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Merkel cell carcinoma of the skin
British Journal of Phstic Surgery (1996), 49, 491-496 % 1996 The British Association of Plastic Surgeons
Merkel cell carcinoma of the skin S. K. Al-Ghazal,
D. S. Arora*,
R. H. W. Simpson* and P. Saxby
Department of Plastic and Reconstructive Surgery, Royal Devon und Exeter Hospital and *Postgraduate Medical School, University qf’ Exeter, Exeter, UK SUMMA R Y. Primary neuroendocrine carcinoma of the skin or Merkel cell carcinoma is an aggressive primary neoplasm. It is commonly seen in the elderly, on the head, neck and extremities, where it can mimic a benign or less malignant skin tumour. Pathological examination shows a generally dense growth of small dark cells, with immunohistochemical evidence of neuroendocrine differentiation. The microscopic appearance is very similar to metastatic oat cell carcinoma from the lung and this must be excluded by clinical means and appropriate imaging studies. In this study we present 13 new cases of Merkel cell carcinoma (the largest published series in the UK) and summarize 214 cases from the literature in which the survival data are given. In our series, 5 of 13 patients died from spread of the Merkel cell carcinoma. From this and other studies, it appears that early diagnosis and wide local excision may be the only way to prolong survival. No other adjuvant therapy has proved effective.
Friedrich Merkel’ first identified the cells that bear his name in 1875. They are special sensory cells of the skin which are usually associated with hair follicles, forming complexes with terminal axons. They are also found as isolated cells in the dermis, epidermis and oral cavity,’ where they are located within the basal layer of the epithelium. Typically, the Merkel cell has an oval shape and is connected to surrounding keratinocytes by desmosomes. It sends fine projections, or trabeculations, into the adjacent cells and, for this reason, it is sometimes referred to as the trabecular cell. It is felt to be neuroendocrine in origin because of the presence of cytoplasmic granules which on immunohistochemical staining are positive for chromogranin A. Merkel cells also express neuron specific enolase and synaptophysin and also display a characteristic paranuclear staining with cytokeratins.3,4 The tumour was originally described as ‘trabecular carcinoma’ in 1972.5 Cullen et a1.6 called it ‘small cell carcinoma’ of the skin. It is now more generally known as either Merkel cell carcinoma or primary neuroendocrine carcinoma of the skin.’
dilution 1: 500), chromogranin A (Dako, 1: loo), cytokeratin CAM 5.2 (Becton-Dickinson, 1: lo), cytokeratin AEl (ICN, 1 : 300), human milk factor globulin 1 & 2 (Oxoid, 1:400), leukocyte common antigen (Dako, 1: 150) and SlOO protein (Dako, 1 : 750). Appropriate positive and negative controls were employed. A high power field, as described in the results, has an area of 0.28 mm*.
Results Clinical details The thirteen patients had a mean age of 79.3 years (range 68-86 years). Ten were female and three were male. Mean follow-up was 21.8 months (range: 6-48 months). In one case, the tumour presented as skin ulceration (Fig. 1) and in the remaining cases the tumours were nodular (Fig. 2). In case 12, the consistency was soft, such that the initial clinical diagnosis was an epidermal cyst. In five patients the tumour was on the head and neck, in two patients on the upper limbs and in the remaining six patients the tumour was on the lower limb. In each case there was no evidence of any other primary tumour, either at the time of presentation or subsequently. In particular, no lesions were seen on chest x-ray. The treatments and outcomes are summarized in Table 2. Twelve patients had surgery, four of whom required skin grafting and one a local forehead flap. The tumour was always completely excised with a margin of l-3 cm depending on the size and location of the turnout-. One patient had primary radiotherapy as she was considered unfit for surgery. Nine of the twelve cases who had surgery also had
Patients and methods Thirteen cases of Merkel cell carcinoma (MCC) of the skin have been identified at the Royal Devon and Exeter Hospital between 1989 and 1994. Clinical data and follow-up information were collected and are summarized in Table 1. Sections from paraffin-embedded tissue were cut and prepared in the conventional manner, stained with haematoxylin and eosin and by other methods. Various commercially available antisera were applied to sections using the streptavidin-biotin technique. These included neuron specific enolase (Dako, 491
British Journal of Plastic Surgery
492 Table 1 Details of patients
NO.
Age
Sex
Presentation
Site
Treatment
L. N.D.
F F F M F F
nodule nodule nodule nodule nodule
L.neck Nose
ext. + graft -
Radiation
Chemo.
Rec.
R. L.N.
-
-
-
-
D.Met.
(years)
I 2 3 4 5 6 7
85 83 80 79 81 85 68
8
75
M F
9
13
F
10
78
F
11 12 13
74 86 84
F F
M
ext. +flap
-
L.arm ext. R.thigh ext. yes L.leg ext. + graft yes
nodule nodule nodule nodule ulcer nodule nodule nodule
L.leg
ext.
L.arm L.leg Face R.leg L.leg Face Face
ext. ext. + graft yes ext. ext. + graft ext. radiotherapyext.
yes
yes
yes
yes -
:: 48 24 24 36
yes yes yes yes -
yes
18
yes
15
-
18 6
yes
24
yes
18 7
yes yes yes
yes yes
-
yes
yes yes yes yes yes yes
yes
F. U. (moni
-
-
-
Dead
yes
yes yes yes
yes
L.N.D. = Lymph node dissection Rec.= Local recurrence R.L.N. = Regional lymphadenopathy D.Met. =Distal metastases F.U.(mon) = Follow-up (months).
