Atypical Fibroxanthoma: A case series and review of literature

Auris Nasus Larynx 42 (2015) 469–471

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Atypical Fibroxanthoma: A case series and review of literature Sridhayan Mahalingam a,*, Aadarsh Shah b, Andrew Stewart a a b

Epsom and St Helier University Hospitals NHS Trust, Wrythe Lane, Carshalton SM5 1AA, United Kingdom North Middlesex University Hospital, Sterling Way, London N18 1QX, United Kingdom

A R T I C L E I N F O

A B S T R A C T

Article history: Received 18 November 2014 Accepted 5 April 2015 Available online 22 April 2015

Intro/objective: Atypical Fibroxanthoma (AFX) is a rare cutaneous neoplasm arising from myofibroblast or fibroblast-like cells that predominantly affects the head and neck region. It commonly mimics more invasive neoplasms and is a diagnostic challenge to clinicians. The aim of this study was to develop a better understanding of AFX, focusing on recent developments in diagnosis and management. Methods: A retrospective case series and review of recent literature were carried out. Results: Over a 17-year period, seven cases were identified (six male, mean age at presentation was 75.9 years). Two patients underwent complete excision and five patients had curettage and cauterisation. Two patients developed local recurrence but none demonstrated signs suggestive of metastatic spread. Histologically all seven lesions displayed a spindle cell pattern. Where performed, immunohistochemical staining was positive for Vimentin, CD10, CD68 and actin, and negative for CAM 5.2, CD34, Melan-A, S100 protein, HMB45, Cytokeratin A1/A3. Conclusion: Our patient demographics, histopathology and immunohistochemistry are comparable to previous studies. Although advances have been made in immunohistochemical analysis, we are yet to discover a specific diagnostic immunostain for AFX. Clinical findings should therefore be correlated with histology and a panel of immunohistochemical stains should be used. Given the potential for recurrence or metastases, Moh’s Micrographic Surgery with regular follow-up may be the preferred management. ß 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: Atypical Fibroxanthoma AFX

1. Introduction Atypical Fibroxanthoma (AFX) is a rare cutaneous neoplasm that predominantly affects the head and neck region. It was originally defined in 1961 as a dermal tumour composed of atypical spindle cells with a benign clinical course [1]. An accumulation of evidence in conjunction with recent advances in histopathology and immunohistochemistry has allowed us to develop a greater understanding of this condition over time. Contrary to initial beliefs, it is currently defined as a tumour of intermediate malignant potential arising from myofibroblast or fibroblast-like cells [2,3]. Previous studies have suggested that AFX has a greater male to female preponderance [4], with ultraviolet (UV) radiation thought to be the major risk factor [2]. Given its rarity and lack of differentiating factors from other potentially more aggressive cutaneous neoplasms, the clinical diagnosis is challenging and

* Corresponding author at: Epsom and St Helier University Hospitals NHS Trust, Wrythe Lane, Carshalton SM5 1AA, United Kingdom. Tel.: +44 02082962435; fax: +44 02082963233. E-mail address: [email protected] (S. Mahalingam). http://dx.doi.org/10.1016/j.anl.2015.04.001 0385-8146/ß 2015 Elsevier Ireland Ltd. All rights reserved.

often it is a diagnosis of exclusion. It commonly presents to dermatologists and plastic surgeons, however due to its preponderance for the head and neck it is often frequently encountered by Head and Neck Surgeons. Thus its clinical significance must be recognized within the specialty of Otolaryngology and Head and Neck Surgery. Here we present a case series of patients diagnosed with AFX and a review of recent literature in an attempt to develop a better understanding of this condition (Fig. 1). 2. Materials and methods A retrospective case series of all the patients diagnosed with AFX was carried out in one hospital site over a 17-year period. For each individual case, we reviewed patient demographics, key clinical features, histopathology, immunohistochemistry, treatment modalities and follow-up. Results were correlated with recent literature. 3. Results Seven cases of AFX were identified with a 6:1 male to female ratio (Table 1). All the patients were of Caucasian origin and mean

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suggest that curettage and cauterisation are appropriate for small (<1 cm) well-defined slow growing tumours in the hands of someone experienced, whilst surgical excision should be considered otherwise. Therefore, five patients initially underwent curettage and cauterisation and two patients underwent complete excision with greater than 5 mm margins. At a follow-up of two years, two patients who had undergone curettage and cauterisation developed local recurrence and underwent complete excision with no further recurrences thereafter. 4. Discussion

