J Cutan Pathol 2006: 33: 318322 Blackwell Munksgaard.

Printed in Singapore

Copyright # Blackwell Munksgaard 2006

Journal of

Cutaneous Pathology

Atypical fibroxanthoma with perineural or intraneural invasion: report of two cases

Abstract: We report two cases of atypical fibroxanthoma (AFX) that both had the previously unreported feature of neural invasion (one perineural and the other intraneural). AFXs recur in approximately 10% of cases but only rarely metastasize. Features associated with recurrence are inadequate excision and invasion into fat. Features associated with metastasis include recurrence, vascular invasion, deep tissue invasion, and tumor necrosis. Both of these tumors invaded deeply into subcutaneous fat and reached the deep fascia. Some authors would regard such cases as malignant fibrous histiocytoma (MFH) because of such deep extension; however, the concept of AFX as a superficial variant of MFH is outmoded AFX is a distinct clinicopathologic entity with established clinical, histological, and immunohistochemical features.

Andrew Dettrick and Geoff Strutton

Queensland Health Pathology Service Princess Alexandra Hospital, Woolloongabba, Australia

Dettrick A, Strutton G. Atypical fibroxanthoma with perineural or intraneural invasion: report of two cases. J Cutan Pathol 2006; 33: 318322. # Blackwell Munksgaard 2006. Atypical fibroxanthoma (AFX) was a term coined in 1961 by Helwig1 for a lesion he considered was a reactive process. About the same time, Bourne2 reported similar lesions as a pseudosarcoma. Since then, the concept that AFX is a neoplasm has been confirmed, and the distinct clinicopathological features of this tumor have been established.3 Small numbers of cases have been reported to metastasize (<1%) and local recurrences are not uncommon, occurring in approximately 10%.4 Extremely rare deaths have been reported.4,5 Features associated with recurrence are inadequate excision and invasion into fat.3,4 Features associated with metastasis include recurrence, vascular invasion, deep tissue invasion, tumor necrosis, and possibly immunosuppression.4 Most reported cases and series simply do not mention perineural or intraneural spread; however, perineural or intraneural invasion has not previously been mentioned in the literature. We report two cases of AFX with neural invasion. Case reports Case 1 A 94-year-old man presented with a raised pink lesion on the scalp. Excision with split skin graft was undertaken. Histological examination showed an ulcerated, poorly circumscribed, dermal tumor with pleomorphic,

Andrew Dettrick, Anatomical Pathology, The Prince Charles Hospital, Rode Road, Chermside 4032, Australia Tel: 61 7 3350 8544 Fax: 61 7 3350 8546 e-mail: andrew_dettrick@health.qld.gov.au Accepted for publication March 30, 2005

predominantly spindle cell morphology. The tumor cells were arranged into long fascicles and storiform patterns. Bizarre giant cells, frequent mitoses, and abnormal mitoses were all seen. Adnexal structures were largely spared. The adjacent dermis showed solar elastosis. Tumor invaded deeply through subcutaneous fat and into the superficial part of the deep fascial layer. Perineural infiltration was seen in the subcutaneous part of the lesion, involving a nerve measuring 0.2 mm diameter. The lesion was clear of margins. Immunohistochemical staining of the cells was negative for CD34, HMB45, S100, and cytokeratins (AE1/AE3, Cam 5.2, MNF116). There was focal, weak staining with desmin and smooth muscle actin; however, the tumor did not have the morphology of a leiomyosarcoma (Fig. 1). Unfortunately, the skin graft failed, and hence, the wound was left to heal by second intention. At last follow up (only 8 weeks post-excision), the wound was healing well, and there was no sign of recurrence or metastasis at this early stage. No further treatment is planned. Case 2 A 72-year-old man with an extensive history of sun cancers presented with a nodular, ulcerated,

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keratotic lesion on the scalp. The lesion was excised and split skin grafting carried out. Histological examination showed a pleomorphic, spindle cell lesion in the dermis. The tumor was poorly circumscribed and extended into fat and underlying fascia. The tumor cells were growing in short fascicles that tended to intersect at right angles. Bizarre giant cells were present, mitoses were numerous, and abnormal mitoses were also seen. Tumor tended to surround but not destroy adnexal structures. Invasion into a nerve (intraneural infiltration) was seen in the deepest part of the lesion, involving a nerve measuring 0.2 mm in diameter. The adjacent epidermis showed solar keratosis. Solar elastosis was present in the adjacent dermis. The lesion was clear of margins. The tumor cells were negative for S100, epithelial antigen membrane (EMA), cytokeratins (AE1/AE3, Cam 5.2, MNF116), and desmin. They were positive with CD99 and CD10, and there was a weak positive reaction with smooth muscle actin (Fig. 2).
A

