The relation between atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) has led to confusion and debate in the literature over the years.1 Both tumors present in patients of advanced age, predominantly in men, and mainly on sun-exposed skin and on the head and neck, with lesions that are often ulcerated (Fig. 1).2 Both are comprised of a variable admixture of histiocytoid, spindle-shaped, epithelioid, and multinucleated giant cells with pleomorphic nuclei (Fig. 2) often with abundant aberrant mitosis. There are no immunohistochemical diagnostic techniques for these entities and diagnosis should be by ruling out other possibilities.1

Figure 1.

Exophytic ulcerated tumor on the right temple, consistent with atypical fibroxanthoma after histopathologic study.

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Figure 2.

Detail of an admixture of epithelioid and spindle-shaped cells in an atypical fibroxanthoma (H&E, 40x).

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These are uncommon tumors and their incidence is unknown, although the incidence of AFX in one Spanish health area has recently been estimated in the literature as 0.59 cases/100 000 inhabitants,3 which contrasts with the incidence of other tumors in Spain, such as basal cell carcinoma (113.05/100 000 inhabitants), squamous cell carcinoma (38.16/100 000), and melanoma (8.76/100 000 inhabitants).4 There are no figures available for the incidence of PDS.

Their etiology, in most cases, is related to chronic exposure to sunlight. The implication of ultraviolet light in their etiopathogenesis is supported by the demonstration of p53 mutations.5

The current histopathologic definition of AFX includes the following characteristics1:

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  Well-circumscribed dermal neoplasm, comprised of an admixture of histiocytoid, spindle-shaped, epithelioid, and multinucleated giant cells with pleomorphic nuclei

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  Exophytic, nodular, or polypoid growth (Fig. 3a)

  
  

  Figure 3.

  A, Atypical fibroxanthoma with polypoid morphology. Well-circumscribed dermal tumor with no invasion of subcutaneous cellular tissue (H&E). B, Pleomorphic dermal sarcoma under a magnifying glass. Extensive tumor tissue with involvement of the deep margin (H&E).

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  Absence of diffuse infiltrate of subcutaneous cellular tissue, tumor necrosis, or lymphovascular or perineural invasion

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  Diagnosis by exclusion based on analysis of the entire resection piece, and after ruling out the main differential diagnoses—squamous-cell, sarcomatous, or spindle-cell carcinoma, spindle-cell melanoma, poorly differentiated leiomyosarcoma, and angiosarcoma—with an appropriate immunohistochemical panel

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  Possible presence of an epidermal collarette

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  The deep margin is usually predominantly expansive

PDS has histopathologic features similar to AFX, but with diffuse invasion of subcutaneous cellular tissue or deep structures, tumor necrosis, or lymphovascular or perineural invasion6 (Fig. 3b). When these diagnostic criteria are strictly applied, the clinical behavior of AFX is considered benign, with infrequent local recurrence. Those AFX lesions reported with metastases in the literature are probably other tumors that have been incorrectly diagnosed. The terms undifferentiated pleomorphic sarcoma of the skin and superficial and deep malignant fibrous histiocytoma are poorly documented and not currently used to refer to these tumors.2

Although AFX and PDS are tumors that have been studied in detail, there is still some debate in the scientific literature as to how these entities are related and there are some outstanding questions, such as whether AFX can transform into PDS over time, with the 2 belonging to the same entity and with a prognosis depending on the depth of the neoplasm.1 In this literature review, we will attempt to determine the exact histopathologic features of the 2 entities, according to series published in the literature and those aspects that link them together.

For this review, a literature search was performed in the PubMed (Medline), Cochrane Library, Embase, SciELO, and Trip databases with the following terms: “atypical fibroxanthoma” AND “pleomorphic dermal sarcoma,” on September 4, 2020. The initial search retrieved 126 results (53 after eliminating duplicates). The summaries and abstracts were read and screened according to the following criteria:

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  Criteria for inclusion in the review:

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    Case series published in peer-reviewed journals in the last 10 years, which included AFX and/or PDS, with both tumors described according to currently used terms. Additionally, series that deal with the relationship between these 2 tumors, according to a given feature.