Fig. 1. Photograph of AFX on left temporal region. Reproduced with permission from DermNet NZ.

age at presentation was 75.9 years (range 58–89). All the patients presented with lesions on the head and neck region (five scalp, one forehead and one cheek). Five patients exhibited evidence of previous actinic skin damage (four with solar keratosis, one with previous basal cell carcinoma). Every patient presented with a solitary lesion; of whom four demonstrated evidence of ulceration, and two appeared haemorrhagic. Mean diameter was 9.8 mm (range 3–22), and depth 5.8 mm (range 3–8). Histologically, all seven lesions displayed a spindle cell pattern, with prominent mitotic activity in three cases. Where performed, immunohistochemical analysis showed that cells were positive for Vimentin, CD10, CD68 and actin, and negative for CAM 5.2, CD34, Melanin A, S100 protein, HMB45, Cytokeratin A1/A3 and Epithelial Membrane Antigen (EMA) (Table 2). All the lesions were initially suspected to be squamous cell carcinoma. Hence treatment modalities were selected according to lesion size, the experience and preference of the operating surgeon. The more recent cases were managed as recommended by the Multi-professional guidelines for Squamous Cell Carcinoma published by the British Association of Dermatologists [5], which

AFX is a relatively rare mesenchymal neoplasm, which is reflected in our limited number of cases over nearly two decades. Despite the true incidence remaining unknown one study reported that 0.24% of skin cancers treated with Moh’s Micrographic Surgery (MMS) were diagnosed as AFX [6]. Although actinic damage induced by UV radiation is considered to be the major causative factor, other possible risk factors include immunosuppression, Xray radiation, skin trauma [7] and other underlying skin disorders such as xeroderma pigmentosa [8]. Interestingly, amongst the transplant population the incidence of AFX has been recorded as high as 78 per 100,000 patients [9]. The majority of cases present in the head and neck region, however it has also been reported in the trunk and limbs. The latter is thought to occur in a younger cohort of patients (median age 39 vs. 69 years in the head and neck) [4]. AFX usually presents as a solitary nodular or papular lesion, which are generally less than 2 cm in size. Our mean diameter of 9.8 mm of the lesions at presentation is comparable to previous literature. It most commonly appears as an exophytic polyp which is rapidly enlarging and can exhibit ulceration and haemorrhage [10]. Dermoscopic findings can be varied and nonspecific. Based on clinical examination alone it is often initially misdiagnosed as another more common skin disorder such as basal cell carcinoma, squamous cell carcinoma, melanoma or pyogenic granuloma. Given its rarity it is most often a diagnosis of exclusion based on histology and immunohistochemistry findings.

Table 1 Key features of AFX identified from the case series. Patient

Age

Sex

Previous skin conditions

Site

Examination

Size (mm)

Depth (mm)

Initial management

Further management

1 2 3 4 5

58 83 77 89 82

M M M M M

Solar keratosis BCC Nose None None Solar keratosis

Scalp Scalp Scalp Scalp Scalp

Central dome shaped lesion Ulcerated lesion, bleeding Amelanotic nodule Ulcerated lesion, bleeding Ulcerated lesion, crusting

20  22 33 10  8 88 56

5 3 7 8 5

Excision Curettage Curettage Curettage Curettage

6

63

F

Forehead

Ulcerated lesion

66

6

Curettage and cautery

7

79

M

Solar keratosis, previous BCC Solar keratosis

Cheek

Nodule with crusting

10  6

3

Excision

No recurrence No recurrence No recurrence No recurrence Curettage and cautery x3, excision after 2 yrs. Excision–no recurrence thereafter. No recurrence

and and and and

cautery cautery cautery cautery

BCC, basal cell carcinoma.