Because of the aggressive features of this tumor, the clinical team elected to offer electron beam radiation as adjuvant therapy which is planned for early this year. He is currently 3 months post-excision, and his skin graft is well healed with no evidence of recurrence. He has had a positron emission tomography scan down to the thighs which showed no uptake (i.e., no evidence of metastatic disease). His history of sun-induced skin lesions includes multiple solar keratoses, squamous cell carcinomas and basal cell carcinomas, and one previous AFX. The AFX was on the scalp and was treated with excision in 1989 (15 years previously). The wound was very slow to heal, and more extensive excision was undertaken 3 months later. Histology of the re-excision specimen showed features of chronic ulceration but no evidence of malignancy. The patient was followed regularly for 6 years, and there was no recurrence of the lesion. For both the cases, all immunohistochemical stains were performed with appropriate controls. Enzymatic antigen retrieval was used for AE1/3, MNF116, Cam5.2, S100, and HMB45. Heatinduced antigen retrieval (microwave) was used for EMA, CD99, Desmin, SMA, and CD34.

Discussion The principle difficulty in studying any rare tumor is its rarity. There are few large series published on AFX with the seminal paper of Fretzin and Helwig from 1973 remaining the principle reference.3 It is a testimony to the power of their morphology-based classification that the entity still exists today. It is necessary, however, to view cases and series published prior to the widespread availability of immunohistochemistry with some caution, as some desmoplastic melanomas and spindle-cell carcinomas may have been included. With this proviso in mind, we have reviewed the published data on 401 cases of AFX searching for mention of perineural or intraneural invasion and have found none.1,330 Clinical features AFX typically occurs as a rapidly growing, solitary, gray to pink to red nodule on the head and heck of the elderly. They are usually <20 mm in diameter and may ulcerate. Another, less common, clinical variant occurs in younger adults, these lesions being larger, more slow growing and having a predilection for the trunk and extremities.31,32

Fig. 1. Case 1 Atypical fibroxanthoma with perineural spread. A) Ulcerated surface and bizarre giant cells (H&E 200). B) Perineural permeation arrows indicate atypical cells (H&E 400).

Typical histology AFX is usually a cellular dermal tumor that is wellcircumscribed and non-encapsulated. It is usually

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A

Fig. 2. Case 2 Atypical fibroxanthoma with intraneural invasion. A) Spindle cells, pleomorphism, mitoses, abnormal mitoses, and short, intersecting fascicles (H&E 100). B) Intraneural invasion arrows indicate atypical cells (H&E 200).

separated from the epidermis by a thin Grenz zone but may be contiguous with it. Extension into subcutaneous fat is uncommon; extension into deeper structures like parotid gland15 has been reported. The epidermis is often thin or ulcerated. There is florid pleomorphism, with atypical and bizarre cells. There are usually three cell types: plump, spindle cells with a prominent, vesicular nucleus arranged in poorly formed fascicles; haphazardly arranged, large, polyhedral cells; and giant cells. Both the polyhedral cells and giant cells may have vaculoated, lipid-containing cytoplasm hence, the origin of the tumor name. Adnexae are surrounded or distorted but not involved. Rare variants include clear cell, osteoclastic giant cell, granular cell, and pigmented.31,32 The typical immunohistochemical profile of AFX is vimentin, S100, cytokeratin, EMA, CD99.21,32 Positivity for actin and desmin is not uncommon.16 A high proportion of cases are positive for CD10.33

The majority of AFXs are biologically benign. Local recurrence is not uncommon, occuring in approximately 10% of cases, often in those tumors which were incompletely excised.3 Features that indicate a propensity to local recurrence are inadequate excision margins and invasion into fat.3,4 Multiple local recurrences have rarely been reported.8 Metastases seem to occur in less than 1% of cases with regional (parotid) nodes often involved.4 Two cases of metastasis to the lung have been reported.4,5 Localized cutaneous metastasis has been reported once19 and another possible case exists which was written up as multiple primary tumors.24 Features seen more commonly in metastasising tumors include recurrence, vascular invasion, deep tissue invasion, tumor necrosis, and possibly immunosuppression.4 There are rare case reports of multiple tumors.24 As mentioned above, we have reviewed 401 cases of AFX reported in the English literature.1,330 No cases report perineural or intraneural spread. One of the cases reported by Ly et al.34 recently showed perineural spread in the recurrence of a tumor that was re-classified as malignant fibrous histiocytoma (MFH); it was initially classified as AFX. A possible confounding factor in our claim to be reporting the first two AFXs to show neural spread (both occuring in our institution within a short time frame no less!) is that AFX has been conceptualized by many as a superficial MFH. This notion includes the concept that a pleomorphic/spindle cell lesion which is negative for keratin, S100, and desmin and extends deeply into subcutis or shows other signs of aggressive behavior must be a true MFH. Therefore, the authors propose that previous cases of AFX with neural spread may have been reported as superficial MFH. The recurrences reported by Ly et al.34, for example, may fall into this group. We believe this concept of AFX as a superficial variant of MFH is outmoded for several reasons: 1. AFXs typically occur on the head and neck of the elderly, a fact which has long suggested a role for sun exposure in tumorigenesis. Studies have shown pyrimidine mutations in the p53 gene in AFXs which are induced by UV radiation, lending support to the hypothesis that AFX is a sun-cancer.16,18 AFX has been reported in children with xeroderma pigmentosum14,31 an inherited inability to repair UV-induced pyrimidine dimers. MFH occurs in the deep soft tissues remote from UV radiation. In a direct comparison with AFX, a strong role for UV radiation in the pathogenesis of MFH was not demonstrated.29 2. The diagnosis of MFH has almost disappeared from soft tissue pathology. With the advance of