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  Exclusion criteria:

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    Not related with the objective of the review (5 publications)

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    Isolated case reports (11 publications)

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    Narrative reviews of AFX and/or PDS (14 publications)

In total, 24 studies were selected for the full text to be read; of these, 22 were finally included in the present review (Fig. 4). Two studies were excluded because of the grouping of AFX and PDS cases, without applying diagnostic criteria for differentiation between them.

Figure 4.

Flow diagram of the review strategy.

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Of the series included, the following data were collected: patients and tumor, site, diagnostic criteria used, pattern of invasion, size, mitotic index, ulceration, necrosis, perineural invasion, lymphovascular invasion, involvement of the deep margin, variants, immunohistochemistry (negative markers), prognosis, and relationship between tumors.

The results of the series included for AFX,3,7–10 PDS,2,6 and mixed entities11–25 are summarized in Table 1.

The series are in general small, with few patients, rarely exceeding 30 tumors for each type. The site was mainly the head and neck, with all tumors reported at this site in many of the series.

Except for the aforementioned histopathological criteria (invasion of deep structures, tumor necrosis, perineural invasion, and lymphovascular invasion), it is not clear where the differences between AFX and PDS actually lie. The scientific literature is very confusing due to the different terminology, different diagnostic criteria used by the authors, and insufficient immunohistochemical characterization of the tumors,27 especially in older articles.28 It is essential to perform an exhaustive assessment of resected pieces when such tumors are suspected, as the final diagnosis has implications in the subsequent management of the patients.29

Variants of AFX have been described in the literature and knowledge of these is important to avoid diagnostic errors. These include nonpleomorphic spindle-cell AFX, clear-cell AFX, hemosiderotic AFX, myxoid AFX, AFX rich in osteoclast-like giant cells, keloid AFX, and granular cell AFX.1 These changes have also been reported in some PDS, either involving the tumor areas or the entire lesion.2

In AFX, a chronic inflammatory infiltrate can be observed, above all in the tumor periphery and the presence of severe solar elastosis is usually observed in the adjacent dermis.5

The immunohistochemical markers that can help differentiate between AFX and other tumors include CD99, S-100, CD34, cytokeratins, desmin, CD10, vimentin, HMB-45, CD68, and p63, among others.9 Differential diagnosis of these tumors with angiosarcoma is important and CD34 and ERG have been shown to be useful in this context, particularly in AFX-PDS with pseudoangiomatous/hemorrhagic pattern (Fig. 5).11 To date, attempts to differentiate between AFX and PDS with immunohistochemical markers (CD99, LN-2) have not proved successful.12,30

Figure 5.

Diagnostic algorithm for atypical fibroxanthoma and pleomorphic dermal sarcoma.

Abbreviations: AFX, atypical AFX; PDS, pleomorphic dermal sarcoma.

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Strong positivity for CD10 in AFX and PDS can support diagnosis. However, it is important to note that any tumor with spindle-cell morphology can be positive for this marker, including sarcomas such as mixofibrosarcoma.5

It is also important to highlight that dendritic cells present in biopsies of AFX and PDS are positive for S100, but the tumor cells should be negative for this marker to make a diagnosis.5

Of note in this sense is the series of by Müller et al.,9 in which a significant increase in SEC62 expression was reported in tumors with necrosis and a trend to greater expression in tumors with high Clark levels and tumor size greater than 5 cm2. Although the histopathologic features for diagnosis of AFX are not specified in the study, the fact that large tumors with necrosis and subcutaneous invasion were included suggests that, according to current criteria, some tumors would actually be PDS. This increased expression of SEC62 in PDS compared with AFX could be the object of new lines of research in the future, with inclusion of both types of tumor with stricter diagnostic criteria.