Fig. 1 Figure l-ulcerated
Merkel cellcarcinomaon the leg (case10).
postoperative radiotherapy to the site of the primary lesion and to the lymph nodes when involved with metastases. The dose of radiotherapy was 4000-6000 cGy to the head and neck area and 3000 cGy to the leg. The indications for radiotherapy were: ( 1) close margins of excisions (cases 7, 11); (2) local recurrence (cases 5, 7, 8, 9); (3) lymph node metastases (cases 4, 5, 6, 8); (4) lesion over or in close proximity to regional lymph nodes (cases 1, 13); (5) poor general condition (case 12). Only one patient had chemotherapy. During the follow-up period, four patients had local recurrences which we believe, as with malignant melanoma, to be ‘local metastases’ in the scar, or skin graft, at the edge of scar/graft, in transit and not a satellite primary lesion.8,9
Fig. 2 Figure 2-Nodular Merkel cell carcinomaon the face (case2). Table 2 Treatment and outcome
No. Surgery Radiotherapy Surgery (without node dissection) + Radiotherapy Surgery (with node dissection) + Radiotherapy Totals
Alive
Dead
3 1
3 0
0 1
5
3
2
4 13
2 8
2 5
Four patients had regional lymph node metastases (confirmed histologically) followed by therapeutic lymph node dissection. Five patients died as a consequence of the
Merkel
cell carcinoma
of the skin
493
MCC within 24 months. Four of these patients had postoperative radiotherapy and the fifth had primary radiotherapy only. Out of the five patients who had MCC on the head and neck, four are still alive (none of these patients needed lymph node dissection) and the fifth patient (who was in poor general health and had primary radiotherapy alone) is reported dead. In no case was permission for autopsy granted. Pathological jindings Excision biopsy specimens were received from all patients except case 12, in whom only curettings were available. The largest tumour measured 70 x 70 x 22 mm and the smallest 11 x 4 x 2.5 mm. The macroscopic descriptions were of grey nodules, generally firm in consistency, but two were described as soft. Microscopic examination showed densely cellular neoplasms forming solid sheets but also, in most cases, there was a minor component of short illdefined trabecula (Fig. 3). Surface ulceration was noted in three tumours but generally the epidermis was not involved. Indeed, there was often a thin (0.1-0.3 mm) zone immediately beneath it. No Pagetoid pattern was identified. The thicker lesions also showed involvement of the subcutaneous fat and
six tumours displayed lymphatic invasion. Foci of necrosis were frequent, though not usually extensive. In all cases the cells were generally regular and of small to intermediate size, often with indistinct borders. Each contained a single, somewhat darkly staining nucleus with even, finely granular chromatin with a typical diameter approximately three times the size of a mature lymphocyte. The shape was usually round or oval but occasional elongated forms were identified. In places, moulding of adjacent nuclei was noted. Nucleoli were not usually seen, though occasional small central ones were identified. Overall, the nuclei appeared somewhat larger and less hyperchromatic than is usual in metastatic or primary oat cell carcinoma of the lung. The cytoplasm was generally inconspicuous, consisting of a thin pale eosinophilic rim. Mitotic figures were numerous in all cases, with counts per 10 high power fields varying from 16 to at least 300 and possibly higher (because the most mitotically active tumours also showed many pyknotic nuclei, which can be difficult to differentiate from mitotic figures). About half of the tumours showed a mild to moderate reactive lymphocytic infiltrate. Special stains showed neither glycogen nor mucin and only very occasionally could argyrophil granules be demonstrated with the Grimelius method. All tumours displayed strong and generally even cytoplasmic expression of neuron specific enolase and ten showed at least patchy positivity with chromogranin A. In six cases, this was generalised and considered strong or very strong. All tumours reacted with antibodies against low molecular weight cytokeratins, CAM 5.2 and AEl. The staining was cytoplasmic and in most instances characteristic paranuclear ‘dot-like’ condensations were noted (Fig. 4). Most cases showed some cytoplasmic expression of human milk factor globulin but in some cases there were zones where no reaction was seen. All tumours were negative with the antibodies against SlOO protein and leukocyte common antigen (CD45), though they reacted with the appropiate non-neoplastic cells, including the lymphoid infiltrate with the latter. Some
Fig. 4 Fig. 3 Figure3-The staining tumour
dermis contains masses of closely packed, cells (haematoxlin and eosin x 200).
darkly
Figure 4-Positive Frequently, there 5.2 x 400).
cytoplasmic is a dot-like
staining with cytokeratin paranuclear condensation
antibody. (CAM
494
British Journal of Plastic Surgery
other antisera (vimentin, CEA, neurofilament protein, PGP 9.5) were applied to a small number of cases and were all negative. Electron microscopy was performed on formalinfixed material for one case (case 11) and showed occasional small paranuclear deposits of intermediate filaments but no neurosecretory granules. The tumour deposits in the lymph nodes metastases were histologically identical to their primaries. Discussion
The histological features in our series of 13 cases are typical of Merkel cell carcinoma and the immunohistochemical findings are characteristic, as are the ultrastructural findings in the one case available for study. Although the first clinical series describing Merkel cell carcinoma was reported only in 1982,” the literature currently contains enough information for this rare tumour to be reasonably accurately characterised. The aetiology of Merkel cell carcinoma is still unknown, but it has been suggested that sunlight may play a role, as most of the lesions are in exposed areas of the body.” Typically it is found in patients in their seventh and eighth decades.” Although some authors reported no sex predominancer2-r4 women were affected more often in the series of Best et a1.r5 and Szadowska et a1.r6 as well as in the present study. Although any part of the body may be affected, the most frequent sites are the head, neck and lower limbs.‘3~17 The typical clinical presentation is as a skin ulcer or nodule which is usually firm in consistency, pink to red in colour and which can be confused with other skin malignancies”? Excisional biopsy is recommended for diagnosis. The pathological differential diagnoses includes non-Hodgkin lymphoma and malignant melanoma which can be composed of sheets of hyperchromatic cells of similar size to Merkel cell carcinoma. However, immunohistochemistry shows reaction to lymphoid markers and
SlOO protein respectively and negativity with neuron specific enolase. 14,19 There are some histological differences from metastatic oat cell carcinoma of the lung but there is a degree of morphological overlap and it is rarely possible to exclude this diagnosis purely on histological examination. It is therefore recommended that appropriate clinical and imaging studies be performed, in particular a postero-anterior and lateral chest x-ray.20 The behaviour of Merkel cell carcinoma is often aggressive. Murphy et a1.21 noted that 75% of their patients had local recurrence, 75% had regional lymphadenopathy, 50% had distant metastases and 25% of the cases died of the disease. Other studies on the clinical course of this tumour have been generally similar3,‘2,‘4,‘6,‘8,19 and are summarized in Table 3. Due to the high local recurrence rate of Merkel cell carcinoma, an adequate wide margin of clearance is necessary, but how wide is ‘wide excision’ and does it reduce the local recurrence? In the absence of clear guidlines about the excision margins, it has been suggested that wide excision such as practised for thick melanoma might reduce the recurrence rate.6.‘3 Shack et a1.3 suggested wide excision or re-excision with a l-3 cm margin, depending on the size and location of the tumour, although they did not give specific figures about local recurrence in their series. Another study recommended margins of 2.5-3 cm at most.17 Because the tumour shows extensive vertical growth, the deep margins of the resection must be carefully examined and it was only Meland and Jackson,” according to their experience in the Mayo Clinic, who suggested that a layer of normal deep fascia and/or bone is included in the resection; such excision of deep fascia in malignant melanoma is rarely done nowadays.22 As a result of frequent regional recurrences following the excision of the primary lesion, some authors suggested a need to consider prophylactic regional lymph node dissection.7,‘3*‘7.23 Raaf et all3 justified this because more than 50% of the patients will have regional disease, although it is not known whether
Table 3 Summary of casesreported in the literature Authors
Year of publication
Av. l? U.
