in recurrences despite of repeated surgery combined with radiotherapy 1 or in the case of advanced disease. 2, 24

Local recurrences are found in around 40-54% of patients 2,7,14, 15,  most presenting within 12 months of primary treatment. Metastasis, after primary treatment, will appear in 25-50% of cases affecting sites such as skin, bone, brain, orbit, extradur­al space, retroperitoneum 2,8,25 or tissues like tonsil 19 or parotid gland, like in our Case 5.

The prognostic factors of MCT are similar to those in malignant melanoma. 15. The presence of lymph nodes, systemic disease, central site (trunk, face, neck) and/or loco regional disease carry bad progno­sis. Spontaneous remission has been described 2, but ultimately the behaviour of this tumour cannot be predicted. Age and condition of the patient, depth of invasion are other factors to take into account. Incomplete excision , usually deep margin, requires further surgery should one want to improve the probability of success.

Conclusion

Merkel cell tumour is an aggressive carcinoma of the skin with high rate of recurrence and metastasis. The best results are achieved in those patients with complete excision of the tumour, followed by radiotherapy. Chemotherapy or radical radiotherapy as primary treatment need to be looked into and more studies should be conducted for this purpose.

Figure Legends

FIGURE 1:  Merkel Cell Tumour composed of sheets of tumour cells with prominent nucleoli and abundant mitosis.( Haematoxylin and eosin. 63x)

 

 

FIGURE 2: Dense core neurosecretory granules in Merkel Cell Tumour (56000X)

 

 

FIGURE 3: Merkel Cell Tumour showing positivity, in some cells as a paranuclear dot, with anti-cytokeratin antibody (Cam 5.2.63X)

 

 

 

Acknowledgements

The author is grateful to Mr.Malcolm Deane,  Mr.Lance Sully and Miss Fiona Bailie , Consultants in Plastic Surgery at Nottingham  City Hospital Trust for allowing me to publish  their cases and also to Dr.Mike Sokal, Consultant Radiotherapist, Nottingham General Hospital for his special interest in this subject and publication. The author also acknowledges the contribution of Dr.Sarah Pinder in production of histological printouts.

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