Review
Atypical fibroxanthoma: new insights Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 02/06/15 For personal use only.
Expert Rev. Anticancer Ther. 14(9), 1075–1088 (2014)
Mahmoud Rezk Abdelwahed Hussein Department of Pathology, Faculty of Medicine and Assuit University Hospitals, Assiut University, Assiut, Egypt Tel.: +20 093 258 1258 [email protected]
Atypical fibroxanthoma (AFX) is an ultraviolet radiation-associated dermal neoplasm. To address the clinicopathologic and molecular features of this particular neoplasm. The author conducted a literature review using PubMed searching for articles relating to AFX. AFX usually appears as a rapidly growing nodular or nodulo-ulcerative lesion. It occurs on sun-exposed skin of elderly peoples. AFX may be composed predominantly of pleomorphic, spindle, epithelioid cells, or admixture of these cells. The differential diagnosis of AFX includes pleomorphic dermal sarcoma, squamous cell carcinoma, malignant melanoma and leiomyosarcoma. Several observations favor a mesenchymal origin for AFX. These reviews address the clinicopathologic features, molecular pathology, prognosis and treatment of this neoplasm. KEYWORDS: atypical fibroxanthoma • clinicopathologic • dermal sarcoma • pathogenesis • ultraviolet light
In 1963, the term, ‘atypical fibroxanthoma (AFX, pseudosarcoma of the skin, paradoxical fibrosarcoma, pseudosarcomatous dermatofibroma, pseudosarcomatous xanthofibroma and pseudosarcomatous reticulohistiocytoma)’ was proposed by Helwig for a lesion that was initially viewed as a reactive process [1–3]. In 1973, AFX was established as a distinct clinicopathologic entity [3]. Herein, the clinicopathologic features, differential diagnosis, prognosis, treatment and molecular mechanisms of this particular neoplasm are addressed. Clinical features of AFX
Clinically, AFX appears as a rapidly growing light-brown, red or pink papule, nodule or nodulo-ulcerative lesion, which is usually 2.0 cm), extensive involvement of the subcutis, tumor necrosis or vascular invasion. AFX diagnosed using these infiltrative margin with invasion of the fascia, muscle or adjastrict criteria have essentially benign behavior [43,44]. Of note, cent organs. Other supporting features include: tumor necrosis, the terms ‘pleomorphic dermal sarcoma’ and ‘undifferentiated perineural infiltration and vascular invasion [26,27,46]. One study pleomorphic sarcoma, previously known as malignant fibrous indicated that the expression of LN-2 (CD74) is typical of histiocytoma’ are used somewhat synonymously in the literature, undifferentiated sarcoma and is usually negative in AFX [47]. albeit with the reservation that the appellation of ‘undifferentiated pleomorphic sarcoma’ to a cutaneous lesion Separation of AFX from other fibrohistiocytic tumors should be avoided given the implication of a more aggressive Other fibrohistiocytic tumors that should be separated from AFX course [40,45]. Moreover, AFX and pleomorphic dermal sarcoma include atypical fibrous histiocytoma and dermatofibrosarcoma informahealthcare.com
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usually atrophic and nuclear pleomorphism is not a feature. In the author’s experience, expression of CD34 is not a feature in AFX, and if present, it is usually patchy or limited to the vascular endothelium [50]. Hanly et al. reported a diagnostic utility for Ki67 (proliferation marker) in the evaluation of the fibrohistiocytic neoplasms. A high proliferative index (Ki67) is usually noted in both AFX and undifferentiated pleomorphic sarcoma. A low proliferative index is usually seen in dermatofibrosarcoma protuberans [51]. Separation of AFX from squamous cell carcinoma
Helpful features that favor squamous cell carcinoma (sarcomatoid, spindle cell types or lesions with osteoclast-like giant CD34 CK5/6 CD68 cells) include: presence of squamous dysplastic changes/squamous cell carcinoma Figure 3. Atypical fibroxanthoma of the left upper forehead. A 72-year-old male in situ, epidermal attachment and the presented with an ill-defined, 0.7 cm tan, glistening lesion on the left upper forehead. characteristic immunohistochemical stainSections show ovoid-shaped symmetric, well-defined dermal nodule with smooth ing with antibodies to cytokeratins (espepushing deep margin. The overlying epidermis is atrophic with obliteration of the Grenz cially high-molecular-weight cytokeratins). zone. The tumor is formed of spindle cells with some pleomorphic cells arranged in solid pattern, with rare atypical mitosis. Tumor necrosis, perineural infiltration or vascular Of note, some squamous cell carcinomas invasions are not seen. Occasionally, skin adnexa are found within the tumor, but they (especially spindle cell or sarcomatoid are not infiltrated. The tumor cells are positive for vimentin and CD10, smooth muscle types) not uncommonly show weak or actin (diffuse and moderate reactivity) and CD68 (patchy staining especially in the negative staining for pancytokeratin cockgigantic and histiocytoid cells). Negative stains include: pancytokeratin AE1/AE3, hightail or low-molecular-weight cytokeratin molecular-weight cytokeratin (CK5/6), S100, Melan-A, desmin and CD34 (some stains are not shown in this figure). The diagnosis of AFX was rendered. The surgical margins and strong reactivity for vimentin. In this were free of lesion. There was no local recurrence and no regional lymphadenopathy for regard, high-molecular-weight cytokeratins 1 year. There was no abnormality detected on thoracic and abdominal computed (CK5/6 and CK34BE12 and MNF116) tomography. Comment: The reactivity for smooth muscle actin and CD68 in AFX are useful markers and usually show suggests the concept of ‘fibrohistiocytic and myofibroblastic’ phenotypes in strong positivity [52]. this neoplasm. Data taken from [27,29,67]. Of note, p63 reactivity argues against the diagnosis of AFX and is therefore protuberans. Atypical fibrous histiocytoma is a variant of fibrous useful in separating this particular neoplasm from squamous histiocytoma that usually involves the trunk and extremities of cell carcinoma [53,54]. CD99 is usually negative in squamous middle-aged women. It is composed of fairly well-circum- cell carcinoma [31]. Procollagen-1-positive staining in the scribed, essentially dermal nodular fibrohistiocytic proliferation. tumor cells was observed in about one-third of the desmoIts constituent cells (fibrohistiocytes) show some atypical histo- plastic squamous cell carcinoma [33,55]. logic features such as nuclear pleomorphism, hyperchromatism, nucleolar prominence and atypical mitosis. The lesional cells are Separation of AFX from malignant melanoma usually reactive for CD68, CD163 and factor XIIIa. Negative Features that favor malignant melanoma include: junctional stains include CD34, CD31, desmin, smooth muscle actin, melanocytic component and characteristic immunohistochemiCAM 5.2, keratin 5/6 and S100 [48,49]. Features that favor atypi- cal staining with markers of melanocytic lineage (positive stains: cal fibrous histiocytoma over AFX include: epidermal hyperpla- S100, Melan-A, tyrosinase, HMB-45 and microphthalmiasia, pigmentation of the basal cell layer, free Grenz zone and associated transcription factor) [52]. D2-40 and p75 are useful diffuse pleomorphism. Dermatofibrosarcoma protuberans is markers in separating AFX (D2-40 positive and p75 negative) another diagnostic consideration. This is a nodular dermal, sub- from spindle cell malignant melanoma (D2-40 negative and cutaneous tumor composed of a uniform population of slender, p75 positive) [56]. About 10–60% of malignant melanomas strongly and diffusely CD34+ cells arranged in a uniform stori- show positive staining for CD99 [30,31]. Procollagen-1-positive form pattern par excellence [26,27,46]. The overlying epidermis is staining in the tumor cells was observed in desmoplastic 1078
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malignant melanomas [33,55]. CD68 is also detectable in 86% of malignant melanoma cases [57].
