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Review
Malignant cutaneous adnexal tumours of the head and neck: an update on management B. Green a,∗ , D. Godden b , P.A. Brennan c a b c
Craniofacial Unit, Great Ormond Street Hospital for Children, London, UK Department of Oral & Maxillofacial Surgery, Gloucestershire Royal Hospital, UK Department of Oral & Maxillofacial Surgery, Queen Alexandra Hospital, Portsmouth, UK
Accepted 12 March 2015
Abstract Adnexal tumours form a heterogeneous group of relatively rare neoplasms. Many of them have a poor prognosis and treatment can sometimes be difficult and controversial. We summarise the latest publications relating to malignant cutaneous adnexal tumours of the head and neck, and give an update on their management. We discuss Merkel cell carcinoma and other rare malignant adnexal tumours including dermatofibrosarcoma protuberans and atypical fibroxanthoma. © 2015 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Keywords: Review; Adnexal tumours; Head and neck
Introduction
Merkel cell carcinoma (MCC)
In the United Kingdom, skin cancer is managed by specialist multidisciplinary teams of which maxillofacial surgeons are usually core members. Most skin cancers are basal cell carcinoma, squamous cell carcinoma, or melanoma, but it is important to understand the management of less common cutaneous malignancies (Table 1). We review the heterogeneous group of adnexal cancers of the skin, and outline their management.
Merkel cells contain neurosecretory granules and are found on the basal layer of the epidermis.1 Previously, MCC was described as trabecular carcinoma or cutaneous neuroendocrine carcinoma.1 Its incidence is higher in men than in women (2:1)2 and it is rare in young people with most cases occurring in those over 50 years of age.3 White-skinned people have the highest risk. As with other non-melanoma skin cancers, its incidence is high in areas exposed to ultraviolet (UV) light and the sites most commonly affected are on the head and neck (48%).4 Although its cause is poorly understood, UV light is implicated and has been identified in cases in immunocompromised patients with autoimmune and iatrogenic diseases; partial regression of metastases has been reported after immunosuppression has been stopped.5–8 In patients having psoralen-UV treatment for psoriasis its incidence is about 100 times higher than that seen in the general population,
∗ Corresponding author at: Craniofacial Unit, Great Ormond Street Hospital for Children, Great Ormond Street, London WC1N 3JH, UK. E-mail addresses: [email protected], [email protected] (B. Green), [email protected] (D. Godden), [email protected] (P.A. Brennan).
http://dx.doi.org/10.1016/j.bjoms.2015.03.005 0266-4356/© 2015 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Green B, et al. Malignant cutaneous adnexal tumours of the head and neck: an update on management. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.03.005
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Table 1 Number of cases of cutaneous adnexal tumours reported in England in 2012.
Table 2 TNM criteria for Merkel cell carcinoma (based on Lemos et al.20 ).
Adnexal tumour
No. of cases
T:
Merkel cell carcinoma Microcystic adnexal carcinoma Sebaceous carcinoma Malignant fibrous histiocytoma/pleomorphic sarcoma
227 23 115 110
which indicates that both UVA and UVB radiation have a role.9 Viral infection could also be an important factor.10 A new virus, Merkel cell polyomavirus (MCPyV) has been found in 80% of patients over 50,11 and although little is known about transmission and latency, its prevalence in MCC lesions has been reported to range from 40% to 100%.12,13 As it is present in both primary and metastatic disease,14 it can be argued that MCPyV is a carcinogen.15 Commonly, MCC develops as an asymptomatic, rapidly growing, flesh-coloured, firm, and non-tender nodule but plaque-like variants also occur (Fig. 1).16 The vascular pattern consists of polymorphic vessels. To act as an aide-mémoire for its clinical characteristics, the acronym “AEIOU” has been suggested: asymptomatic, rapidly expanding, immunosuppressed, older patient, UV exposure.16 Differential diagnoses can include atypical fibroxanthoma, lymphoma, and amelanotic melanoma. Since its description, several staging systems have been suggested and one by the American Joint Committee on Cancer in 2010 has been generally accepted (Tables 2 and 3). Recurrence has been reported to be between 25% and 30%. Regional lymph nodes are reported to be involved in 52% to 59%, and distal metastases in 34% to 36% of all cases, and as MCC has higher metastatic and mortality rates than melanoma, treatment needs to be aggressive.17–20 Operation is the primary treatment.9 Some surgeons support the use of wide excision margins (1–2 cm), and Mohs micrographic surgery (MMS) has been suggested as a viable alternative as local recurrence rates were comparable to those after wide excision.21 Further treatment depends on the route
Tx T0 Tis T1 T2 T3 T4 N: Nx N0 cN0 cN1 pN0 pNx N1a N1b N2 M: Mx M0 M1 M1a M1b M1c
Primary tumour cannot be assessed No primary tumour In situ primary tumour Primary tumour less than 2 cm Primary tumour more than 2 cm but less than 5 cm Primary tumour more than 5 cm Primary tumour invades bone, muscle, fascia, or cartilage Regional nodes cannot be assessed No regional nodal metastasis Nodes not clinically detectable Nodes detected clinically No nodal disease on pathological evaluation Nodes not evaluated pathologically Micrometastases Macrometastases In-transit metastases Distant metastases cannot be assessed No distant metastases Distant metastases Distant skin, distant subcutaneous tissue or distant lymph node metastases Metastases to lung Metastasis to other visceral sites
of drainage of the primary lymph nodes.22 Overall 5-year survival is around 62%.23 Five-year survival for patients with local disease is 64%, but for those with nodal disease and distant metastases it is only 39% and 18%, respectively. The low rate for local disease is the result of the discrepancy between T1 lesions (79% 5-year survival) and T4 lesions (47% 5-year survival), which both fall into this category.20 There is also a mucosal variant but this has a much lower incidence (4.5%).21 It most commonly affects the larynx followed by the nasal cavity, pharynx, mouth, and tongue, and has a poorer prognosis than the cutaneous type. Overall survival is 49% at 2 years.23 As metastases are common in MCC, and microscopic disease has been found in up to 50% of patients who have elective neck dissection,24 there is much discussion about appropriate management when there are no sign of metastases in the neck. Gillenwater et al.19 reported that recurrence developed in 23/24 patients who had presented with a clinically N0 neck Table 3 Merkel cell staging (based on Lemos et al.20 ).