No.
Rec.
Cotlar et a1.l9 Hitchcock et al.” Kroll & Taker” Murphy et al.” Meland & Jackson’* Raaf et al.13
1986 1988 1982 1990 1986 1986
20.6 24 44.3 35.3 28.8 31.8
50 20 39 75 43 36
62.5 80 22 75 52 53
75 60 26 50 26 28
37.5 20 22 25 35 25
Shack et al.3 Sibley et al.14 Szadowska et al.“’ Present study
1994 1985 1989 1995
34.2 20.9 21.8
8 5 23 4 23 80 (4 personal, 76 literature) 15 43 13 13
30 38 30.8
33.3 65 61 30.8
66.7 40 46 38.5
66.7 33 61 38.5
Av.F.U. =Average follow-up (months) No. = No. of patients Rec. = Local recurrence R.L.N. = Regional lymphadenopathy D.Met. =Distal metastases.
(%)
R.L.N.
(5%)
D. Met.
(99)
Deaths (“Ai
Merkel cell carcinoma of the skin prophylactic node dissection will prolong survival. Cotlar et al.i9 recommended prophylactic lymphadenectomy only in patients whose lesions have been present for longer than 6 weeks or when the primary tumour measures 1.5 cm or more in diameter. We think the high incidence of recurrence, particularly in the head and neck, is largely on the basis of narrow excision margins being used for cosmetic reasons. In the present study, we tried to avoid this by using early wide excision. We believe also that routine lymph node dissection is not necessary, as four patients out of the five with tumours on the head and neck are still alive with follow-up range from 10 months to 3 years and none of them have had lymph node dissection. We share the view with Best et al.” that the efficacy of prophylactic node dissection in limiting disease progression is not known, and of course factors such as the age and general health of the patient must obviously be considered before such surgery. There is some evidence to suggest tumour radiosensitivity.i3,” Haslez4 reported rapid regression of Merkel cell carcinoma treated primarily with radiotherapy; the patient died of distal metastases after 31 months. Brierly et al.” reported a case of complete clinical resolution of groin lymph node metastases treated with radiotherapy but the patient died after 41 months. In summary, although some limited case reports suggest some benefit from radiotherapy, this has not been studied prospectively or in controlled trials because the numbers of patients in various series are inadequate to establish a statistically meaningful trend. 6 ‘i In the meantime, it is reasonable to follow the practice of Hitchcock et al.” who suggested that radiotherapy should be considered in the following circumstances: (1) where the tumour is close to the margin of the resection; (2) when there is histological evidence of vascular space involvement; (3) when nodal metastases are present. We did not use radiotherapy routinely and there was no evidence in our series that radiotherapy improved the outcome (Table 2). Our series confirms the need for further research to identify any role for radiotherapy in this disease. Similarly, there is still an ongoing debate on the utility of chemotherapy.“j Some isolated case reports described a partial response or temporary limitation of tumour enlargement after chemotherapy,27,28 for example Kroll and Taker” noted that tumour regression and shrinkage after chemotherapy was rapid but the tumour recurred within 6-12 months. Hitchcock et al.12 used cyclophosphamide, doxorubicin and VP-16 in one patient with a biopsy-proven abdominal metastatic lesion, leading to clear shrinkage of the mass, and the patient was alive at 28 months with no clinical evidence of tumour. However, as with melanoma, most authors agree that there is no effective chemotherapy for Merkel cell carcinoma as a general rule.3.4,‘7 We feel that our series is too small to demonstrate any statistically significant results in those treated adjuvantly but we find both radiation and chemotherapy disappointing. All five patients who died had radiotherapy, including one who also had chemo-
495 therapy. Therefore, on the basis of our own experience, we believe that early wide and deep excision remains the treatment of choice for this aggressive skin tumour. Although 5 of our 13 patients (38%) are tumour free at the time of reporting our series and 3 (23%) of our patients survived for 3 years or more, these follow-up periods are still somewhat short. Kroll and Taker” reported that only 20% of their patients survived for more than 5 years and, as a result of the high mortality, this skin tumour must still be considered as an aggressive tumour.2.3 Conclusions Merkel cell carcinoma is an uncommon, aggressive skin tumour that is frequently misdiagnosed and undertreated. Patients with Merkel cell carcinoma have a high rate of local recurrence, regional metastases, distant metastases and mortality. If the cure rate in this disease is to be improved, early and more accurate diagnosis accompanied by wide local resection need to be considered and a high index of suspicion is important in considering any atypical skin lesion of the head, neck and lower limbs. A better understanding of the role of radiotherapy and chemotherapy will, it is hoped, improve the outcome and the survival rate of this disease. The recent widespread publications in the pathological and dermatological literature about this tumour have led to more awareness by dermatologists and pathologists. It is felt to be of the utmost importance that plastic surgeons also be as well informed about this tumour, since they will be called on to treat it. References 1. Merkel F. Tastzellen und Tastkiirperchen bei den Hausthieren und beim Menschen. Arch Mikrosc Anat 1875, I 1: 636652. 