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Separation of AFX from leiomyosarcoma & angiosarcoma
Features that favor cutaneous leiomyosarcoma include: distinct intersecting fascicles of eosinophilic spindle cells with ovoid to cigar-shaped nuclei, demonstrating desmin positivity and abundant cytoplasmic glycogen [26,27,46]. Hemorrhagic AFX or lesions with pseudoangiomatous pattern should be separated from angiosarcoma. AFX is usually confined to the dermis, whereas angiosarcoma may invade into underlying fascia. AFX is usually negative for CD34 and erythroblast transformation-specific related gene, whereas angiosarcoma is positive for these markers [23]. Moreover, D2-40 (podoplanin) staining of AFX is usually weak (when positive), whereas Friend leukemia integration 1 transcription factor staining of angiosarcomas is usually strong and nuclear [37]. It should be emphasized that CD31 staining can occur in AFX because cells with histiocytic differentiation can express CD31. This is an important pitfall that can lead to an erroneous diagnosis of angiosarcoma. AFX & undifferentiated pleomorphic sarcoma
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Figure 4. Atypical fibroxanthoma of the right cheek. An 89-year-old male presented with a 1.2 cm raised tan nodulo-ulcerative lesion on the right cheek. Sections show dome-shaped well-circumscribed dermal proliferation. The tumor is restricted to the dermis and does not show appreciable extension into the subcutaneous tissue. The overlying epidermis is attenuated and ulcerated centrally. The tumor is composed of pleomorphic spindle, epithelioid and histiocytoid cells with vesicular nuclei and prominent nucleoli. The cells are arranged in fascicular and solid patterns. Great numbers of mitotic figures with some atypical forms are noted. The cells have wide, eosinophilic and scarcely vacuolated cytoplasm. The neoplastic cells show strong and diffuse reactivity for vimentin and CD10. Patchy CD68 positivity is noted, especially in the giant and histiocytoid cells. S100 decorated some dendritic cells. Negative stains include: pancytokeratin AE1/AE3, high-molecular-weight cytokeratin (CK5/6 and 34D-E12), p63, Melan-A, CD34 and desmin (some stains are not shown in this figure). Solar elastosis and a suggestion of epidermal collarets are noted. The diagnosis of AFX was made. The surgical margins were free of lesion. There was no local recurrence and no regional lymphadenopathy for 1 year. There was no pathology detected on thoracic and abdominal computed tomography. Comment: Focal HMB45 and MART-1 (giant and clear cells) and S100 (dendritic cells) expression has been reported in AFX and these may represent entrapped dendritic cells. Data taken from [36,38,67,128].
There is a considerable controversy regarding the relationships between AFX and undifferentiated pleomorphic sarcoma, as their immunohistological separation may be sometimes difficult. Some studies have proposed that AFX and undifferentiated pleomorphic sarcoma are related neoplasms with a split biological ‘personality’ [58–63]. Alternatively, some observations suggest that AFX and undifferentiated pleomorphic sarcoma represent separate and completely unrelated entities. In support, the lower proliferative activity in AFX than that of undifferentiated pleomorphic sarcoma [64], and the diploid nature of AFX in contrast to undifferentiated pleomorphic sarcoma, which is usually aneuploid [65]. Additionally, ras gene mutations are absent in AFX versus being present in undifferentiated pleomorphic sarcoma [66]. It is possible that these neoplasms arise from a common mesenchymal progenitor cells with the capacity to differentiate along different molecular pathways [67]. Molecular pathology of AFX
To date, the etiopathogenesis of AFX is poorly understood. Risk factors include exposure to ultraviolet and ionizing informahealthcare.com
radiations and immunosuppression. The development of AFX may be associated with alterations of nucleotide excision repair system, tumor suppressor gene p53 [22,60,68,69] and its related molecules Bcl-2-associated X protein, growth arrest and DNA damage [70]. There is DNA damage and accumulation of DNA photoproducts [71]. Reactivation of telomerase has been implicated in tumorigenesis. Telomerase reverse transcriptase is the gene coding for the catalytic subunit of telomerase. Activating mutations in the Telomerase reverse transcriptase promoter lead to increased telomerase expression and therefore allowing cells to proliferate continuously without entering apoptosis or senescence. Griewank et al. examined Telomerase reverse transcriptase promoter mutations in 27 AFX using conventional Sanger sequencing. Telomerase reverse transcriptase promoter mutations were identified in 25 cases. They were found to have a UV 1079
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Usually T or CC > TT) and were largely identical to those detected in cutaneous melanoma. These findings not only support the pathogenetic role of UV exposure in AFX, but also suggest that telomere maintenance through increased expression of telomerase plays an important role in the pathogenesis of these lesions [41]. There is a suggestion that viral factors may contribute to the development of AFX. Some risk factors of AFX (ultraviolet and ionizing radiations) are almost identical to those of Merkel cell carcinoma. The latter may be pathogenetically associated with Merkel cell polyomavirus. Interestingly, Merkel cell polyomavirus DNA has been reported in 17% of AFX, and may act as a cofactor in the tumorigenesis of this particular neoplasm [72]. However, it should be noted that this relationship with Merkel cell polyomavirus is very tentative, at best, as normal skin also may demonstrate this virus. This virus is currently associated with many neoplasms and there is no significant basis for its implication in this neoplasm [73–75]. AFX has been reported in immunosuppressed individuals such as cardiac or renal transplant recipients [76,77], HIV-infected [78] or cancer patients (basal cell carcinoma, squamous cell carcinoma, mycosis fungoides, chronic lymphocytic leukemia and non-Hodgkin lymphomas) [79,80]. AFX has a mesenchymal origin (fibroblastic, fibrohistiocytic or myofibroblastic nature), that is, it may be derived from fibroblasts, fibrohistiocytes or myofibroblasts [59,67,81]. In 1973, VargasCortes et al. suggested that AFX may arise from the tissue histiocytes. Its spindle-cell elements were proposed to represent facultative fibroblasts. The progenitor cells may represent an undifferentiated mesenchymal cell capable of differentiating in both a histiocytic and fibroblastic direction [82]. The mesenchymal derivation of AFX is supported by several ultrastructural, immunophenotypic and molecular observations. At ultrastructural level, there is a transition from fibroblasts to large gigantic cells with intermediate forms exhibiting features of both [83]. AFX with spindle cell morphology on light microscopy is ultrastructurally composed of undifferentiated 1081