Fig. 1. Merkel cell carcinoma.
Stage
Stage grouping (TNM)
0 IA IB IIA IIB IIC IIIA IIIB IV
Tis T1 T1 T2/T3 T2/T3 T4 Any T Any T Any T
N0 pN0 cN0 pN0 cN0 N0 N1a N1b/N2 Any N
M0 M0 M0 M0 M0 M0 M0 M0 M1
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and had had no treatment, and 42% had died of their disease, which indirectly supports the use of elective neck dissection in these cases. Nodal recurrence in patients with a cN0 neck who had operation alone was 50% compared with 19% in those who had had adjuvant radiotherapy. The drainage nodes can be included in an en-bloc field that also treats the primary site.25 Smith et al. found 65% recurrence and 29% mortality in patients who had local treatment only, whereas in those treated locoregionally at presentation it was 27% and 14%, respectively. Locoregional treatment has been advocated at the time of presentation in all patients, and it could therefore be argued that elective neck dissection should be done regardless of stage.26
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were too low.30 Chaput et al. found that with MMS, most patients needed one operation (72%) with median clinical excision margins of 17 mm, and only direct closure was required.31 They particularly advocated the technique for lesions on the head and neck as it is essential to spare as much tissue as possible. However, it is important to tell patients that more than one operation may be needed.29 Radiotherapy has been used as an adjuvant to excision but it is also used when resection is not possible.32 Newer treatments being investigated include imatinib mesylate, a tyrosine-kinase inhibitor that is active against tumours with the chromosomal translocation t(17;22)(q22;q13), which is often found in dermatofibrosarcoma protuberans.33 It has been shown to be useful particularly for locally advanced or metastatic disease.34
Dermatofibrosarcoma protuberans Dermatofibrosarcoma protuberans presents as a slowly expanding, painless, firm plaque or nodule that is fixed to the underlying skin. It can be red-brown or skin-coloured and may be mistaken for a keloid or dermatofibroma that grows over months or years with no history of previous operation. They can be very large at presentation because of their indolent growth, and 50% to 60% arise on the trunk, often around the shoulder and chest. The remaining 35% are found on the limbs, and 10% to 15% affect the head and neck. Unlike other cutaneous malignancies, patients aged between 24 and 50 have the highest risk, and 80% occur in this group. Overall, local recurrence has been reported at 60% but the rate of distant metastases is low.27,28 The treatment of choice is excision either with a wide margin or using MMS. Margins of 2–4 cm are needed if wide excision is done, and deep margins should extend to the underlying investing fascia (Fig. 2). Kokkinos et al. showed that wide excision has the advantage of achieving clear margins in a single procedure.29 Meguerditchian et al. found higher rates of recurrence after wide excision than after MMS, but the difference was not significant because the numbers
Microcystic adnexal carcinoma Microcystic adnexal carcinoma is a rare, malignant, adnexal tumour, possibly a low-grade carcinoma of the sweat glands, that typically occurs on the head and neck (88%),35,36 most often on the central face (73%).37 It is locally aggressive but has little metastatic potential. Most people affected are white.37 UV and ionising radiation together with immunosuppression are thought to be risk factors, although no definite association has been made. Clinical presentation can vary, but most present as fleshcoloured, smooth, asymptomatic nodules that seem to have an indolent growth pattern. Clinical and histopathological diagnoses can be difficult and many cases are misdiagnosed as basal cell carcinoma.38 Although the tumour rarely metastasises, recurrence of up to 60% makes it difficult to treat.39 Perineural invasion occurs in up to 87.5% of recurrent tumours40 and deep extension into the subcutaneous and adjacent normal tissue can add to the difficulty of complete excision. This means that there are no accepted safe margins for conventional excision so MMS has been suggested as the treatment of choice with recurrence of 0% to 12%.36,41 Postoperative radiotherapy has been found to improve disease control if operation is not successful.42 It can also be used alone if an operation is likely to result in a poor cosmetic outcome.42
Malignant fibrous histiocytoma (pleomorphic sarcoma)
Fig. 2. Dermatofibrosarcoma protuberans.