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immunohistochemistry and our understanding of soft tissue tumors, few pleomorphic or poorly differentiated soft tissue tumors remain which do not show any differentiation at all. Those that remain unclassifiable are best reported as pleomorphic/poorly differentiated sarcoma, unclassifiable.35 If MFH has all but disappeared from soft tissue pathology, it seems unreasonable to retain the notion of a superficial variant in the skin. 3. Evidence previously presented to support the concept of AFX as a superficial variant of MFH is not always strong. For example, Westermann et al.17 studied a small number of AFXs (eight cases) and MFHs (nine cases) in terms of apoptotic counts and p53 and bcl2 expression and found no significant differences. They therefore conclude that this result supports the contention that AFX should be regarded as a form of pleomorphic MFH. However, these parameters are entirely nonspecific, and the number of cases in the study is too small to achieve statistical significance anyway. There is now evidence that there are immunological differences between the two entities. Lazova et al.26 have shown that CD74 is positive in 90% of MFHs and negative in 90% of AFXs. Interestingly, the 2 cases of AFXs which stained strongly for CD74 were both >20 mm and extended deeply into subcutaneous fat. Confusion over the issue of superficial MFH is still prevalent in contemporary literature. Giuffrida et al. in 200419 in reviewing Nadjem and Grahams24 report of multiple AFXs in the same patient state, These [tumors] could well have represented . . . misdiagnosed MFHs . . . [because] All of the tumors extended into the subcutaneous fat histologically, one tumor invaded muscle, and two others had vascular invasion. In light of other reports that AFX can extend into deep tissues and vessels4,15, the conclusion that the diagnoses were wrong based on this behaviour alone seems unsupported. Another erroneous concept surrounding AFX is that it is a wastebasket diagnosis. This is not correct, because AFX has characteristic clinical, gross, histologic, and immunologic features as outlined above. Certainly, one really has to demonstrate negative staining for keratin and S100 before making the diagnosis; however, as mentioned, a number of positive markers other than vimentin exist including CD99 and CD10. Herein, we report the first two cases of AFX with perineural and intraneural invasion. AFX is a distinct clinicopathologic entity that should not be regarded as a superficial variant of MFH.