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mesenchymal cells. AFX with highly pheomorphic appearance on light microscopy is ultrastructurally formed of atypical histiocytic cells and abundant Langerhans cells [84]. At the immunophenotypical level, both AFX and undifferentiated pleomorphic sarcoma are positive for mesenchymal (vimentin, smooth muscle actin, CD31 and D2-40) and fibrohistiocytic markers (procollagen-1, factor XIIIa and CD68) [19,23,33,36,37,67]. At the molecular level, AFX and the undifferentiated high-grade pleomorphic sarcoma have deletions on chromosomes 9p and 13q suggestive of a common pathogenetic pathway. However, the difference in the magnitude of these changes may contribute to the different biological behavior of these tumors [85], that is, benign behavior of AFX versus high-grade malignant potential for high-grade pleomorphic sarcoma [60,63]. In 1989, the experimentations of Phelps and his colleagues lended further support to the mesenchymal origination of AFX. The authors examined a dermal derived malignant mesenchymal neoplasm arising in ultraviolet irradiated mice [86]. Ten-week-old hairless albino mice (Skh/hr-1) were irradiated with photocarcinogenic dosages of ultraviolet light for 30 weeks or longer. A high proportion of the animals developed dermal round and flesh colored nodules. On histology, the dermal nodules consisted of poorly circumscribed proliferations that efface the dermal microarchitecture and infiltrate the subcutis and skeletal muscle. The lesional cells include mitotically active, atypical spindly and pleomorphic and multinucleated giant cells (features reminiscent of AFX in human). The overlying epidermis was attenuated or ulcerated, but an unequivocal transition from keratinocytes to the neoplastic cells in the underlying dermis was not observed. The neoplastic cells expressed mesenchymal markers (vimentin, procollagens I and III, type I collagen and lysozyme) [86]. They were negative for both wide-spectrum keratin and epidermally derived keratin, a finding that argues against epithelial derivation. At the ultrastructural level, the two populations of cells were identified: filiform, fibroblastic cells and larger, rounded histiocytic cells, with occasional transitional forms between the two. The cells contained abundant endoplasmic reticulum, filopodia and lysosomes, but unequivocal evidence of epithelial differentiation (i.e., intercellular junctions and tonofilaments) was not identified. Further propagation of the explants (from the dermal round and flesh colored nodules) in tissue culture resulted in the growth of rounded or amoeboid cells that lacked syncytia or confluent growth despite long periods of feeding. Ultrastructurally, this in vitro cell culture cells had features consistent with a mesenchymal phenotype [86]. McCalmont and his colleagues described a case of AFX on the shoulder of 45 years old lady that evolved from a fibrous histiocytoma [87]. The lesion was stable for 20 years before undergoing rapid increase in size. Histologically, there was a large spindle cell proliferation that involved the dermis and subcutaneous tissue that can be stratified into different components. The first component (most of the lesion) was composed of small bland looking uniform cells (interpreted by 1082
the authors as a large longstanding benign fibrous histiocytoma component). The interest consists of multinucleate cells and collagen fibrous, with rare mitotic figures. The remainder (central superficial part of the lesion) consisted of giant cells and large pleomorphic patently atypical cells with easily identifiable atypical mitotic figures (interpreted by the authors as the AFX component). The dermatofibroma and AFX components had a similar immunohistochemical phenotype. Ki67 proliferative index in the AFX component was evidently higher as compared with the dermatofibroma component [87]. The authors raised several notions based on the phenomenon of ‘AFX evolving from benign fibrous histiocytoma’. They include: common lineage/derivation of both AFX and benign fibrous histiocytoma (mesenchymal origin) and the neopalstic nature of benign fibrous histiocytoma. Also, the evolution of malignant phenotype (AFX) can occur in a background of benign lesions (benign fibrous histiocytoma). This evolution is analogous to evolution of the following malignancies: malignant melanomas in a background of nevi (including dysplastic nevi) [88], basal cell carcinomas in a background of trichoepitheliomas or trichoblastomas [89] or hidradenocarcinomas in a background of hidradenomas [87,90,91]. A speculative view about AFX & epithelial-mesenchymal transition of squamous cell carcinoma
The author speculates that AFX could develop by epithelialmesenchymal transition (EMT) of squamous cell carcinoma (epithelial origin) into a mesenchymal cancer phenotype [15,92,93]. The speculation that AFX may represent EMT of squamous cell carcinoma is based on some clinical and molecular observations. Clinically, collision of AFX and acantholytic squamous cell carcinoma in situ has been reported [94]. AFX, lentigo maligna melanoma and squamous cell carcinoma arising at the site of a thermal burn treated with skin grafts have been observed [95–97]. Immunohistochemically, both AFX and squamous cell carcinomas are positive for broad-spectrum cytokeratin antibodies, albeit being focal in the former [98,99]. At the molecular level, both AFX and squamous cell carcinoma show alterations of p53, other pro-apoptotic and anti-apoptotic molecules [60,70,100,101]. EMT is a developmental process during which cells of epithelial origin (squamous cells) lose epithelial features and acquire a mesenchymal phenotype (spindle, epithelioid and pleomorphic cells). In AFX, EMT is associated with loss or downregulation of epithelial makers (loss of pancytokeratin AE1/AE3, high-molecular-weight cytokeratins: CK5/6 and CK MNF116 in AFX), upregulation of mesenchymal markers (vimentin, smooth muscle actin, CD31 and D2-40), acquisition of fibroblasts, fibrohistiocytes (procollagen-1, factor XIIIa, CD68) or myofibroblasts-like (Actin) morphologies [102–104]. Transforming growth factor family members (TGF-b) are secretory molecules with dual tumor-suppressor and oncogenic roles. They signal through kinase receptor complexes on the cell surface, which phosphorylate cytoplasmic mediators Expert Rev. Anticancer Ther. 14(9), (2014)
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(SMADs, mothers against decapentaplegic: MAD and the Caenorhabditis elegans protein SMA: from gene sma for small body size). Upon phosphorylation, SMADs translocate to the nucleus and interact with co-activators or co-repressors to mediate the transcriptional regulation of several genes. In neoplasia, malignant cells escape from the tumor-suppressive effects of TGF family members (TGF-b) by mutational inactivation of some molecules in TGF-b signaling pathway [105]. The epithelial cells undergoing an EMT express a transcription factor Snail1 and mesenchymal markers like vimentin and fibronectin, whereas the expression of E-cadherin is downregulated. Nakamura et al. reported a case of squamous cell carcinoma mimicking AFX in an 80-year-old man. The tumor expressed both vimentin and Snail1 and failed to express keratin. These findings suggest possible involvement of EMT in tumorigenesis. The authors proposed that EMT underlies the pathogenesis of not only AFX, but also spindle cell carcinoma in some cases [93]. TGF-b/SMADs signaling pathway play critical roles in the progression of squamous cell carcinoma. Lack of SMAD2 expression in squamous cell carcinoma is associated with upregulation of Snail1 and poor differentiation, indicating the involvement of EMT. Therefore, TGF-b-SMADs signaling pathway is a well-known inducer of this transition and it might be a target for the new therapeutic approach for poorly differentiated squamous cell carcinoma [93,103,105]. Although the author speculates that AFX could develop by EMT of squamous cell carcinoma, he acknowledges several notions that argue against this speculation. The association between TGF-b component/Snail and EMT relies on a single case report and more investigations are mandatory before such a model would be considered scientifically valid [93,103,105]. The speculation that AFX (with its essentially benign clinical behavior) represents the end result of squamous cell carcinoma (with its well-known metastatic potential) undergoing EMT may not conform to the well-documented association in the literature between EMT and an increased propensity for metastasis. Namely, EMT is widely considered to play a pivotal role in promoting metastasis in epithelial-derived malignancies [106–110]. Also, poor differentiation among cutaneous squamous cell carcinomas confers an aggressive behavior, yet AFX usually has a comparatively benign clinical behavior.