2. Mercer D, Brander P, Liddell K. Merkel cell carcinoma: the clinical course. Ann Plast Surg 1990; 25: 13641. 3. Shack RB, Barton RM, Delozier J, Rees R, Lynch J. Is aggressive surgical management justified in the treatment of Merkel cell carcinoma? Plast Reconstr Surg 1994: 94: 970-4. 4. Weil R. Pathologic quiz. Arch Otolaryngol Head Neck Surg 1992; 118: 440-2. 5. Toker C. Trabecular carcinoma of the skin. Arch Dermatol 1972; 105: 107710. 6. Cullen KW, Subbuswamy SC, Lamberty BGH. Small cell carcinoma of the skin: a report of two cases. Br J Plast Surg 1985: 38: 575-8. 7. Rice RD, Chonkich CD, Thompson KS, Chase D. Merkel cell tumor of the head and neck: five new cases with literature review. Arch Otolaryngol Head Neck Surg 1993: 119: 78226. 8. Griffiths RW, Briggs JC. Incidence of locally metastatic (recurrent) cutaneous malignant melanoma following conventional wide margin excisional surgery for invasive clinical stage I tumours: importance of maximal primary tumour thickness. Br J Surg 1986; 73: 349953. 9. Russell RC. Malignant melanoma. Br J Surg 1986; 73: 77334. 10. Kroll M, Toker C. Trabecular carcinoma of the skin: further clinicopathologic and morphologic study. Arch Pathol Lab Med 1982; 106: 40448. Il. Pitale M, Sessions R, Husain S. An analysis of prognostic cutaneous factors in nemoendocrine carcinoma. Laryngoscope 1992; 102: 24449.
496 12. Hitchcock C, Bland K, Laney R, Franzini D, Harris B, Cooland E. Neuroendocrine (Merkel cell ) carcinoma of the skin: its natural history, diagnosis and treatment. Ann Surg 1988; 207: 201-7. 13. Raaf JH, Urmacher C, Knapper WK, Shiu M, Cheng E. Trabecular (Merkel cell) carcinoma of the skin: treatment of primary, recurrent, and metastatic disease. Cancer 1986; 57: 178-82. 14. Sibley RK, Dehner LP, Rosai J. Primary neuroendocrine (Merkel cell?) carcinoma of the skin: a clinicopathologic and ultrastructural study of 43 cases. Am J Surg Pathol 1985; 9: 955108. 15. Best TJ, Metcalfe JB, Moore RB, Nguyen GK. Merkel cell carcinoma of the scrotum. Ann Plast Surg 1994; 33: 83-5. 16. Szadowska A, Wozniak L, Lasota J, Mirecka B, Wolska H. Neuroendocrine (Merkel cell) carcinoma of the skin: a clinico-morphological study of 13 cases. Histopathology 1989; 15: 483-93. 17. Shaw JH, Rumba11 E. Merkel cell tumour: clinical behaviour and treatment. Br J Surg 1991; 78: 138842. 18. Meland N, Jackson I. Merkel cell tumour: diagnosis, prognosis, and treatment. Plast Reconstr Surg 1986; 77: 632-8. 19. Cotlar A, Gates J, Gibbs F. Merkel cell carcinoma: combined surgery and radiation therapy. Am J Surg 1986; 52: 159-64. 20. Ratner D, Nelson B, Brown M, Johnson T. Merkel cell carcinoma. J Am Acad Dermatol 1993; 29: 143-56. 21. Murphy R Jr, Li JK, Mincer FK, Strauch B. Trabecular (neuroendocrine) carcinoma of the skin. Report of four cases and review of the literature. NY State J Med 1990; 90: 3558. 22. Timmons MJ. Malignant melanoma excision margins: plastic surgery audit in Britain and Ireland, 1991, and a review. Br J Plast Surg 1993; 46: 525531. 23. Wilder R, Harari P, Graham A, Shimm D, Cassady R. Merkel cell carcinoma: improved locoregional control with postoperative radiation therapy. Cancer 1991; 68: 100448.
British Journal of Plastic Surgery 24. Hasle H. Merkel cell carcinoma: the role of primary treatment with radiotherapy. Clin Oncol 1991; 3: 114-16. 25. Brierly J, Stockdale A, Rostom A. Merkel cell (trabecular) carcinoma of the skin treated by radiotherapy. Clin Oncol 1991; 3: 117-18. 26. Bortolani A, Barisoni D, Colombari R, Furlan S. Merkel cell carcinoma of the skin. Plast Reconstr Surg 1992; 89: 751-4. 27. Crown J, Lipzstein R, Cohen S, Goldsmith M, Wisch N, Paciucci P, et al. Chemotherapy of metastatic Merkel cell cancer. Cancer Invest 1991; 9: 129-32. 28. Sharma D, Flora G, Grunberg S. Chemotherapy of metastatic Merkel cell carcinoma: case report and review of the literature. Am J Clin Oncol 1991; 14: 16669.
The Authors Sharif Kaf Al-Ghazal MD, MS, Formerly Senior House Officer, Department of Plastic and Reconstructive Surgery, Royal Devon and Exeter Hospital, Exeter Deep S. Arora MD, DipRCPath, Registrar in Histopathology, Roval Devon and Exeter Hosuital. Exeter Rode&k H.W. Simpson BSc, ‘MB: ChB, MMed (Anat Path), FRCPath, Consultant and Senior Lecturer in Histopathology, Postgraduate Medical School, University of Exeter, Exeter Peter Saxby MCh, FRCS (Plast), Consultant Plastic and Reconstructive Surgeon, Royal Devon and Exeter Hospital, Exeter, UK. Correspondence to Sharif Kaf Al-Ghazal MD, Department of Plastic Surgery, Nottingham Hucknall Road, Nottingham NG5 IPB, UK. Paper received 21 July 1995. Accepted 10 June 1996, after
revision.