Malignant fibrous histiocytoma occurs most commonly on the skin of the head and neck and presents in the fifth to seventh decades of life,43 typically as a nodule or ulcer. Management consists of resection either with wide excision or MMS.9 Although specific measurements have not been set to ensure that margins are clear, it is generally accepted that 2 cm is required around the tumour. Magnetic resonance (MR) and
Please cite this article in press as: Green B, et al. Malignant cutaneous adnexal tumours of the head and neck: an update on management. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.03.005
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Sebaceous carcinoma
Fig. 3. Atypical fibroxanthoma.
other types of imaging can be used when tumours are likely to have penetrated deeply. Deep margins should include fascia, soft-tissue, and bone.43,44 Recurrence is estimated to occur in 2% to 20% of cases.45 Metastases have been reported in 44% of cases, but this was reduced to 18% when only the subcutaneous tissues were involved. The size and histological grade of the tumour have the greatest impact on survival: 5-year survival for tumours of less than 5 cm is 79% whereas for those between 5 and 10 cm, or over 10 cm in size, it drops to 65% and 41%, respectively.46,47 Hardison et al. suggested that chemotherapy should be used if distant metastases are detected, and that adjuvant chemotherapy should be considered if the surgical margins are in question and resection is not possible.48
Atypical fibroxanthoma Atypical fibroxanthoma is a fibrohistocytic tumour that most often occurs on the head and neck (75%).43 It was first described in 1961 as a dermal tumour and is thought to arise as a result of actinic and UV damage.49,50 Most arise in older men, and the male to female ratio is 7:1. The patient’s age and the anatomical level of the lesion at the time of diagnosis increase the risk of malignancy.51 Chronic presentation consists of a single nodule less than 2 cm in size (Fig. 3).52 Secondary ulceration can occur. Differential diagnoses include malignant fibrous histiocytoma and spindle cell squamous cell carcinoma, so biopsy examination is essential. Treatment is by wide excision or MMS, but radiotherapy and cryotherapy have also been described. Recurrence after wide excision occurs in around 10% of cases, and margins of 1–2 cm with the deep margin deep to the fascial plane, are recommended.9 It was recently shown that recurrence is less likely if safety margins are wider than 2 cm,53 and it is reduced if MMS is used because of the subclinical extension outside normal excision margins.54 If it does recur, particularly within 6 months, some authors suggest prompt surgical re-excision, sentinel lymph node biopsy (SLNB), and radiographic staging for systemic disease.55
This is a rare malignancy of the adnexal structures of the dermis and subcutaneous tissues.56 It is commonly found on the head and neck and has a propensity to occur on the eyelid in association with the meibomian glands. In a recent review of the surveillance, epidemiology and end results (SEER) database, Tryggvason et al. evaluated 1836 cases and identified a male predominance (85%) occurring at an average age of 70. Forty-two percent of the tumours were on the scalp, face, ear, neck, and lip, and 34% on the eyelid56 so it is classified as ocular or extraocular.57 The aetiology is not well understood although lesions tend not to occur in pre-existing sebaceous conditions, and variation in the clinical presentation can make diagnosis difficult. Extraocular lesions commonly present as firm papules that have a yellow hue because of the high content of fat. Ocular lesions can mimic a common chalazion (so diagnosis may be delayed), and can also present as diffuse erythema and oedema of the eyelid which resemble inflammatory processes. Biopsy examination is therefore essential for the correct diagnosis. Extraocular tumours are more likely to display intraepithelial spread.9 If sebaceous carcinoma is diagnosed, it is important to evaluate patients for Muir-Torre syndrome. This is an autosomal dominant geno-dermatosis which has mutations in the MLH1 and MSH2 genes involved in DNA mismatch repair. Clinically, the syndrome consists of one cutaneous neoplasm of the skin and one low-grade colorectal or genitourinary malignancy. Therefore, if the syndrome is suspected, further close follow-up is required.9 Excision is the mainstay of treatment. As sebaceous carcinoma is infiltrative, particularly if ocular in origin, MMS is recommended, but wide excision may be used for extraocular tumours.58,59 For more advanced orbital lesions, exenteration may be required. Recurrence has been reported to vary from 6% to 56% at 5 years.58,59 Appropriate imaging such as MR should be done to detect metastases. Regional lymph node metastases have been reported at 2.4%. The overall risk of lymph nodes being involved is higher for ocular (4.4%) than for extraocular tumours (1.4%).56 Poorly differentiated tumours metastasised to the lymph nodes in 13.9% of cases whereas well-differentiated tumours showed no signs of metastatic disease.56 To find the cause of the high reported rate of nodal metastases, Nijhawan et al. showed that in intraocular tumours, lymphatic drainage is to the preauricular and submandibular nodes, and based on these findings, they advocated close observation of the neck and elective neck dissection if required.60 Patients have had neck dissections for both primary and recurrent disease. Erovic et al. examined data from 46 patients between 1958 and 2008.61 A total of 37 had primary operations and 3 of them had neck dissections. Ten parotidectomies were done with neck dissection for recurrent disease. Most metastases were detected in parotid lymph nodes (80%) but
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they were also found in level I (40%), level II (10%), and level III (10%). None were detected in levels IV and V. Survival after recurrence was poorer (37 months) for intraocular than for extraocular tumours (81 months).61
Conflict of interest We have no conflicts of interest.
Ethics statement/confirmation of patient permission Patients have given their permission.
Acknowledgements We are grateful to Public Health England for providing the latest data on the incidence of adnexal tumours of the skin.