safety margins is the treatment of choice [115]. Davis et al. compared the outcome of Mohs micrographic surgery versus wide local excision in 45 patients with AFX. In patients treated with Mohs micrographic surgery, there were no recurrences after a mean follow-up of 29.6 months. There were three first recurrences in 25 patients treated with wide local excision after a mean follow-up of 73.6 months. One patient had a single local recurrence, and two patients each had two local recurrences. Parotid node metastasis eventually developed in one of the patients with two local recurrences. The authors concluded that microscopic control of the surgical margins with Mohs micrographic surgery in the treatment of AFX results in a lower recurrence rate than that with wide local excision and conserves normal tissue [116]. Seavolt and McCall examined the files of 13 patients with AFX treated only with Mohs micrographic surgery. Of our 13 patients, only 6 had long-term follow-up, none of which had clinical recurrence of their AFX [117].
Treatment of AFX
Expert commentary
There is no clear recommendation on treatment of AFX in medical literature. Two treatment modalities are known: Mohs micrographic surgery and wide local excision [111–114]. There have been several reports of treatment with Mohs micrographic surgery, which showed a lower local recurrence rate than with excision. Wollina et al. examined the files of 25 patients with AFX. Complete microhistographic controlled surgery (‘Mohs like’) was feasible in all cases followed by mesh-graft transplantation in three patients. Eighteen patients showed a complete remission. Four patients had a relapse within 2 years of follow-up treated by surgery. One patient is still under radiotherapy. The authors concluded that micrographic controlled surgery with wide 2 cm
In the author’s opinion, AFX may have epithelial (spindle, sarcomatoid squamous cell carcinoma or lesions with osteoclast like giant cells) or mesenchymal derivations. The difference in the biologic behavior among AFX (metastases from AFX are almost unheard of) and squamous cell carcinoma or undifferentiated pleomorphic sarcoma (documented rate of metastasis) may be due to the superficial location, low proliferative activity, diploidy and lack of ras gene mutations in the former. In contrast, both squamous cell carcinoma and undifferentiated pleomorphic sarcoma may have deep location (invasion of subcutis), high proliferative activity, diploidy and ras gene mutations [63,64,66]. A diagnosis of AFX is not only a challenging
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Prognosis of AFX
AFX was originally described as a low-grade dermal tumor of atypical spindle cells, but this view has changed [46,118]. Some authorities consider the behavior of this particular as benign one, if strict diagnostic criteria are applied for diagnosis [40,43,44]. The recurrence rate has been reported to range between 5% [22,119] and 10% [3,120]. Multiple local recurrences are rare [121]. Previous studies indicated that metastases occurred in approximately 1% (about 26 cases to date) of reported cases of AFX [116,118,120,122]. They were in the form of localized cutaneous metastasis or metastasis to other organs such as cervical lymph nodes [120,121,123], lungs and peritoneum [124]. Some authorities (a correspondence between McCalmont and Fletcher) indicated that there is only one convincing case of AFX with well-documented metastasis [124]. Lum and King reported a case of AFX on the scalp of an 81-year-old man who developed widespread peritoneal metastases 3 years later. Although the tumor was highly pleomorphic, there was no indication of adverse features (lymphovascular space invasion, deep invasion and tumor necrosis). On histology, the peritoneal metastasis was similar to the original scalp lesion [124]. In their opinion, reports of metastatic AFX antedate rigorous modern immunohistochemical markers or are based on application of flawed diagnostic criteria [43,44].
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task, but also the diagnosis of exclusion of other malignant neoplasms with similar morphology. This should be made only after applying the stringent histological criteria. Immunostains are essential in the accurate diagnosis of AFX. Pertinent clues that argue against the diagnosis of AFX include: deep tissue invasion (subcutis, muscle or fascia), tumor necrosis, perineural and lymphovascular invasion. It is possible that AFX reported with recurrence or metastases are misdiagnosed sarcomas or poorly differentiated squamous cell carcinoma. The author acknowledges two notions about the relationship between AFX and poorly differentiated squamous cell carcinoma. The possibility that a subset of AFX could represent metaplastic squamous cell carcinoma where the epithelial component was not sampled may be erroneous: such a lesion may be simply poorly differentiated carcinoma, and would be revealed as such following complete excision and evaluation of the entire lesion. The possibility that a subset of AFX represent poorly differentiated squamous cell carcinoma where cytokeratin expression is lost, applying in particular to occasional AFX cases with p63 expression could be also erroneous for two reasons. The presence of variable p63 positivity is not unequivocal
evidence of an epithelial derivation in AFX, but rather, a lack of specificity of conventional p63 antibodies (4A4), which might cross-react with other p63 homologs, notably p53 [125]. Five-year view
In the author’s opinion, UV exposure may have a pathogenetic role in AFX. Several molecules (TGF-b/SMADs, Snail, p53, Bcl-2-associated X protein, GAAD45 and Telomerase reverse transcriptase) may be involved in the development of AFX. To address these issues, and to have an understanding of the pathogenesis of this neoplasm, the establishment of cell lines from AFX and their further molecular characterization would open avenues for future research. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Clinically, atypical fibroxanthoma (AFX) appears as a rapidly growing light-brown, red or pink papule, nodule or nodulo-ulcerative lesion, which is usually
Atypical fibroxanthoma: new insights Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 02/06/15 For personal use only.