Table 2 Immunohistochemical analysis of individual lesions. Patient

Actin

1 2 3 4 5 6 7

+ve NA NA NA NA NA +ve

CAM 5.2

+ve (stained positive),

ve ve ve ve ve ve ve

CK 5/6

CD 34

Melanin A

S100

Vimentin

HMB45

Cytokeratin A1/A3

CD10

CK903

CD 68

EMA

Desmin

ve NA ve NA NA NA NA

ve NA ve NA NA ve NA

ve ve ve NA ve ve ve

ve ve NA ve ve ve NA

NA +ve NA NA +ve NA NA

NA ve ve ve ve ve NA

NA ve NA NA ve ve NA

NA NA +ve NA NA +ve +ve

NA NA ve NA NA NA -ve

NA NA NA +ve +ve NA NA

NA NA NA ve ve NA ve

NA NA NA NA NA NA ve

ve (stained negative), NA (not assessed).

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Histologically AFX cells are most commonly seen to have a spindle, epithelioid or multi-nucleate giant cell morphology [11]. The cells demonstrate highly atypical mitotic activity, are pleiomorphic with hyperchromatism and can express intracytoplasmic lipidization [8,12]. Vascular and peri-neural invasion is rare and alongside subcutaneous extension and necrosis suggests a more aggressive lesion. Formerly known as malignant fibrous histiocytoma (MFH), undifferentiated pleomorphic sarcoma (UPS) is known to be more aggressive than AFX with higher rates of recurrence, metastases and a much poorer prognosis. Due to their similarities histologically some authors argue that cases of metastatic AFX are actually UPS or they represent a spectrum of disease rather than distinct processes [2,13]. However, recent evidence suggests that UPS shows more complex cytogenetics [10] as well as mutations in the H-ras and K-ras pathway which is absent in AFX [14]. The distinctions between UPS and aggressive AFX lesions are key as the former is more aggressive and has a poorer prognosis. AFX also shows varied morphological characteristics giving rise to variants including spindle cell, clear-cell, desmoplastic, granular, angiomatoid, hemosiderotic, myxoid and others [10]. Based on its varied histological findings it can mimic other tumours including spindle cell squamous cell carcinomas (SCC), desmoplastic melanomas. Thus immunohistochemistry is used to help differentiate AFX from these cutaneous malignancies. Multiple case series have shown that AFX stains positive for vimentin, CD10 [15,16], CD99 and CD68 [17], however these are non-specific [7]. The lack of positive stain for cytokeratins and S100 protein helps distinguish AFX from spindle cell SCC and malignant melanoma respectively [10]. S-100 protein is useful when differentiating AFX from desmoplastic melanomas as they can stain negative for HMB-45 and Melan-A, stains that are normally positive in other melanomas [8]. Leiomyosarcomas will stain positively for Desmin and in some cases cytokeratinins which again is negative in AFX [18]. No single stain has been found to help differentiate UPS from AFX and the earlier promising evidence [19] of CD74 (LN-2) as a differentiator has more recently been refuted [20]. Although studies have attempted to identify immunological markers that are specific for AFX, they are yet to be identified. AFX very much remains a diagnosis of exclusion reached through a combination of clinical, histopathological and immunohistochemical findings. Many different treatment modalities have been employed. These include cryotherapy, curettage, wide local excision (WLE) and MMS. Recurrence rates can vary and it is thought to occur most commonly due to inadequate initial clearance. Although we experienced no cases of metastatic AFX, it is important to note that there have been such cases reported in the literature [3]. Given the lack of certainty in diagnosis and the potential for recurrence or metastases, it has been suggested that MMS should be the preferred modality of treatment [7]. MMS offers the advantage of microscopic control of surgical margins, a lower recurrence rate than that with WLE and conserves normal tissue [21]. There is no general consensus on the duration of follow-up, however due to the possibility of recurrence, metastases and development of other skin malignancies, one review has suggested that patients diagnosed with AFX should undergo 6-monthly review [7]. 5. Conclusion Here we report a case series of seven patients diagnosed and treated for AFX and a review of the most recent literature. Given the possibility of recurrence or metastatic spread it is important for