References
1. Helwig EB. Atypical fiboxanthoma. Proceedings of 18th Annual Tumor Seminar of San Antonio Society of Pathologists, 1961. Tex State J Med 1963; 59: 664. 2. Bourne RG. Paradoxical fibrosarcoma of skin (pseudosarcoma): a review of 13 cases. Med J Aust 1963; 1: 504. 3. Fretzin DF, Helwig EB. Atypical fibroxanthoma of the skin: a clinicopathologic study of 140 cases. Cancer 1973; 31: 1541. 4. Helwig EB, May D. Atypical fibroxanthoma of the skin with metastasis. Cancer 1986; 57: 368. 5. Kargi E, Gungor E, Verdi M, et al. Atypical fibroxanthoma and metastasis to the lung (letter). Plast Reconstr Surg 2003; 111 (5): 1760. 6. Ricci A, Cartun RW, Zakowski MF. Atypical fibroxanthoma: a study of 14 cases emphasizing the presence of Langerhans histiocytes with implications for differential diagnosis by antibody panels. Am J Surg Pathol 1988; 12 (8): 591. 7. Anderson PJ, McPhaden AR, Ratcliffe RJ. Atypical fibroxanthoma of the scalp. Head Neck 2001; 23: 399. 8. Jacobs DS, Edwards WD, Ye RC. Metastatic atypical fibroxanthoma of skin. Cancer 1975; 35: 457. 9. Sankar NM, Pang KS, Thiruchelvam T, et al. Metastasis from atypical fibroxanthoma of skin. Med J Aust 1998; 168 (8): 418. 10. Chilkuri S, Alam M, Goldberg LH. Two atypical fibroxanthomas of the ear. Dermatol Surg 2003; 29: 408. 11. Ferrara N, Baldi G, Di Marino MP, et al. Atypicl fibroxanthoma with osteoclast-like multinucleated giant cells. In Vivo 2000; 14 (1): 105. 12. Youssef N, Vabres P, Buisson T, et al. Two unusual tumors in a patient with xerderma pigmentosum: atypical fibroxanthoma and basosquamous carcinoma. J Cutan Pathol 1999; 26 (9): 430. 13. Orosz Z. Atypical fibroxanthoma with granular cells (letter). Histopathology 1998; 33: 88. 14. Dilek FH, Akpolat N, Metin A, et al. Atypical fibroxanthoma of the skin and the lower lip in xeroderma pigmentosum. Br J Dermatol 2000; 143: 618. 15. Skoulas IG, Price M, Andrew JE, et al. Recurrent atypical fibroxanthoma of the cheek. Am J Otolaryngol 2001; 22: 73. 16. Sakamoto A, Oda Y, Yamamoto H, et al. Calponin and histocaldesmon expression in atypical fibroxanthoma and superficial leiomyosarcoma. Virchows Arch 2002; 440: 404. 17. Westermann FN, Langlois NEI, Simpson JG. Apoptosis in atypical fibroxanthoma and pleomorphic malignant fibrous histiocytoma. Am J Dermatopathol 1997; 19 (3): 228. 18. Dei-Tos AP, Maestro R, Doglioni C, et al. Ultraviolet-induced p53 mutations in atypical fibroxanthoma. Am J Pathol 1994; 145 (1): 11. 19. Giuffrida TJ, Kligora CJ, Goldstein GD. Localized cutaneous metastases from an atypical fibroxanthoma. Dermatol Surg 2004; 30: 1561. 20. Requena L, Sangueza OP, Sanchez Yus E, et al. Clear-cell atypical fibroxanthoma: an uncommon histopathologic variant of atypical fibroxanthoma. J Cutan Pathol 1997; 24: 176. 21. Monteagudo C, Calduch L, Navarro S, et al. CD99 immunoreactivity in atypical fibroxanthoma: a common feature of diagnostic value. Am J Clin Pathol 2002; 117: 126.

321

Dettrick & Strutton

22. Longacre TA, Smoller BR, Rouse RV. Atypical fibroxanthoma: multiple immunohistologic profiles. Am J Surg Pathol 1993; 17 (12): 1199. 23. Crowson AN, Carlson-Sweet K, Macinnis C, et al. Clear cell atypical fibroxanthoma: a clinicopathologic study. J Cutan Pathol 2002; 29: 374. 24. Nadjem MA, Graham JH. Case for diagnosis. Mil Med 1986; 151 (12): 666. 25. Hudson AW, Winkelmann RK. Atypical fibroxanthoma of the skin. a reappraisal of 19 cases in which the original diagnosis was spindle cell squamous carcinoma. Cancer 1972; 29 (2): 413. 26. Lazova R, Moynes R, May D, et al. LN-2 (CD74) A marker to distinguish atypical fibroxanthoma from malignant fibrous histiocytoma. Cancer 1997; 79 (11): 2115. 27. Kempson RL, McGavran M. Atypical fibroxanthomas of the skin. Cancer 1964; 17 (11): 1463. 28. Kuwano H, Hashimoto H, Enjoji M. Atypical fibroxanthoma distinguishable from spindle cell carcinoma in sarcoma-like skin lesions. Cancer 1985; 55: 172. 29. Sakamoto A, Oda Y, Itakura E, et al. Immunoexpression of ultraviolet photoproducts and p53 mutation analysis in atypical fibroxanthoma and superficial malignant fibrous histiocytoma. Mod Pathol 2001; 14 (6): 581. Leong AS-Y, Milios J. Atypical fibroxanthoma of the skin: a clinicopathological and immunohistochemical study and a discussion of its histogeneis. Histopathology 1987; 11 (5): 463. Weedon D. Skin Pathology, 2nd ed. London: Elsevier Science, 2002; 936. Murphy GF, Elder DE. Non-melanocytic tumors of the skin: atlas of tumor pathology, third series, fascicle 1. Washington: Armed Forces Institute of Pathology, 1991; 229. Weedon D, Williamson RM, Mirza B. CD10 a useful marker for atypical fibroxanthoma: letter to the editor. Am J Derm Pathol (in press). Ly H, Selva D, James CL, Huilgol SC. Superficial malignant fibrous histiocytoma presenting as recurrent atypical firboxanthoma. Australas J Dermatol 2004; 45: 106. Fletcher CDM, van den Berg E, Molenaar WM. Pleomorphic malignant fibrous histiocytoma/undifferentiated high grade pleomorphic sarcoma. In: Fletcher CDM, Unni KK, Mertens F, eds. Tumours of soft tissue and bone; World Health Organization classification of tumours pathology and genetics. Lyon: IARC Press, 2000; 120.

30.

31. 32.

33.

34.

35.

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