Expert Rev. Anticancer Ther. 14(9), 1075–1088 (2014)
Mahmoud Rezk Abdelwahed Hussein Department of Pathology, Faculty of Medicine and Assuit University Hospitals, Assiut University, Assiut, Egypt Tel.: +20 093 258 1258 [email protected]
Atypical fibroxanthoma (AFX) is an ultraviolet radiation-associated dermal neoplasm. To address the clinicopathologic and molecular features of this particular neoplasm. The author conducted a literature review using PubMed searching for articles relating to AFX. AFX usually appears as a rapidly growing nodular or nodulo-ulcerative lesion. It occurs on sun-exposed skin of elderly peoples. AFX may be composed predominantly of pleomorphic, spindle, epithelioid cells, or admixture of these cells. The differential diagnosis of AFX includes pleomorphic dermal sarcoma, squamous cell carcinoma, malignant melanoma and leiomyosarcoma. Several observations favor a mesenchymal origin for AFX. These reviews address the clinicopathologic features, molecular pathology, prognosis and treatment of this neoplasm. KEYWORDS: atypical fibroxanthoma • clinicopathologic • dermal sarcoma • pathogenesis • ultraviolet light
In 1963, the term, ‘atypical fibroxanthoma (AFX, pseudosarcoma of the skin, paradoxical fibrosarcoma, pseudosarcomatous dermatofibroma, pseudosarcomatous xanthofibroma and pseudosarcomatous reticulohistiocytoma)’ was proposed by Helwig for a lesion that was initially viewed as a reactive process [1–3]. In 1973, AFX was established as a distinct clinicopathologic entity [3]. Herein, the clinicopathologic features, differential diagnosis, prognosis, treatment and molecular mechanisms of this particular neoplasm are addressed. Clinical features of AFX
Clinically, AFX appears as a rapidly growing light-brown, red or pink papule, nodule or nodulo-ulcerative lesion, which is usually 2.0 cm), extensive involvement of the subcutis, tumor necrosis or vascular invasion. AFX diagnosed using these infiltrative margin with invasion of the fascia, muscle or adjastrict criteria have essentially benign behavior [43,44]. Of note, cent organs. Other supporting features include: tumor necrosis, the terms ‘pleomorphic dermal sarcoma’ and ‘undifferentiated perineural infiltration and vascular invasion [26,27,46]. One study pleomorphic sarcoma, previously known as malignant fibrous indicated that the expression of LN-2 (CD74) is typical of histiocytoma’ are used somewhat synonymously in the literature, undifferentiated sarcoma and is usually negative in AFX [47]. albeit with the reservation that the appellation of ‘undifferentiated pleomorphic sarcoma’ to a cutaneous lesion Separation of AFX from other fibrohistiocytic tumors should be avoided given the implication of a more aggressive Other fibrohistiocytic tumors that should be separated from AFX course [40,45]. Moreover, AFX and pleomorphic dermal sarcoma include atypical fibrous histiocytoma and dermatofibrosarcoma informahealthcare.com
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usually atrophic and nuclear pleomorphism is not a feature. In the author’s experience, expression of CD34 is not a feature in AFX, and if present, it is usually patchy or limited to the vascular endothelium [50]. Hanly et al. reported a diagnostic utility for Ki67 (proliferation marker) in the evaluation of the fibrohistiocytic neoplasms. A high proliferative index (Ki67) is usually noted in both AFX and undifferentiated pleomorphic sarcoma. A low proliferative index is usually seen in dermatofibrosarcoma protuberans [51]. Separation of AFX from squamous cell carcinoma
Helpful features that favor squamous cell carcinoma (sarcomatoid, spindle cell types or lesions with osteoclast-like giant CD34 CK5/6 CD68 cells) include: presence of squamous dysplastic changes/squamous cell carcinoma Figure 3. Atypical fibroxanthoma of the left upper forehead. A 72-year-old male in situ, epidermal attachment and the presented with an ill-defined, 0.7 cm tan, glistening lesion on the left upper forehead. characteristic immunohistochemical stainSections show ovoid-shaped symmetric, well-defined dermal nodule with smooth ing with antibodies to cytokeratins (espepushing deep margin. The overlying epidermis is atrophic with obliteration of the Grenz cially high-molecular-weight cytokeratins). zone. The tumor is formed of spindle cells with some pleomorphic cells arranged in solid pattern, with rare atypical mitosis. Tumor necrosis, perineural infiltration or vascular Of note, some squamous cell carcinomas invasions are not seen. Occasionally, skin adnexa are found within the tumor, but they (especially spindle cell or sarcomatoid are not infiltrated. The tumor cells are positive for vimentin and CD10, smooth muscle types) not uncommonly show weak or actin (diffuse and moderate reactivity) and CD68 (patchy staining especially in the negative staining for pancytokeratin cockgigantic and histiocytoid cells). Negative stains include: pancytokeratin AE1/AE3, hightail or low-molecular-weight cytokeratin molecular-weight cytokeratin (CK5/6), S100, Melan-A, desmin and CD34 (some stains are not shown in this figure). The diagnosis of AFX was rendered. The surgical margins and strong reactivity for vimentin. In this were free of lesion. There was no local recurrence and no regional lymphadenopathy for regard, high-molecular-weight cytokeratins 1 year. There was no abnormality detected on thoracic and abdominal computed (CK5/6 and CK34BE12 and MNF116) tomography. Comment: The reactivity for smooth muscle actin and CD68 in AFX are useful markers and usually show suggests the concept of ‘fibrohistiocytic and myofibroblastic’ phenotypes in strong positivity [52]. this neoplasm. Data taken from [27,29,67]. Of note, p63 reactivity argues against the diagnosis of AFX and is therefore protuberans. Atypical fibrous histiocytoma is a variant of fibrous useful in separating this particular neoplasm from squamous histiocytoma that usually involves the trunk and extremities of cell carcinoma [53,54]. CD99 is usually negative in squamous middle-aged women. It is composed of fairly well-circum- cell carcinoma [31]. Procollagen-1-positive staining in the scribed, essentially dermal nodular fibrohistiocytic proliferation. tumor cells was observed in about one-third of the desmoIts constituent cells (fibrohistiocytes) show some atypical histo- plastic squamous cell carcinoma [33,55]. logic features such as nuclear pleomorphism, hyperchromatism, nucleolar prominence and atypical mitosis. The lesional cells are Separation of AFX from malignant melanoma usually reactive for CD68, CD163 and factor XIIIa. Negative Features that favor malignant melanoma include: junctional stains include CD34, CD31, desmin, smooth muscle actin, melanocytic component and characteristic immunohistochemiCAM 5.2, keratin 5/6 and S100 [48,49]. Features that favor atypi- cal staining with markers of melanocytic lineage (positive stains: cal fibrous histiocytoma over AFX include: epidermal hyperpla- S100, Melan-A, tyrosinase, HMB-45 and microphthalmiasia, pigmentation of the basal cell layer, free Grenz zone and associated transcription factor) [52]. D2-40 and p75 are useful diffuse pleomorphism. Dermatofibrosarcoma protuberans is markers in separating AFX (D2-40 positive and p75 negative) another diagnostic consideration. This is a nodular dermal, sub- from spindle cell malignant melanoma (D2-40 negative and cutaneous tumor composed of a uniform population of slender, p75 positive) [56]. About 10–60% of malignant melanomas strongly and diffusely CD34+ cells arranged in a uniform stori- show positive staining for CD99 [30,31]. Procollagen-1-positive form pattern par excellence [26,27,46]. The overlying epidermis is staining in the tumor cells was observed in desmoplastic 1078
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Atypical fibroxanthoma
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malignant melanomas [33,55]. CD68 is also detectable in 86% of malignant melanoma cases [57].