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17. Akthar S, Oza KK, Wright J. Merkel cell carcinoma: report of 10 cases and review of the literature. J Am Acad Dermatol 2000;43: 755–67. 18. Medina-Franco H, Urist MM, Fiveash J, et al. Multimodality treatment of Merkel cell carcinoma: case series and literature review of 1024 cases. Ann Surg Oncol 2001;8:204–8. 19. Gillenwater AM, Hessel AC, Morrison WH, et al. Merkel cell carcinoma of the head and neck: effect of surgical excision and radiation on recurrence and survival. Arch Otolaryngol Head Neck Surg 2001;127: 149–54. 20. Lemos BD, Storer BE, Iyer JG, et al. Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system. J Am Acad Dermatol 2010;63:751–61. 21. Pellitteri PK, Takes RP, Lewis Jr JS, et al. Merkel cell carcinoma of the head and neck. Head Neck 2012;34:1346–54. 22. Gupta SG, Wang LC, Pe˜nas PF, et al. Sentinel lymph node biopsy for evaluation and treatment of patients with Merkel cell carcinoma: the Dana-Farber experience and meta-analysis of the literature. Arch Dermatol 2006;142:685–90. 23. Agelli M, Clegg LX, Becker JC, et al. The etiology and epidemiology of Merkel cell carcinoma. Curr Probl Cancer 2010;34:14–37. 24. Goepfert H, Remmier D, Silva E, et al. Merkel cell carcinoma (endocrine carcinoma of the skin) of the head and neck. Arch Otolaryngol 1984;110:707–12. 25. Veness M, Foote M, Gebski V, et al. The role of radiotherapy alone in patients with Merkel cell carcinoma: reporting the Australian experience of 43 patients. Int J Radiat Oncol Biol Phys 2010;78:703–9. 26. Smith DE, Bielamowicz S, Kagan AR, et al. Cutaneous neuroendocrine (Merkel cell) carcinoma. A report of 35 cases. Am J Clin Oncol 1995;18:199–203. 27. Rouhani P, Fletcher CD, Devesa SS, et al. Cutaneous soft tissue sarcoma incidence patterns in the U.S.: an analysis of 12,114 cases. Cancer 2008;113:616–27. 28. Stoljadinovic A, Karpoff HM, Antonescu CR, et al. Dermatofibrosarcoma protuberans of the head and neck. Ann Surg Oncol 2000;7: 696–704. 29. Kokkinos C, Sorkin T, Powell B. To Mohs or not to Mohs. J Plast Reconstr Aesthet Surg 2014;67:23–6. 30. Meguerditchian AN, Wang J, Lema B, et al. Wide excision or Mohs micrographic surgery for the treatment of primary dermatofibrosarcoma protuberans. Am J Clin Oncol 2010;33:300–3. 31. Chaput B, Filleron T, Le Guellec S, et al. Dermatofibrosarcoma protuberans: margins reduction using slow-Mohs micrographic surgery. Experience with 35 patients. Ann Chir Plast Esthet 2014;59:219–25. 32. McArthur G. Dermatofibrosarcoma protuberans: recent clinical progress. Ann Surg Oncol 2007;14:2876–86. 33. Rubin BP, Schuetze SM, Eary JF, et al. Molecular targeting of plateletderived growth factor B by imatinib mesylate in a patient with metastatic dermatofibrosarcoma protuberans. J Clin Oncol 2002;20: 3586–91. 34. Llombart B, Serra-Guillén C, Monteagudo C, et al. Dermatofibrosarcoma protuberans: a comprehensive review and update on diagnosis and management. Semin Diagn Pathol 2013;30:13–28. 35. Wetter R, Goldstein GD. Microcystic adnexal carcinoma: a diagnostic and therapeutic challenge. Dermatol Ther 2008;21:452–8. 36. Friedman PM, Friedman RH, Jiang B, et al. Microcystic adnexal carcinoma: collaborative series review and update. J Am Acad Dermatol 1999;41:225–31. 37. Nadiminti H, Nadiminti U, Washington C. Microcystic adnexal carcinoma in African-Americans. Dermatol Surg 2007;33:1384–7. 38. Martorell-Calatayud A, Requena-Caballero C, Botella-Estrada R, et al. [Microcystic adnexal carcinoma: Mohs micrographic surgery as the treatment of choice]. Actas Dermosifiliogr 2009;100:693–9 [in Spanish]. 39. Chiller K, Passaro D, Scheuller M, et al. Microcystic adnexal carcinoma: forty-eight cases, their treatment and their outcome. Arch Dermatol 2000;136:1355–9.