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clinicians from different specialties to be aware of the current diagnostic and treatment options. Conflict of interest None declared. Financial support Self-funded. Acknowledgements The authors would like to thank Dr. Stephen Sampson (Consultant Histopathologist at Epsom & St Helier University Hospitals NHS Trust) for reviewing and ensuring accuracy of this manuscript, and for Dr. James Kelly (Brighton and Sussex University Hospitals NHS Trust) for obtaining access to Figure 1. References [1] Helwig EB. Atypical fibroxanthoma, in tumor seminar: proceedings of 18th annual seminar of San Antonio society of pathologists, 1961. Tex J Med 1963;59:664–7. [2] Weiss SW, Goldblum JR. Malignant fibrous histiocytoma (pleomorphic undifferentiated sarcoma). In: Enzinger & Weiss’s soft tissue tumors. 5th edition, Mosby: Elsevier; 2008. p. 403–27. [3] Helwig EB, May D. Atypical fibroxanthoma of the skin with metastasis. Cancer 1986;57:368–76. [4] Fretzin DF, Helwig EB. Atypical fibroxanthoma of the skin. A clinicopathologic study of 140 cases. Cancer 1973;31:1541–52. [5] Motley RJ, Preston PW, Lawrence CM. Multi-professional Guidelines for the Management of the Patient with Primary Cutaneous Squamous Cell Carcinoma. British Association of Dermatologists; 2015 , http://www.bad.org.uk/ library-media%5Cdocuments%5CSCC_2009.pdf (accessed 01.15). [6] Anderson HL, Joseph AK. A pilot feasibility study of a rare skin tumor database. Dermatol Surg 2007;33:693–6. [7] Hiscutt EL, Adams JR, Ryan JM, Langtry JA, Natarajan S. Atypical fibroxanthoma, lentigo maligna melanoma and squamous cell carcinoma arising in the site of a thermal burn treated with skin grafts. Br J Oral Maxillofac Surg 2009;47: 157–8. [8] Lorizzo LJ, Brown MD. Atypical fibroxanthoma: a review of the literature. Dermatol Surg 2011;37:146–57. [9] Hafner J, Kunzi W, Weinreich T. Malignant fibrous histiocytoma and atypical fibroxanthoma in renal transplant recipients. Dermatology 1999;198:29–32. [10] Gru AA, Santa Cruz DJ. Atypical fibroxanthoma: a selective review. Semin Diagn Pathol 2013 Feb;30:4–12. [11] Luzar B, Calonje E. Morphological and immunohistochemical characteristics of atypical fibroxanthoma with a special emphasis on potential diagnostic pitfalls: a review. J Cutan Pathol 2010;37:301–9. [12] Beer TW, Drury P, Heenan PJ. Atypical fibroxanthoma: a histological and immunohistochemical review of 171 cases. Am J Dermatopathol 2010;32: 533–40. [13] New D, Bahrami S, Malone J, Callen JP. Atypical Fibroxanthoma with regional lymph node metastasis. Arch Dermatol 2010;146:1399–404. [14] Sakamoto A, Oda Y, Itakura E, et al. H-, K-, and N-ras gene mutation in atypical fibroxanthoma and malignant fibrous histiocytoma. Hum Pathol 2001;32: 1225–31. [15] Clarke LE. Fibrous and fibrohistiocytic neoplasms: an update. Dermatol Clin 2012;30:643–56. [16] Smith KJ, Skelton HG, Morgan AM, Barrett TL, Lupton GP. Spindle cell neoplasms coexpressing cytokeratin and vimentin (metaplastic squamous cell carcinoma). J Cutan Pathol 1992;19:286–93. [17] Monteagudo C, Calduch L, Navarro S, Joan-Figueroa A, Llombart-Bosch A. CD99 immunoreactivity in atypical fibroxanthoma: a common feature of diagnostic value. Am J Clin Pathol 2002;117:126–31. [18] Iwata J, Fletcher CD. Immunohistochemical detection of cytokeratin and epithelial membrane antigen in leiomyosarcoma: a systematic study of 100 cases. Pathol Int 2000;50:7–14. [19] Lazova R, Moynes R, May D, Scott G. LN-2 (CD74). A marker to distinguish atypical fibroxanthoma from malignant fibrous histiocytoma. Cancer 1997;79: 2115–24. [20] Hollmig ST, Rieger KE, Henderson MT, West RB, Sundram UN. Reconsidering the diagnostic and prognostic utility of LN-2 for undifferentated pleomorphic sarcoma and Atypical Fibroxanthoma. Am J Dermatopathol 2013;35:176–9. [21] Davis JL, Randle HW, Zalla MJ, Roenigk RK, Brodland DG. A comparison of Mohs micrographic surgery and wide excision for the treatment of atypical fibroxanthoma. Dermatol Surg 1997;23:105–10.