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Separation of AFX from leiomyosarcoma & angiosarcoma
Features that favor cutaneous leiomyosarcoma include: distinct intersecting fascicles of eosinophilic spindle cells with ovoid to cigar-shaped nuclei, demonstrating desmin positivity and abundant cytoplasmic glycogen [26,27,46]. Hemorrhagic AFX or lesions with pseudoangiomatous pattern should be separated from angiosarcoma. AFX is usually confined to the dermis, whereas angiosarcoma may invade into underlying fascia. AFX is usually negative for CD34 and erythroblast transformation-specific related gene, whereas angiosarcoma is positive for these markers [23]. Moreover, D2-40 (podoplanin) staining of AFX is usually weak (when positive), whereas Friend leukemia integration 1 transcription factor staining of angiosarcomas is usually strong and nuclear [37]. It should be emphasized that CD31 staining can occur in AFX because cells with histiocytic differentiation can express CD31. This is an important pitfall that can lead to an erroneous diagnosis of angiosarcoma. AFX & undifferentiated pleomorphic sarcoma
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Figure 4. Atypical fibroxanthoma of the right cheek. An 89-year-old male presented with a 1.2 cm raised tan nodulo-ulcerative lesion on the right cheek. Sections show dome-shaped well-circumscribed dermal proliferation. The tumor is restricted to the dermis and does not show appreciable extension into the subcutaneous tissue. The overlying epidermis is attenuated and ulcerated centrally. The tumor is composed of pleomorphic spindle, epithelioid and histiocytoid cells with vesicular nuclei and prominent nucleoli. The cells are arranged in fascicular and solid patterns. Great numbers of mitotic figures with some atypical forms are noted. The cells have wide, eosinophilic and scarcely vacuolated cytoplasm. The neoplastic cells show strong and diffuse reactivity for vimentin and CD10. Patchy CD68 positivity is noted, especially in the giant and histiocytoid cells. S100 decorated some dendritic cells. Negative stains include: pancytokeratin AE1/AE3, high-molecular-weight cytokeratin (CK5/6 and 34D-E12), p63, Melan-A, CD34 and desmin (some stains are not shown in this figure). Solar elastosis and a suggestion of epidermal collarets are noted. The diagnosis of AFX was made. The surgical margins were free of lesion. There was no local recurrence and no regional lymphadenopathy for 1 year. There was no pathology detected on thoracic and abdominal computed tomography. Comment: Focal HMB45 and MART-1 (giant and clear cells) and S100 (dendritic cells) expression has been reported in AFX and these may represent entrapped dendritic cells. Data taken from [36,38,67,128].
There is a considerable controversy regarding the relationships between AFX and undifferentiated pleomorphic sarcoma, as their immunohistological separation may be sometimes difficult. Some studies have proposed that AFX and undifferentiated pleomorphic sarcoma are related neoplasms with a split biological ‘personality’ [58–63]. Alternatively, some observations suggest that AFX and undifferentiated pleomorphic sarcoma represent separate and completely unrelated entities. In support, the lower proliferative activity in AFX than that of undifferentiated pleomorphic sarcoma [64], and the diploid nature of AFX in contrast to undifferentiated pleomorphic sarcoma, which is usually aneuploid [65]. Additionally, ras gene mutations are absent in AFX versus being present in undifferentiated pleomorphic sarcoma [66]. It is possible that these neoplasms arise from a common mesenchymal progenitor cells with the capacity to differentiate along different molecular pathways [67]. Molecular pathology of AFX
To date, the etiopathogenesis of AFX is poorly understood. Risk factors include exposure to ultraviolet and ionizing informahealthcare.com
radiations and immunosuppression. The development of AFX may be associated with alterations of nucleotide excision repair system, tumor suppressor gene p53 [22,60,68,69] and its related molecules Bcl-2-associated X protein, growth arrest and DNA damage [70]. There is DNA damage and accumulation of DNA photoproducts [71]. Reactivation of telomerase has been implicated in tumorigenesis. Telomerase reverse transcriptase is the gene coding for the catalytic subunit of telomerase. Activating mutations in the Telomerase reverse transcriptase promoter lead to increased telomerase expression and therefore allowing cells to proliferate continuously without entering apoptosis or senescence. Griewank et al. examined Telomerase reverse transcriptase promoter mutations in 27 AFX using conventional Sanger sequencing. Telomerase reverse transcriptase promoter mutations were identified in 25 cases. They were found to have a UV 1079
1080 Usually >2.0 cm Present
Positive/negative
Usually negative
The lesion is strictly dermal tumor
Usually T or CC > TT) and were largely identical to those detected in cutaneous melanoma. These findings not only support the pathogenetic role of UV exposure in AFX, but also suggest that telomere maintenance through increased expression of telomerase plays an important role in the pathogenesis of these lesions [41]. There is a suggestion that viral factors may contribute to the development of AFX. Some risk factors of AFX (ultraviolet and ionizing radiations) are almost identical to those of Merkel cell carcinoma. The latter may be pathogenetically associated with Merkel cell polyomavirus. Interestingly, Merkel cell polyomavirus DNA has been reported in 17% of AFX, and may act as a cofactor in the tumorigenesis of this particular neoplasm [72]. However, it should be noted that this relationship with Merkel cell polyomavirus is very tentative, at best, as normal skin also may demonstrate this virus. This virus is currently associated with many neoplasms and there is no significant basis for its implication in this neoplasm [73–75]. AFX has been reported in immunosuppressed individuals such as cardiac or renal transplant recipients [76,77], HIV-infected [78] or cancer patients (basal cell carcinoma, squamous cell carcinoma, mycosis fungoides, chronic lymphocytic leukemia and non-Hodgkin lymphomas) [79,80]. AFX has a mesenchymal origin (fibroblastic, fibrohistiocytic or myofibroblastic nature), that is, it may be derived from fibroblasts, fibrohistiocytes or myofibroblasts [59,67,81]. In 1973, VargasCortes et al. suggested that AFX may arise from the tissue histiocytes. Its spindle-cell elements were proposed to represent facultative fibroblasts. The progenitor cells may represent an undifferentiated mesenchymal cell capable of differentiating in both a histiocytic and fibroblastic direction [82]. The mesenchymal derivation of AFX is supported by several ultrastructural, immunophenotypic and molecular observations. At ultrastructural level, there is a transition from fibroblasts to large gigantic cells with intermediate forms exhibiting features of both [83]. AFX with spindle cell morphology on light microscopy is ultrastructurally composed of undifferentiated 1081
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Hussein