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40. Sebastien TS, Nelson BR, Lowe L, et al. Microcystic adnexal carcinoma. J Am Acad Dermatol 1993;29:840–5. 41. Snow S, Madjar DD, Hardy S, et al. Microcystic adnexal carcinoma: report of 13 cases and review of the literature. Dermatol Surg 2001;27:401–8. 42. Pugh TJ, Lee NY, Pacheco T, et al. Microcystic adnexal carcinoma of the face treated with radiation therapy: a case report and review of the literature. Head Neck 2012;34:1045–50. 43. Withers AH, Brougham ND, Barber RM, et al. Atypical fibroxanthoma and malignant fibrous histiocytoma. J Plast Reconstr Aesthet Surg 2011;64:e273–8. 44. Stadler FJ, Scott GA, Brown MD. Malignant fibrous tumors. Semin Cutan Med Surg 1998;17:141–52. 45. Kim JP, Ko GH, Kim JY, et al. Atypical fibroxanthoma in head and neck. Clin Exp Otorhinolaryngol 2014;7:73–5. 46. Weiss SW, Enzinger FM. Malignant fibrous histiocytoma: an analysis of 200 cases. Cancer 1978;41:2250–66. 47. Pezzi CM, Rawlings Jr MS, Esgro JJ, et al. Prognostic factors in 227 patients with malignant fibrous histiocytoma. Cancer 1992;69:2098–103. 48. Hardison SA, Davis III PL, Browne JD. Malignant fibrous histiocytoma of the head and neck: a case series. Am J Otolaryngol 2013;34:10–5. 49. Dei Tos AP, Maestro R, Doglioni C, et al. Ultraviolet induced p53 mutations in atypical fibroxanthoma. Am J Pathol 1994;145:11–7. 50. Davis JL, Randle HW, Zalla MJ, et al. A comparison of Mohs micrographic surgery and wide excision for the treatment of atypical fibroxanthoma. Dermatol Surg 1997;23:105–10. 51. Davidson JS, Demsey D. Atypical fibroxanthoma: clinicopathologic determinants for recurrence and implications for surgical management. J Surg Oncol 2012;105:559–62.
52. Love WE, Schmitt AR, Bordeaux JS. Management of unusual cutaneous malignancies: atypical fibroxanthoma, malignant fibrous histiocytoma, sebaceous carcinoma, extramammary Paget disease. Dermatol Clin 2011;29:201–16. 53. Wollina U, Schönlebe J, Ziemer M, et al. Atypical fibroxanthoma: a series of 56 tumors and an unexplained uneven distribution of cases in southeast Germany. Head Neck 2014 [Epub ahead of print]. 54. Sahn RE, Lang PG. Sentinel lymph node biopsy for high-risk nonmelanoma skin cancers. Dermatol Surg 2007;33:786–93. 55. Cooper JZ, Newman SR, Scott GA, et al. Metastasizing atypical fibroxanthoma (cutaneous malignant histiocytoma): report of five cases. Dermatol Surg 2005;31:221–5. 56. Tryggvason G, Bayon R, Pagedar NA. Epidemiology of sebaceous carcinoma of the head and neck: implications for lymph node management. Head Neck 2012;34:1765–8. 57. Shields JA, Demirci H, Marr BP, et al. Sebaceous carcinoma of the ocular region: a review. Surv Ophthalmol 2005;50:103–22. 58. Spencer JM, Nossa R, Tse DT, et al. Sebaceous carcinoma of the eyelid treated with Mohs micrographic surgery. J Am Acad Dermatol 2001;44:1004–9. 59. Thomas CJ, Wood GC, Marks VJ. Mohs micrographic surgery in the treatment of rare aggressive cutaneous tumors: the Geisinger experience. Dermatol Surg 2007;33:333–9. 60. Nijhawan N, Marriott C, Harvey JT. Lymphatic drainage patterns of the human eyelid: assessed by lymphoscintigraphy. Ophthal Plast Reconstr Surg 2010;26:281–5. 61. Erovic BM, Goldstein DP, Kim D, et al. Sebaceous gland carcinoma of the head and neck: the Princess Margaret Hospital experience. Head Neck 2013;35:316–20.
Please cite this article in press as: Green B, et al. Malignant cutaneous adnexal tumours of the head and neck: an update on management. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.03.005
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British Journal of Oral and Maxillofacial Surgery xxx (2015) xxx–xxx
Review
Malignant cutaneous adnexal tumours of the head and neck: an update on management B. Green a,∗ , D. Godden b , P.A. Brennan c a b c
Craniofacial Unit, Great Ormond Street Hospital for Children, London, UK Department of Oral & Maxillofacial Surgery, Gloucestershire Royal Hospital, UK Department of Oral & Maxillofacial Surgery, Queen Alexandra Hospital, Portsmouth, UK
Accepted 12 March 2015
Abstract Adnexal tumours form a heterogeneous group of relatively rare neoplasms. Many of them have a poor prognosis and treatment can sometimes be difficult and controversial. We summarise the latest publications relating to malignant cutaneous adnexal tumours of the head and neck, and give an update on their management. We discuss Merkel cell carcinoma and other rare malignant adnexal tumours including dermatofibrosarcoma protuberans and atypical fibroxanthoma. © 2015 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Keywords: Review; Adnexal tumours; Head and neck
Introduction
Merkel cell carcinoma (MCC)
In the United Kingdom, skin cancer is managed by specialist multidisciplinary teams of which maxillofacial surgeons are usually core members. Most skin cancers are basal cell carcinoma, squamous cell carcinoma, or melanoma, but it is important to understand the management of less common cutaneous malignancies (Table 1). We review the heterogeneous group of adnexal cancers of the skin, and outline their management.