MS, City
Registrar, Hospital,
Merkel cell carcinoma of the skin S. K. Al-Ghazal,
D. S. Arora*,
R. H. W. Simpson* and P. Saxby
Department of Plastic and Reconstructive Surgery, Royal Devon und Exeter Hospital and *Postgraduate Medical School, University qf’ Exeter, Exeter, UK SUMMA R Y. Primary neuroendocrine carcinoma of the skin or Merkel cell carcinoma is an aggressive primary neoplasm. It is commonly seen in the elderly, on the head, neck and extremities, where it can mimic a benign or less malignant skin tumour. Pathological examination shows a generally dense growth of small dark cells, with immunohistochemical evidence of neuroendocrine differentiation. The microscopic appearance is very similar to metastatic oat cell carcinoma from the lung and this must be excluded by clinical means and appropriate imaging studies. In this study we present 13 new cases of Merkel cell carcinoma (the largest published series in the UK) and summarize 214 cases from the literature in which the survival data are given. In our series, 5 of 13 patients died from spread of the Merkel cell carcinoma. From this and other studies, it appears that early diagnosis and wide local excision may be the only way to prolong survival. No other adjuvant therapy has proved effective.
Friedrich Merkel’ first identified the cells that bear his name in 1875. They are special sensory cells of the skin which are usually associated with hair follicles, forming complexes with terminal axons. They are also found as isolated cells in the dermis, epidermis and oral cavity,’ where they are located within the basal layer of the epithelium. Typically, the Merkel cell has an oval shape and is connected to surrounding keratinocytes by desmosomes. It sends fine projections, or trabeculations, into the adjacent cells and, for this reason, it is sometimes referred to as the trabecular cell. It is felt to be neuroendocrine in origin because of the presence of cytoplasmic granules which on immunohistochemical staining are positive for chromogranin A. Merkel cells also express neuron specific enolase and synaptophysin and also display a characteristic paranuclear staining with cytokeratins.3,4 The tumour was originally described as ‘trabecular carcinoma’ in 1972.5 Cullen et a1.6 called it ‘small cell carcinoma’ of the skin. It is now more generally known as either Merkel cell carcinoma or primary neuroendocrine carcinoma of the skin.’
dilution 1: 500), chromogranin A (Dako, 1: loo), cytokeratin CAM 5.2 (Becton-Dickinson, 1: lo), cytokeratin AEl (ICN, 1 : 300), human milk factor globulin 1 & 2 (Oxoid, 1:400), leukocyte common antigen (Dako, 1: 150) and SlOO protein (Dako, 1 : 750). Appropriate positive and negative controls were employed. A high power field, as described in the results, has an area of 0.28 mm*.
Results Clinical details The thirteen patients had a mean age of 79.3 years (range 68-86 years). Ten were female and three were male. Mean follow-up was 21.8 months (range: 6-48 months). In one case, the tumour presented as skin ulceration (Fig. 1) and in the remaining cases the tumours were nodular (Fig. 2). In case 12, the consistency was soft, such that the initial clinical diagnosis was an epidermal cyst. In five patients the tumour was on the head and neck, in two patients on the upper limbs and in the remaining six patients the tumour was on the lower limb. In each case there was no evidence of any other primary tumour, either at the time of presentation or subsequently. In particular, no lesions were seen on chest x-ray. The treatments and outcomes are summarized in Table 2. Twelve patients had surgery, four of whom required skin grafting and one a local forehead flap. The tumour was always completely excised with a margin of l-3 cm depending on the size and location of the turnout-. One patient had primary radiotherapy as she was considered unfit for surgery. Nine of the twelve cases who had surgery also had
Patients and methods Thirteen cases of Merkel cell carcinoma (MCC) of the skin have been identified at the Royal Devon and Exeter Hospital between 1989 and 1994. Clinical data and follow-up information were collected and are summarized in Table 1. Sections from paraffin-embedded tissue were cut and prepared in the conventional manner, stained with haematoxylin and eosin and by other methods. Various commercially available antisera were applied to sections using the streptavidin-biotin technique. These included neuron specific enolase (Dako, 491
British Journal of Plastic Surgery
492 Table 1 Details of patients
NO.
Age
Sex
Presentation
Site
Treatment
L. N.D.
F F F M F F
nodule nodule nodule nodule nodule
L.neck Nose
ext. + graft -
Radiation
Chemo.
Rec.
R. L.N.
-
-
-
-
D.Met.
(years)
I 2 3 4 5 6 7
85 83 80 79 81 85 68
8
75
M F
9
13
F
10
78
F
11 12 13
74 86 84
F F
M
ext. +flap
-
L.arm ext. R.thigh ext. yes L.leg ext. + graft yes
nodule nodule nodule nodule ulcer nodule nodule nodule
L.leg
ext.
L.arm L.leg Face R.leg L.leg Face Face
ext. ext. + graft yes ext. ext. + graft ext. radiotherapyext.
yes
yes
yes
yes -
:: 48 24 24 36
yes yes yes yes -
yes
18
yes
15
-
18 6
yes
24
yes
18 7
yes yes yes
yes yes
-
yes
yes yes yes yes yes yes
yes
F. U. (moni
-
-
-
Dead
yes
yes yes yes
yes
L.N.D. = Lymph node dissection Rec.= Local recurrence R.L.N. = Regional lymphadenopathy D.Met. =Distal metastases F.U.(mon) = Follow-up (months).