mesenchymal cells. AFX with highly pheomorphic appearance on light microscopy is ultrastructurally formed of atypical histiocytic cells and abundant Langerhans cells [84]. At the immunophenotypical level, both AFX and undifferentiated pleomorphic sarcoma are positive for mesenchymal (vimentin, smooth muscle actin, CD31 and D2-40) and fibrohistiocytic markers (procollagen-1, factor XIIIa and CD68) [19,23,33,36,37,67]. At the molecular level, AFX and the undifferentiated high-grade pleomorphic sarcoma have deletions on chromosomes 9p and 13q suggestive of a common pathogenetic pathway. However, the difference in the magnitude of these changes may contribute to the different biological behavior of these tumors [85], that is, benign behavior of AFX versus high-grade malignant potential for high-grade pleomorphic sarcoma [60,63]. In 1989, the experimentations of Phelps and his colleagues lended further support to the mesenchymal origination of AFX. The authors examined a dermal derived malignant mesenchymal neoplasm arising in ultraviolet irradiated mice [86]. Ten-week-old hairless albino mice (Skh/hr-1) were irradiated with photocarcinogenic dosages of ultraviolet light for 30 weeks or longer. A high proportion of the animals developed dermal round and flesh colored nodules. On histology, the dermal nodules consisted of poorly circumscribed proliferations that efface the dermal microarchitecture and infiltrate the subcutis and skeletal muscle. The lesional cells include mitotically active, atypical spindly and pleomorphic and multinucleated giant cells (features reminiscent of AFX in human). The overlying epidermis was attenuated or ulcerated, but an unequivocal transition from keratinocytes to the neoplastic cells in the underlying dermis was not observed. The neoplastic cells expressed mesenchymal markers (vimentin, procollagens I and III, type I collagen and lysozyme) [86]. They were negative for both wide-spectrum keratin and epidermally derived keratin, a finding that argues against epithelial derivation. At the ultrastructural level, the two populations of cells were identified: filiform, fibroblastic cells and larger, rounded histiocytic cells, with occasional transitional forms between the two. The cells contained abundant endoplasmic reticulum, filopodia and lysosomes, but unequivocal evidence of epithelial differentiation (i.e., intercellular junctions and tonofilaments) was not identified. Further propagation of the explants (from the dermal round and flesh colored nodules) in tissue culture resulted in the growth of rounded or amoeboid cells that lacked syncytia or confluent growth despite long periods of feeding. Ultrastructurally, this in vitro cell culture cells had features consistent with a mesenchymal phenotype [86]. McCalmont and his colleagues described a case of AFX on the shoulder of 45 years old lady that evolved from a fibrous histiocytoma [87]. The lesion was stable for 20 years before undergoing rapid increase in size. Histologically, there was a large spindle cell proliferation that involved the dermis and subcutaneous tissue that can be stratified into different components. The first component (most of the lesion) was composed of small bland looking uniform cells (interpreted by 1082
the authors as a large longstanding benign fibrous histiocytoma component). The interest consists of multinucleate cells and collagen fibrous, with rare mitotic figures. The remainder (central superficial part of the lesion) consisted of giant cells and large pleomorphic patently atypical cells with easily identifiable atypical mitotic figures (interpreted by the authors as the AFX component). The dermatofibroma and AFX components had a similar immunohistochemical phenotype. Ki67 proliferative index in the AFX component was evidently higher as compared with the dermatofibroma component [87]. The authors raised several notions based on the phenomenon of ‘AFX evolving from benign fibrous histiocytoma’. They include: common lineage/derivation of both AFX and benign fibrous histiocytoma (mesenchymal origin) and the neopalstic nature of benign fibrous histiocytoma. Also, the evolution of malignant phenotype (AFX) can occur in a background of benign lesions (benign fibrous histiocytoma). This evolution is analogous to evolution of the following malignancies: malignant melanomas in a background of nevi (including dysplastic nevi) [88], basal cell carcinomas in a background of trichoepitheliomas or trichoblastomas [89] or hidradenocarcinomas in a background of hidradenomas [87,90,91]. A speculative view about AFX & epithelial-mesenchymal transition of squamous cell carcinoma
The author speculates that AFX could develop by epithelialmesenchymal transition (EMT) of squamous cell carcinoma (epithelial origin) into a mesenchymal cancer phenotype [15,92,93]. The speculation that AFX may represent EMT of squamous cell carcinoma is based on some clinical and molecular observations. Clinically, collision of AFX and acantholytic squamous cell carcinoma in situ has been reported [94]. AFX, lentigo maligna melanoma and squamous cell carcinoma arising at the site of a thermal burn treated with skin grafts have been observed [95–97]. Immunohistochemically, both AFX and squamous cell carcinomas are positive for broad-spectrum cytokeratin antibodies, albeit being focal in the former [98,99]. At the molecular level, both AFX and squamous cell carcinoma show alterations of p53, other pro-apoptotic and anti-apoptotic molecules [60,70,100,101]. EMT is a developmental process during which cells of epithelial origin (squamous cells) lose epithelial features and acquire a mesenchymal phenotype (spindle, epithelioid and pleomorphic cells). In AFX, EMT is associated with loss or downregulation of epithelial makers (loss of pancytokeratin AE1/AE3, high-molecular-weight cytokeratins: CK5/6 and CK MNF116 in AFX), upregulation of mesenchymal markers (vimentin, smooth muscle actin, CD31 and D2-40), acquisition of fibroblasts, fibrohistiocytes (procollagen-1, factor XIIIa, CD68) or myofibroblasts-like (Actin) morphologies [102–104]. Transforming growth factor family members (TGF-b) are secretory molecules with dual tumor-suppressor and oncogenic roles. They signal through kinase receptor complexes on the cell surface, which phosphorylate cytoplasmic mediators Expert Rev. Anticancer Ther. 14(9), (2014)
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(SMADs, mothers against decapentaplegic: MAD and the Caenorhabditis elegans protein SMA: from gene sma for small body size). Upon phosphorylation, SMADs translocate to the nucleus and interact with co-activators or co-repressors to mediate the transcriptional regulation of several genes. In neoplasia, malignant cells escape from the tumor-suppressive effects of TGF family members (TGF-b) by mutational inactivation of some molecules in TGF-b signaling pathway [105]. The epithelial cells undergoing an EMT express a transcription factor Snail1 and mesenchymal markers like vimentin and fibronectin, whereas the expression of E-cadherin is downregulated. Nakamura et al. reported a case of squamous cell carcinoma mimicking AFX in an 80-year-old man. The tumor expressed both vimentin and Snail1 and failed to express keratin. These findings suggest possible involvement of EMT in tumorigenesis. The authors proposed that EMT underlies the pathogenesis of not only AFX, but also spindle cell carcinoma in some cases [93]. TGF-b/SMADs signaling pathway play critical roles in the progression of squamous cell carcinoma. Lack of SMAD2 expression in squamous cell carcinoma is associated with upregulation of Snail1 and poor differentiation, indicating the involvement of EMT. Therefore, TGF-b-SMADs signaling pathway is a well-known inducer of this transition and it might be a target for the new therapeutic approach for poorly differentiated squamous cell carcinoma [93,103,105]. Although the author speculates that AFX could develop by EMT of squamous cell carcinoma, he acknowledges several notions that argue against this speculation. The association between TGF-b component/Snail and EMT relies on a single case report and more investigations are mandatory before such a model would be considered scientifically valid [93,103,105]. The speculation that AFX (with its essentially benign clinical behavior) represents the end result of squamous cell carcinoma (with its well-known metastatic potential) undergoing EMT may not conform to the well-documented association in the literature between EMT and an increased propensity for metastasis. Namely, EMT is widely considered to play a pivotal role in promoting metastasis in epithelial-derived malignancies [106–110]. Also, poor differentiation among cutaneous squamous cell carcinomas confers an aggressive behavior, yet AFX usually has a comparatively benign clinical behavior.