Merkel cells contain neurosecretory granules and are found on the basal layer of the epidermis.1 Previously, MCC was described as trabecular carcinoma or cutaneous neuroendocrine carcinoma.1 Its incidence is higher in men than in women (2:1)2 and it is rare in young people with most cases occurring in those over 50 years of age.3 White-skinned people have the highest risk. As with other non-melanoma skin cancers, its incidence is high in areas exposed to ultraviolet (UV) light and the sites most commonly affected are on the head and neck (48%).4 Although its cause is poorly understood, UV light is implicated and has been identified in cases in immunocompromised patients with autoimmune and iatrogenic diseases; partial regression of metastases has been reported after immunosuppression has been stopped.5–8 In patients having psoralen-UV treatment for psoriasis its incidence is about 100 times higher than that seen in the general population,
∗ Corresponding author at: Craniofacial Unit, Great Ormond Street Hospital for Children, Great Ormond Street, London WC1N 3JH, UK. E-mail addresses: [email protected], [email protected] (B. Green), [email protected] (D. Godden), [email protected] (P.A. Brennan).
http://dx.doi.org/10.1016/j.bjoms.2015.03.005 0266-4356/© 2015 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Green B, et al. Malignant cutaneous adnexal tumours of the head and neck: an update on management. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.03.005
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Table 1 Number of cases of cutaneous adnexal tumours reported in England in 2012.
Table 2 TNM criteria for Merkel cell carcinoma (based on Lemos et al.20 ).
Adnexal tumour
No. of cases
T:
Merkel cell carcinoma Microcystic adnexal carcinoma Sebaceous carcinoma Malignant fibrous histiocytoma/pleomorphic sarcoma
227 23 115 110
which indicates that both UVA and UVB radiation have a role.9 Viral infection could also be an important factor.10 A new virus, Merkel cell polyomavirus (MCPyV) has been found in 80% of patients over 50,11 and although little is known about transmission and latency, its prevalence in MCC lesions has been reported to range from 40% to 100%.12,13 As it is present in both primary and metastatic disease,14 it can be argued that MCPyV is a carcinogen.15 Commonly, MCC develops as an asymptomatic, rapidly growing, flesh-coloured, firm, and non-tender nodule but plaque-like variants also occur (Fig. 1).16 The vascular pattern consists of polymorphic vessels. To act as an aide-mémoire for its clinical characteristics, the acronym “AEIOU” has been suggested: asymptomatic, rapidly expanding, immunosuppressed, older patient, UV exposure.16 Differential diagnoses can include atypical fibroxanthoma, lymphoma, and amelanotic melanoma. Since its description, several staging systems have been suggested and one by the American Joint Committee on Cancer in 2010 has been generally accepted (Tables 2 and 3). Recurrence has been reported to be between 25% and 30%. Regional lymph nodes are reported to be involved in 52% to 59%, and distal metastases in 34% to 36% of all cases, and as MCC has higher metastatic and mortality rates than melanoma, treatment needs to be aggressive.17–20 Operation is the primary treatment.9 Some surgeons support the use of wide excision margins (1–2 cm), and Mohs micrographic surgery (MMS) has been suggested as a viable alternative as local recurrence rates were comparable to those after wide excision.21 Further treatment depends on the route
Tx T0 Tis T1 T2 T3 T4 N: Nx N0 cN0 cN1 pN0 pNx N1a N1b N2 M: Mx M0 M1 M1a M1b M1c
Primary tumour cannot be assessed No primary tumour In situ primary tumour Primary tumour less than 2 cm Primary tumour more than 2 cm but less than 5 cm Primary tumour more than 5 cm Primary tumour invades bone, muscle, fascia, or cartilage Regional nodes cannot be assessed No regional nodal metastasis Nodes not clinically detectable Nodes detected clinically No nodal disease on pathological evaluation Nodes not evaluated pathologically Micrometastases Macrometastases In-transit metastases Distant metastases cannot be assessed No distant metastases Distant metastases Distant skin, distant subcutaneous tissue or distant lymph node metastases Metastases to lung Metastasis to other visceral sites
of drainage of the primary lymph nodes.22 Overall 5-year survival is around 62%.23 Five-year survival for patients with local disease is 64%, but for those with nodal disease and distant metastases it is only 39% and 18%, respectively. The low rate for local disease is the result of the discrepancy between T1 lesions (79% 5-year survival) and T4 lesions (47% 5-year survival), which both fall into this category.20 There is also a mucosal variant but this has a much lower incidence (4.5%).21 It most commonly affects the larynx followed by the nasal cavity, pharynx, mouth, and tongue, and has a poorer prognosis than the cutaneous type. Overall survival is 49% at 2 years.23 As metastases are common in MCC, and microscopic disease has been found in up to 50% of patients who have elective neck dissection,24 there is much discussion about appropriate management when there are no sign of metastases in the neck. Gillenwater et al.19 reported that recurrence developed in 23/24 patients who had presented with a clinically N0 neck Table 3 Merkel cell staging (based on Lemos et al.20 ).
Fig. 1. Merkel cell carcinoma.