Fig. 1 Figure l-ulcerated
Merkel cellcarcinomaon the leg (case10).
postoperative radiotherapy to the site of the primary lesion and to the lymph nodes when involved with metastases. The dose of radiotherapy was 4000-6000 cGy to the head and neck area and 3000 cGy to the leg. The indications for radiotherapy were: ( 1) close margins of excisions (cases 7, 11); (2) local recurrence (cases 5, 7, 8, 9); (3) lymph node metastases (cases 4, 5, 6, 8); (4) lesion over or in close proximity to regional lymph nodes (cases 1, 13); (5) poor general condition (case 12). Only one patient had chemotherapy. During the follow-up period, four patients had local recurrences which we believe, as with malignant melanoma, to be ‘local metastases’ in the scar, or skin graft, at the edge of scar/graft, in transit and not a satellite primary lesion.8,9
Fig. 2 Figure 2-Nodular Merkel cell carcinomaon the face (case2). Table 2 Treatment and outcome
No. Surgery Radiotherapy Surgery (without node dissection) + Radiotherapy Surgery (with node dissection) + Radiotherapy Totals
Alive
Dead
3 1
3 0
0 1
5
3
2
4 13
2 8
2 5
Four patients had regional lymph node metastases (confirmed histologically) followed by therapeutic lymph node dissection. Five patients died as a consequence of the
Merkel
cell carcinoma
of the skin
493
MCC within 24 months. Four of these patients had postoperative radiotherapy and the fifth had primary radiotherapy only. Out of the five patients who had MCC on the head and neck, four are still alive (none of these patients needed lymph node dissection) and the fifth patient (who was in poor general health and had primary radiotherapy alone) is reported dead. In no case was permission for autopsy granted. Pathological jindings Excision biopsy specimens were received from all patients except case 12, in whom only curettings were available. The largest tumour measured 70 x 70 x 22 mm and the smallest 11 x 4 x 2.5 mm. The macroscopic descriptions were of grey nodules, generally firm in consistency, but two were described as soft. Microscopic examination showed densely cellular neoplasms forming solid sheets but also, in most cases, there was a minor component of short illdefined trabecula (Fig. 3). Surface ulceration was noted in three tumours but generally the epidermis was not involved. Indeed, there was often a thin (0.1-0.3 mm) zone immediately beneath it. No Pagetoid pattern was identified. The thicker lesions also showed involvement of the subcutaneous fat and
six tumours displayed lymphatic invasion. Foci of necrosis were frequent, though not usually extensive. In all cases the cells were generally regular and of small to intermediate size, often with indistinct borders. Each contained a single, somewhat darkly staining nucleus with even, finely granular chromatin with a typical diameter approximately three times the size of a mature lymphocyte. The shape was usually round or oval but occasional elongated forms were identified. In places, moulding of adjacent nuclei was noted. Nucleoli were not usually seen, though occasional small central ones were identified. Overall, the nuclei appeared somewhat larger and less hyperchromatic than is usual in metastatic or primary oat cell carcinoma of the lung. The cytoplasm was generally inconspicuous, consisting of a thin pale eosinophilic rim. Mitotic figures were numerous in all cases, with counts per 10 high power fields varying from 16 to at least 300 and possibly higher (because the most mitotically active tumours also showed many pyknotic nuclei, which can be difficult to differentiate from mitotic figures). About half of the tumours showed a mild to moderate reactive lymphocytic infiltrate. Special stains showed neither glycogen nor mucin and only very occasionally could argyrophil granules be demonstrated with the Grimelius method. All tumours displayed strong and generally even cytoplasmic expression of neuron specific enolase and ten showed at least patchy positivity with chromogranin A. In six cases, this was generalised and considered strong or very strong. All tumours reacted with antibodies against low molecular weight cytokeratins, CAM 5.2 and AEl. The staining was cytoplasmic and in most instances characteristic paranuclear ‘dot-like’ condensations were noted (Fig. 4). Most cases showed some cytoplasmic expression of human milk factor globulin but in some cases there were zones where no reaction was seen. All tumours were negative with the antibodies against SlOO protein and leukocyte common antigen (CD45), though they reacted with the appropiate non-neoplastic cells, including the lymphoid infiltrate with the latter. Some
Fig. 4 Fig. 3 Figure3-The staining tumour
dermis contains masses of closely packed, cells (haematoxlin and eosin x 200).
darkly
Figure 4-Positive Frequently, there 5.2 x 400).
cytoplasmic is a dot-like
staining with cytokeratin paranuclear condensation
antibody. (CAM
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British Journal of Plastic Surgery
other antisera (vimentin, CEA, neurofilament protein, PGP 9.5) were applied to a small number of cases and were all negative. Electron microscopy was performed on formalinfixed material for one case (case 11) and showed occasional small paranuclear deposits of intermediate filaments but no neurosecretory granules. The tumour deposits in the lymph nodes metastases were histologically identical to their primaries. Discussion
The histological features in our series of 13 cases are typical of Merkel cell carcinoma and the immunohistochemical findings are characteristic, as are the ultrastructural findings in the one case available for study. Although the first clinical series describing Merkel cell carcinoma was reported only in 1982,” the literature currently contains enough information for this rare tumour to be reasonably accurately characterised. The aetiology of Merkel cell carcinoma is still unknown, but it has been suggested that sunlight may play a role, as most of the lesions are in exposed areas of the body.” Typically it is found in patients in their seventh and eighth decades.” Although some authors reported no sex predominancer2-r4 women were affected more often in the series of Best et a1.r5 and Szadowska et a1.r6 as well as in the present study. Although any part of the body may be affected, the most frequent sites are the head, neck and lower limbs.‘3~17 The typical clinical presentation is as a skin ulcer or nodule which is usually firm in consistency, pink to red in colour and which can be confused with other skin malignancies”? Excisional biopsy is recommended for diagnosis. The pathological differential diagnoses includes non-Hodgkin lymphoma and malignant melanoma which can be composed of sheets of hyperchromatic cells of similar size to Merkel cell carcinoma. However, immunohistochemistry shows reaction to lymphoid markers and
SlOO protein respectively and negativity with neuron specific enolase. 14,19 There are some histological differences from metastatic oat cell carcinoma of the lung but there is a degree of morphological overlap and it is rarely possible to exclude this diagnosis purely on histological examination. It is therefore recommended that appropriate clinical and imaging studies be performed, in particular a postero-anterior and lateral chest x-ray.20 The behaviour of Merkel cell carcinoma is often aggressive. Murphy et a1.21 noted that 75% of their patients had local recurrence, 75% had regional lymphadenopathy, 50% had distant metastases and 25% of the cases died of the disease. Other studies on the clinical course of this tumour have been generally similar3,‘2,‘4,‘6,‘8,19 and are summarized in Table 3. Due to the high local recurrence rate of Merkel cell carcinoma, an adequate wide margin of clearance is necessary, but how wide is ‘wide excision’ and does it reduce the local recurrence? In the absence of clear guidlines about the excision margins, it has been suggested that wide excision such as practised for thick melanoma might reduce the recurrence rate.6.‘3 Shack et a1.3 suggested wide excision or re-excision with a l-3 cm margin, depending on the size and location of the tumour, although they did not give specific figures about local recurrence in their series. Another study recommended margins of 2.5-3 cm at most.17 Because the tumour shows extensive vertical growth, the deep margins of the resection must be carefully examined and it was only Meland and Jackson,” according to their experience in the Mayo Clinic, who suggested that a layer of normal deep fascia and/or bone is included in the resection; such excision of deep fascia in malignant melanoma is rarely done nowadays.22 As a result of frequent regional recurrences following the excision of the primary lesion, some authors suggested a need to consider prophylactic regional lymph node dissection.7,‘3*‘7.23 Raaf et all3 justified this because more than 50% of the patients will have regional disease, although it is not known whether
Table 3 Summary of casesreported in the literature Authors
Year of publication
Av. l? U.