safety margins is the treatment of choice [115]. Davis et al. compared the outcome of Mohs micrographic surgery versus wide local excision in 45 patients with AFX. In patients treated with Mohs micrographic surgery, there were no recurrences after a mean follow-up of 29.6 months. There were three first recurrences in 25 patients treated with wide local excision after a mean follow-up of 73.6 months. One patient had a single local recurrence, and two patients each had two local recurrences. Parotid node metastasis eventually developed in one of the patients with two local recurrences. The authors concluded that microscopic control of the surgical margins with Mohs micrographic surgery in the treatment of AFX results in a lower recurrence rate than that with wide local excision and conserves normal tissue [116]. Seavolt and McCall examined the files of 13 patients with AFX treated only with Mohs micrographic surgery. Of our 13 patients, only 6 had long-term follow-up, none of which had clinical recurrence of their AFX [117].
Treatment of AFX
Expert commentary
There is no clear recommendation on treatment of AFX in medical literature. Two treatment modalities are known: Mohs micrographic surgery and wide local excision [111–114]. There have been several reports of treatment with Mohs micrographic surgery, which showed a lower local recurrence rate than with excision. Wollina et al. examined the files of 25 patients with AFX. Complete microhistographic controlled surgery (‘Mohs like’) was feasible in all cases followed by mesh-graft transplantation in three patients. Eighteen patients showed a complete remission. Four patients had a relapse within 2 years of follow-up treated by surgery. One patient is still under radiotherapy. The authors concluded that micrographic controlled surgery with wide 2 cm
In the author’s opinion, AFX may have epithelial (spindle, sarcomatoid squamous cell carcinoma or lesions with osteoclast like giant cells) or mesenchymal derivations. The difference in the biologic behavior among AFX (metastases from AFX are almost unheard of) and squamous cell carcinoma or undifferentiated pleomorphic sarcoma (documented rate of metastasis) may be due to the superficial location, low proliferative activity, diploidy and lack of ras gene mutations in the former. In contrast, both squamous cell carcinoma and undifferentiated pleomorphic sarcoma may have deep location (invasion of subcutis), high proliferative activity, diploidy and ras gene mutations [63,64,66]. A diagnosis of AFX is not only a challenging
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Prognosis of AFX
AFX was originally described as a low-grade dermal tumor of atypical spindle cells, but this view has changed [46,118]. Some authorities consider the behavior of this particular as benign one, if strict diagnostic criteria are applied for diagnosis [40,43,44]. The recurrence rate has been reported to range between 5% [22,119] and 10% [3,120]. Multiple local recurrences are rare [121]. Previous studies indicated that metastases occurred in approximately 1% (about 26 cases to date) of reported cases of AFX [116,118,120,122]. They were in the form of localized cutaneous metastasis or metastasis to other organs such as cervical lymph nodes [120,121,123], lungs and peritoneum [124]. Some authorities (a correspondence between McCalmont and Fletcher) indicated that there is only one convincing case of AFX with well-documented metastasis [124]. Lum and King reported a case of AFX on the scalp of an 81-year-old man who developed widespread peritoneal metastases 3 years later. Although the tumor was highly pleomorphic, there was no indication of adverse features (lymphovascular space invasion, deep invasion and tumor necrosis). On histology, the peritoneal metastasis was similar to the original scalp lesion [124]. In their opinion, reports of metastatic AFX antedate rigorous modern immunohistochemical markers or are based on application of flawed diagnostic criteria [43,44].
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task, but also the diagnosis of exclusion of other malignant neoplasms with similar morphology. This should be made only after applying the stringent histological criteria. Immunostains are essential in the accurate diagnosis of AFX. Pertinent clues that argue against the diagnosis of AFX include: deep tissue invasion (subcutis, muscle or fascia), tumor necrosis, perineural and lymphovascular invasion. It is possible that AFX reported with recurrence or metastases are misdiagnosed sarcomas or poorly differentiated squamous cell carcinoma. The author acknowledges two notions about the relationship between AFX and poorly differentiated squamous cell carcinoma. The possibility that a subset of AFX could represent metaplastic squamous cell carcinoma where the epithelial component was not sampled may be erroneous: such a lesion may be simply poorly differentiated carcinoma, and would be revealed as such following complete excision and evaluation of the entire lesion. The possibility that a subset of AFX represent poorly differentiated squamous cell carcinoma where cytokeratin expression is lost, applying in particular to occasional AFX cases with p63 expression could be also erroneous for two reasons. The presence of variable p63 positivity is not unequivocal
evidence of an epithelial derivation in AFX, but rather, a lack of specificity of conventional p63 antibodies (4A4), which might cross-react with other p63 homologs, notably p53 [125]. Five-year view
In the author’s opinion, UV exposure may have a pathogenetic role in AFX. Several molecules (TGF-b/SMADs, Snail, p53, Bcl-2-associated X protein, GAAD45 and Telomerase reverse transcriptase) may be involved in the development of AFX. To address these issues, and to have an understanding of the pathogenesis of this neoplasm, the establishment of cell lines from AFX and their further molecular characterization would open avenues for future research. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Clinically, atypical fibroxanthoma (AFX) appears as a rapidly growing light-brown, red or pink papule, nodule or nodulo-ulcerative lesion, which is usually