Stage
Stage grouping (TNM)
0 IA IB IIA IIB IIC IIIA IIIB IV
Tis T1 T1 T2/T3 T2/T3 T4 Any T Any T Any T
N0 pN0 cN0 pN0 cN0 N0 N1a N1b/N2 Any N
M0 M0 M0 M0 M0 M0 M0 M0 M1
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and had had no treatment, and 42% had died of their disease, which indirectly supports the use of elective neck dissection in these cases. Nodal recurrence in patients with a cN0 neck who had operation alone was 50% compared with 19% in those who had had adjuvant radiotherapy. The drainage nodes can be included in an en-bloc field that also treats the primary site.25 Smith et al. found 65% recurrence and 29% mortality in patients who had local treatment only, whereas in those treated locoregionally at presentation it was 27% and 14%, respectively. Locoregional treatment has been advocated at the time of presentation in all patients, and it could therefore be argued that elective neck dissection should be done regardless of stage.26
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were too low.30 Chaput et al. found that with MMS, most patients needed one operation (72%) with median clinical excision margins of 17 mm, and only direct closure was required.31 They particularly advocated the technique for lesions on the head and neck as it is essential to spare as much tissue as possible. However, it is important to tell patients that more than one operation may be needed.29 Radiotherapy has been used as an adjuvant to excision but it is also used when resection is not possible.32 Newer treatments being investigated include imatinib mesylate, a tyrosine-kinase inhibitor that is active against tumours with the chromosomal translocation t(17;22)(q22;q13), which is often found in dermatofibrosarcoma protuberans.33 It has been shown to be useful particularly for locally advanced or metastatic disease.34
Dermatofibrosarcoma protuberans Dermatofibrosarcoma protuberans presents as a slowly expanding, painless, firm plaque or nodule that is fixed to the underlying skin. It can be red-brown or skin-coloured and may be mistaken for a keloid or dermatofibroma that grows over months or years with no history of previous operation. They can be very large at presentation because of their indolent growth, and 50% to 60% arise on the trunk, often around the shoulder and chest. The remaining 35% are found on the limbs, and 10% to 15% affect the head and neck. Unlike other cutaneous malignancies, patients aged between 24 and 50 have the highest risk, and 80% occur in this group. Overall, local recurrence has been reported at 60% but the rate of distant metastases is low.27,28 The treatment of choice is excision either with a wide margin or using MMS. Margins of 2–4 cm are needed if wide excision is done, and deep margins should extend to the underlying investing fascia (Fig. 2). Kokkinos et al. showed that wide excision has the advantage of achieving clear margins in a single procedure.29 Meguerditchian et al. found higher rates of recurrence after wide excision than after MMS, but the difference was not significant because the numbers
Microcystic adnexal carcinoma Microcystic adnexal carcinoma is a rare, malignant, adnexal tumour, possibly a low-grade carcinoma of the sweat glands, that typically occurs on the head and neck (88%),35,36 most often on the central face (73%).37 It is locally aggressive but has little metastatic potential. Most people affected are white.37 UV and ionising radiation together with immunosuppression are thought to be risk factors, although no definite association has been made. Clinical presentation can vary, but most present as fleshcoloured, smooth, asymptomatic nodules that seem to have an indolent growth pattern. Clinical and histopathological diagnoses can be difficult and many cases are misdiagnosed as basal cell carcinoma.38 Although the tumour rarely metastasises, recurrence of up to 60% makes it difficult to treat.39 Perineural invasion occurs in up to 87.5% of recurrent tumours40 and deep extension into the subcutaneous and adjacent normal tissue can add to the difficulty of complete excision. This means that there are no accepted safe margins for conventional excision so MMS has been suggested as the treatment of choice with recurrence of 0% to 12%.36,41 Postoperative radiotherapy has been found to improve disease control if operation is not successful.42 It can also be used alone if an operation is likely to result in a poor cosmetic outcome.42
Malignant fibrous histiocytoma (pleomorphic sarcoma)
Fig. 2. Dermatofibrosarcoma protuberans.
Malignant fibrous histiocytoma occurs most commonly on the skin of the head and neck and presents in the fifth to seventh decades of life,43 typically as a nodule or ulcer. Management consists of resection either with wide excision or MMS.9 Although specific measurements have not been set to ensure that margins are clear, it is generally accepted that 2 cm is required around the tumour. Magnetic resonance (MR) and
Please cite this article in press as: Green B, et al. Malignant cutaneous adnexal tumours of the head and neck: an update on management. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.03.005
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Sebaceous carcinoma
Fig. 3. Atypical fibroxanthoma.
other types of imaging can be used when tumours are likely to have penetrated deeply. Deep margins should include fascia, soft-tissue, and bone.43,44 Recurrence is estimated to occur in 2% to 20% of cases.45 Metastases have been reported in 44% of cases, but this was reduced to 18% when only the subcutaneous tissues were involved. The size and histological grade of the tumour have the greatest impact on survival: 5-year survival for tumours of less than 5 cm is 79% whereas for those between 5 and 10 cm, or over 10 cm in size, it drops to 65% and 41%, respectively.46,47 Hardison et al. suggested that chemotherapy should be used if distant metastases are detected, and that adjuvant chemotherapy should be considered if the surgical margins are in question and resection is not possible.48