No.
Rec.
Cotlar et a1.l9 Hitchcock et al.” Kroll & Taker” Murphy et al.” Meland & Jackson’* Raaf et al.13
1986 1988 1982 1990 1986 1986
20.6 24 44.3 35.3 28.8 31.8
50 20 39 75 43 36
62.5 80 22 75 52 53
75 60 26 50 26 28
37.5 20 22 25 35 25
Shack et al.3 Sibley et al.14 Szadowska et al.“’ Present study
1994 1985 1989 1995
34.2 20.9 21.8
8 5 23 4 23 80 (4 personal, 76 literature) 15 43 13 13
30 38 30.8
33.3 65 61 30.8
66.7 40 46 38.5
66.7 33 61 38.5
Av.F.U. =Average follow-up (months) No. = No. of patients Rec. = Local recurrence R.L.N. = Regional lymphadenopathy D.Met. =Distal metastases.
(%)
R.L.N.
(5%)
D. Met.
(99)
Deaths (“Ai
Merkel cell carcinoma of the skin prophylactic node dissection will prolong survival. Cotlar et al.i9 recommended prophylactic lymphadenectomy only in patients whose lesions have been present for longer than 6 weeks or when the primary tumour measures 1.5 cm or more in diameter. We think the high incidence of recurrence, particularly in the head and neck, is largely on the basis of narrow excision margins being used for cosmetic reasons. In the present study, we tried to avoid this by using early wide excision. We believe also that routine lymph node dissection is not necessary, as four patients out of the five with tumours on the head and neck are still alive with follow-up range from 10 months to 3 years and none of them have had lymph node dissection. We share the view with Best et al.” that the efficacy of prophylactic node dissection in limiting disease progression is not known, and of course factors such as the age and general health of the patient must obviously be considered before such surgery. There is some evidence to suggest tumour radiosensitivity.i3,” Haslez4 reported rapid regression of Merkel cell carcinoma treated primarily with radiotherapy; the patient died of distal metastases after 31 months. Brierly et al.” reported a case of complete clinical resolution of groin lymph node metastases treated with radiotherapy but the patient died after 41 months. In summary, although some limited case reports suggest some benefit from radiotherapy, this has not been studied prospectively or in controlled trials because the numbers of patients in various series are inadequate to establish a statistically meaningful trend. 6 ‘i In the meantime, it is reasonable to follow the practice of Hitchcock et al.” who suggested that radiotherapy should be considered in the following circumstances: (1) where the tumour is close to the margin of the resection; (2) when there is histological evidence of vascular space involvement; (3) when nodal metastases are present. We did not use radiotherapy routinely and there was no evidence in our series that radiotherapy improved the outcome (Table 2). Our series confirms the need for further research to identify any role for radiotherapy in this disease. Similarly, there is still an ongoing debate on the utility of chemotherapy.“j Some isolated case reports described a partial response or temporary limitation of tumour enlargement after chemotherapy,27,28 for example Kroll and Taker” noted that tumour regression and shrinkage after chemotherapy was rapid but the tumour recurred within 6-12 months. Hitchcock et al.12 used cyclophosphamide, doxorubicin and VP-16 in one patient with a biopsy-proven abdominal metastatic lesion, leading to clear shrinkage of the mass, and the patient was alive at 28 months with no clinical evidence of tumour. However, as with melanoma, most authors agree that there is no effective chemotherapy for Merkel cell carcinoma as a general rule.3.4,‘7 We feel that our series is too small to demonstrate any statistically significant results in those treated adjuvantly but we find both radiation and chemotherapy disappointing. All five patients who died had radiotherapy, including one who also had chemo-
495 therapy. Therefore, on the basis of our own experience, we believe that early wide and deep excision remains the treatment of choice for this aggressive skin tumour. Although 5 of our 13 patients (38%) are tumour free at the time of reporting our series and 3 (23%) of our patients survived for 3 years or more, these follow-up periods are still somewhat short. Kroll and Taker” reported that only 20% of their patients survived for more than 5 years and, as a result of the high mortality, this skin tumour must still be considered as an aggressive tumour.2.3 Conclusions Merkel cell carcinoma is an uncommon, aggressive skin tumour that is frequently misdiagnosed and undertreated. Patients with Merkel cell carcinoma have a high rate of local recurrence, regional metastases, distant metastases and mortality. If the cure rate in this disease is to be improved, early and more accurate diagnosis accompanied by wide local resection need to be considered and a high index of suspicion is important in considering any atypical skin lesion of the head, neck and lower limbs. A better understanding of the role of radiotherapy and chemotherapy will, it is hoped, improve the outcome and the survival rate of this disease. The recent widespread publications in the pathological and dermatological literature about this tumour have led to more awareness by dermatologists and pathologists. It is felt to be of the utmost importance that plastic surgeons also be as well informed about this tumour, since they will be called on to treat it. References 1. Merkel F. Tastzellen und Tastkiirperchen bei den Hausthieren und beim Menschen. Arch Mikrosc Anat 1875, I 1: 636652. 