Given that diagnosis of AFX and PDS is by exclusion, negative immunohistochemical markers suggestive of other entities are those that are used for ruling them out. In the literature, the number and type of markers that need to be negative for diagnosis have not been established. Thus, in many cases series, immunohistochemical characterization of tumors is insufficient and can, in actual fact, correspond to other entities.31

It is worth asking whether, faced with tumors as closely related as AFX and PDS, it makes sense to continue using different terms. In situ melanoma does not have the same prognosis as ulcerated melanoma, with lymphovascular invasion and microsatellitosis, but we still refer to both lesions as melanoma. If to date, no significant differences have been found at the cellular, immunohistochemical, genetic, or molecular level, it makes sense to group these tumors in the same spectrum and use the same term to describe them. This is what Winchester et al.32 did in a series of 319 patients with tumors encompassed by the term undifferentiated pleomorphic sarcoma, which included cases of AFX and PDS grouped together, and for this reason, they were not included in this review. In that series, local recurrence was reported in 45 patients (14.1%) and distant metastasis in 33 patients (10.3%). After a complete analysis, the authors concluded that the aggressive behavior in these tumors grouped together depends on invasion beyond subcutaneous fat, tumor size greater than 2cm, immunosuppression, and presence of lymphovascular invasion. Another similar approach was taken by Cesinaro et al.28 in a series of 71 tumors with features consistent with AFX or PDS grouped together and with a follow-up time of between 17 and 125 months. Like the previous study, this one was not included in our review. Only 4 local recurrences were reported and there were no cases of metastasis. The spindle-cell morphology was associated with subcutaneous invasion and recurrence. Some authors consider AFX and PDS to be on the same spectrum of tumors, although they continue to use the individual terms to differentiate between them.33

With regard to subcutaneous invasion, we have shown in this review that the criteria for determining when it is present are by no means homogeneous. These variations of criteria when classifying the tumors have probably led to overdiagnosis of either AFX or PDS, depending on the series, with the subsequent impact on the rates of recurrence and/or metastasis. In the literature, AFX has been defined as a dermal neoplasm limited to the dermis or with minimal invasion of subcutaneous cellular tissue. The exact limit of the extent of invasion required to safely denote the tumor as AFX has never been uniformly established.34,35 According to the classification of the World Health Organization, initially it is specified that AFX is limited to the dermis, without invasion of the subcutaneous cellular tissue to then affirm in the differential diagnosis that lesions that resemble AFX but are larger or show substantial invasion of subcutaneous cellular tissue or beyond that, perineural invasion, lymphovascular invasion, or necrosis, should be classified as dermal pleomorphic sarcoma.36 On the other hand, and although this is an infrequent situation, cases have been described of AFX without subcutaneous invasion that lead to recurrence with invasion of deeper structures3 or even metastasis8; so though uncommon, it is not impossible.

Finally, diagnosis of AFX is currently considered to be performed based on an entire resection piece and not with partial biopsies, given that it is very important to assess the pattern of invasion, invasion of structures, and the other criteria for PDS.1 Although it was attempted to gather information systematically, the only study that specifies the number of cases diagnosed with involvement of the deep margin is that of Iglesias-Pena et al.,3 who also described 2 cases of spontaneous regression after an incisional biopsy. This is relevant because diagnosis of AFX and/or PDS, when the deep margin is positive, always generates a certain degree of uncertainty. It is necessary to establish some clear diagnostic criteria to classify tumors suggestive of AFX that regress after biopsy or incorrectly resected tumors, with involved margins that do not allow distinction between AFX and PDS, particularly when later margin widening gives a negative result.

The series of AFX and PDS published in recent years classify these tumors mainly according to histopathologic features of subcutaneous invasion, tumor necrosis, perineural invasion, and lymphovascular invasion. The series of AFX that specify strict histopathologic criteria show that this is a benign neoplasm, but we lack larger series of patients with PDS to allow us to clearly establish what characteristics are associated with local recurrence or metastasis. Data published to date do not allow clear differentiation between these 2 tumors at other levels, and so some authors consider them the same entity that can follow a more aggressive course according to certain features of poor prognosis. Further studies are needed with large series of patients and careful description of histopathologic features to allow us to establish more rigorously factors of poor prognosis and thus help us choose the most appropriate treatment for our patients.

The authors declare that they have no conflicts of interest.