Atypical fibroxanthoma Atypical fibroxanthoma is a fibrohistocytic tumour that most often occurs on the head and neck (75%).43 It was first described in 1961 as a dermal tumour and is thought to arise as a result of actinic and UV damage.49,50 Most arise in older men, and the male to female ratio is 7:1. The patient’s age and the anatomical level of the lesion at the time of diagnosis increase the risk of malignancy.51 Chronic presentation consists of a single nodule less than 2 cm in size (Fig. 3).52 Secondary ulceration can occur. Differential diagnoses include malignant fibrous histiocytoma and spindle cell squamous cell carcinoma, so biopsy examination is essential. Treatment is by wide excision or MMS, but radiotherapy and cryotherapy have also been described. Recurrence after wide excision occurs in around 10% of cases, and margins of 1–2 cm with the deep margin deep to the fascial plane, are recommended.9 It was recently shown that recurrence is less likely if safety margins are wider than 2 cm,53 and it is reduced if MMS is used because of the subclinical extension outside normal excision margins.54 If it does recur, particularly within 6 months, some authors suggest prompt surgical re-excision, sentinel lymph node biopsy (SLNB), and radiographic staging for systemic disease.55
This is a rare malignancy of the adnexal structures of the dermis and subcutaneous tissues.56 It is commonly found on the head and neck and has a propensity to occur on the eyelid in association with the meibomian glands. In a recent review of the surveillance, epidemiology and end results (SEER) database, Tryggvason et al. evaluated 1836 cases and identified a male predominance (85%) occurring at an average age of 70. Forty-two percent of the tumours were on the scalp, face, ear, neck, and lip, and 34% on the eyelid56 so it is classified as ocular or extraocular.57 The aetiology is not well understood although lesions tend not to occur in pre-existing sebaceous conditions, and variation in the clinical presentation can make diagnosis difficult. Extraocular lesions commonly present as firm papules that have a yellow hue because of the high content of fat. Ocular lesions can mimic a common chalazion (so diagnosis may be delayed), and can also present as diffuse erythema and oedema of the eyelid which resemble inflammatory processes. Biopsy examination is therefore essential for the correct diagnosis. Extraocular tumours are more likely to display intraepithelial spread.9 If sebaceous carcinoma is diagnosed, it is important to evaluate patients for Muir-Torre syndrome. This is an autosomal dominant geno-dermatosis which has mutations in the MLH1 and MSH2 genes involved in DNA mismatch repair. Clinically, the syndrome consists of one cutaneous neoplasm of the skin and one low-grade colorectal or genitourinary malignancy. Therefore, if the syndrome is suspected, further close follow-up is required.9 Excision is the mainstay of treatment. As sebaceous carcinoma is infiltrative, particularly if ocular in origin, MMS is recommended, but wide excision may be used for extraocular tumours.58,59 For more advanced orbital lesions, exenteration may be required. Recurrence has been reported to vary from 6% to 56% at 5 years.58,59 Appropriate imaging such as MR should be done to detect metastases. Regional lymph node metastases have been reported at 2.4%. The overall risk of lymph nodes being involved is higher for ocular (4.4%) than for extraocular tumours (1.4%).56 Poorly differentiated tumours metastasised to the lymph nodes in 13.9% of cases whereas well-differentiated tumours showed no signs of metastatic disease.56 To find the cause of the high reported rate of nodal metastases, Nijhawan et al. showed that in intraocular tumours, lymphatic drainage is to the preauricular and submandibular nodes, and based on these findings, they advocated close observation of the neck and elective neck dissection if required.60 Patients have had neck dissections for both primary and recurrent disease. Erovic et al. examined data from 46 patients between 1958 and 2008.61 A total of 37 had primary operations and 3 of them had neck dissections. Ten parotidectomies were done with neck dissection for recurrent disease. Most metastases were detected in parotid lymph nodes (80%) but
Please cite this article in press as: Green B, et al. Malignant cutaneous adnexal tumours of the head and neck: an update on management. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.03.005
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they were also found in level I (40%), level II (10%), and level III (10%). None were detected in levels IV and V. Survival after recurrence was poorer (37 months) for intraocular than for extraocular tumours (81 months).61
Conflict of interest We have no conflicts of interest.
Ethics statement/confirmation of patient permission Patients have given their permission.
Acknowledgements We are grateful to Public Health England for providing the latest data on the incidence of adnexal tumours of the skin.
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52. Love WE, Schmitt AR, Bordeaux JS. Management of unusual cutaneous malignancies: atypical fibroxanthoma, malignant fibrous histiocytoma, sebaceous carcinoma, extramammary Paget disease. Dermatol Clin 2011;29:201–16. 53. Wollina U, Schönlebe J, Ziemer M, et al. Atypical fibroxanthoma: a series of 56 tumors and an unexplained uneven distribution of cases in southeast Germany. Head Neck 2014 [Epub ahead of print]. 54. Sahn RE, Lang PG. Sentinel lymph node biopsy for high-risk nonmelanoma skin cancers. Dermatol Surg 2007;33:786–93. 55. Cooper JZ, Newman SR, Scott GA, et al. Metastasizing atypical fibroxanthoma (cutaneous malignant histiocytoma): report of five cases. Dermatol Surg 2005;31:221–5. 56. Tryggvason G, Bayon R, Pagedar NA. Epidemiology of sebaceous carcinoma of the head and neck: implications for lymph node management. Head Neck 2012;34:1765–8. 57. Shields JA, Demirci H, Marr BP, et al. Sebaceous carcinoma of the ocular region: a review. Surv Ophthalmol 2005;50:103–22. 58. Spencer JM, Nossa R, Tse DT, et al. Sebaceous carcinoma of the eyelid treated with Mohs micrographic surgery. J Am Acad Dermatol 2001;44:1004–9. 59. Thomas CJ, Wood GC, Marks VJ. Mohs micrographic surgery in the treatment of rare aggressive cutaneous tumors: the Geisinger experience. Dermatol Surg 2007;33:333–9. 60. Nijhawan N, Marriott C, Harvey JT. Lymphatic drainage patterns of the human eyelid: assessed by lymphoscintigraphy. Ophthal Plast Reconstr Surg 2010;26:281–5. 61. Erovic BM, Goldstein DP, Kim D, et al. Sebaceous gland carcinoma of the head and neck: the Princess Margaret Hospital experience. Head Neck 2013;35:316–20.
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