2. Mercer D, Brander P, Liddell K. Merkel cell carcinoma: the clinical course. Ann Plast Surg 1990; 25: 13641. 3. Shack RB, Barton RM, Delozier J, Rees R, Lynch J. Is aggressive surgical management justified in the treatment of Merkel cell carcinoma? Plast Reconstr Surg 1994: 94: 970-4. 4. Weil R. Pathologic quiz. Arch Otolaryngol Head Neck Surg 1992; 118: 440-2. 5. Toker C. Trabecular carcinoma of the skin. Arch Dermatol 1972; 105: 107710. 6. Cullen KW, Subbuswamy SC, Lamberty BGH. Small cell carcinoma of the skin: a report of two cases. Br J Plast Surg 1985: 38: 575-8. 7. Rice RD, Chonkich CD, Thompson KS, Chase D. Merkel cell tumor of the head and neck: five new cases with literature review. Arch Otolaryngol Head Neck Surg 1993: 119: 78226. 8. Griffiths RW, Briggs JC. Incidence of locally metastatic (recurrent) cutaneous malignant melanoma following conventional wide margin excisional surgery for invasive clinical stage I tumours: importance of maximal primary tumour thickness. Br J Surg 1986; 73: 349953. 9. Russell RC. Malignant melanoma. Br J Surg 1986; 73: 77334. 10. Kroll M, Toker C. Trabecular carcinoma of the skin: further clinicopathologic and morphologic study. Arch Pathol Lab Med 1982; 106: 40448. Il. Pitale M, Sessions R, Husain S. An analysis of prognostic cutaneous factors in nemoendocrine carcinoma. Laryngoscope 1992; 102: 24449.
496 12. Hitchcock C, Bland K, Laney R, Franzini D, Harris B, Cooland E. Neuroendocrine (Merkel cell ) carcinoma of the skin: its natural history, diagnosis and treatment. Ann Surg 1988; 207: 201-7. 13. Raaf JH, Urmacher C, Knapper WK, Shiu M, Cheng E. Trabecular (Merkel cell) carcinoma of the skin: treatment of primary, recurrent, and metastatic disease. Cancer 1986; 57: 178-82. 14. Sibley RK, Dehner LP, Rosai J. Primary neuroendocrine (Merkel cell?) carcinoma of the skin: a clinicopathologic and ultrastructural study of 43 cases. Am J Surg Pathol 1985; 9: 955108. 15. Best TJ, Metcalfe JB, Moore RB, Nguyen GK. Merkel cell carcinoma of the scrotum. Ann Plast Surg 1994; 33: 83-5. 16. Szadowska A, Wozniak L, Lasota J, Mirecka B, Wolska H. Neuroendocrine (Merkel cell) carcinoma of the skin: a clinico-morphological study of 13 cases. Histopathology 1989; 15: 483-93. 17. Shaw JH, Rumba11 E. Merkel cell tumour: clinical behaviour and treatment. Br J Surg 1991; 78: 138842. 18. Meland N, Jackson I. Merkel cell tumour: diagnosis, prognosis, and treatment. Plast Reconstr Surg 1986; 77: 632-8. 19. Cotlar A, Gates J, Gibbs F. Merkel cell carcinoma: combined surgery and radiation therapy. Am J Surg 1986; 52: 159-64. 20. Ratner D, Nelson B, Brown M, Johnson T. Merkel cell carcinoma. J Am Acad Dermatol 1993; 29: 143-56. 21. Murphy R Jr, Li JK, Mincer FK, Strauch B. Trabecular (neuroendocrine) carcinoma of the skin. Report of four cases and review of the literature. NY State J Med 1990; 90: 3558. 22. Timmons MJ. Malignant melanoma excision margins: plastic surgery audit in Britain and Ireland, 1991, and a review. Br J Plast Surg 1993; 46: 525531. 23. Wilder R, Harari P, Graham A, Shimm D, Cassady R. Merkel cell carcinoma: improved locoregional control with postoperative radiation therapy. Cancer 1991; 68: 100448.
British Journal of Plastic Surgery 24. Hasle H. Merkel cell carcinoma: the role of primary treatment with radiotherapy. Clin Oncol 1991; 3: 114-16. 25. Brierly J, Stockdale A, Rostom A. Merkel cell (trabecular) carcinoma of the skin treated by radiotherapy. Clin Oncol 1991; 3: 117-18. 26. Bortolani A, Barisoni D, Colombari R, Furlan S. Merkel cell carcinoma of the skin. Plast Reconstr Surg 1992; 89: 751-4. 27. Crown J, Lipzstein R, Cohen S, Goldsmith M, Wisch N, Paciucci P, et al. Chemotherapy of metastatic Merkel cell cancer. Cancer Invest 1991; 9: 129-32. 28. Sharma D, Flora G, Grunberg S. Chemotherapy of metastatic Merkel cell carcinoma: case report and review of the literature. Am J Clin Oncol 1991; 14: 16669.
The Authors Sharif Kaf Al-Ghazal MD, MS, Formerly Senior House Officer, Department of Plastic and Reconstructive Surgery, Royal Devon and Exeter Hospital, Exeter Deep S. Arora MD, DipRCPath, Registrar in Histopathology, Roval Devon and Exeter Hosuital. Exeter Rode&k H.W. Simpson BSc, ‘MB: ChB, MMed (Anat Path), FRCPath, Consultant and Senior Lecturer in Histopathology, Postgraduate Medical School, University of Exeter, Exeter Peter Saxby MCh, FRCS (Plast), Consultant Plastic and Reconstructive Surgeon, Royal Devon and Exeter Hospital, Exeter, UK. Correspondence to Sharif Kaf Al-Ghazal MD, Department of Plastic Surgery, Nottingham Hucknall Road, Nottingham NG5 IPB, UK. Paper received 21 July 1995. Accepted 10 June 1996, after
revision.
MS, City
Registrar, Hospital,