FormalPara Key Summary Points

Atypical fibroxanthoma (AFX), a rare, pleomorphic spindle cell malignancy, often manifests as a solitary erythematous papule or nodule primarily located on the head and neck.

Mohs surgery is currently the established treatment standard for AFX.

This case report introduces the first successful nonsurgical treatment of AFX using a topical regimen of tazarotene, imiquimod, and 5-fluorouracil, potentially expanding patient therapeutic options.

Introduction

Atypical fibroxanthoma (AFX), a rare, pleomorphic spindle cell malignancy, often manifests as a solitary erythematous papule or nodule primarily located on the head and neck. Although AFX is recognized as a superficial variant of pleomorphic dermal sarcoma (PDS), a soft tissue tumor exhibiting similar histologic characteristics to AFX, the interconnection among AFX/PDS and undifferentiated pleomorphic sarcoma remains unclear [1]. Mohs surgery is the preferred treatment method for AFX, but wide excision, radiation, and other therapies have been employed [2]. Gene mutations and expression profiles reveal similarities between AFX and cutaneous squamous cell carcinoma (cSCC), suggesting a high degree of genomic commonality between these entities [3]. Therefore, logically, treatments that target cSCC could treat AFX. Previous studies have demonstrated a high probability of tumor clearance with a nonsurgical combination of retinoids, imiquimod, and 5-fluorouracil in treating keratinocyte carcinomas (KCs), particularly cSCCs [4]. Here, we present a patient with an AFX on the right temple treated successfully with a topical combination of tazarotene cream, imiquimod cream, and 5-fluorouracil solution.

Case Report

An 80-year-old man presented with an enlarging 0.6 cm × 0.6 cm erythematous nodule with erosion on the right temple (Fig. 1). A shave biopsy demonstrated a nodule beneath an eroded epidermis composed of spindle-shaped cells that extended to the margins of the specimen. Individual cells were markedly atypical, with some cells having enlarged hyperchromatic nuclei and some having bizarre mitotic figures (Fig. 2a). Moreover, there was a background of solar elastosis. The immunostains for cytokeratin and SOX-10 were negative, and those for CD10 (Fig. 2c) and CD99 (Fig. 2e) were positive.

Fig. 1
figure 1

AFX on the right temple. Arrow highlights an area that is focally eroded

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Fig. 2
figure 2

a Hematoxylin and eosin stain of AFX before treatment. There is a dermal neoplasm, which is composed of spindle-shaped cells beneath an eroded epidermis. b Hematoxylin and eosin stain of the area after topical treatment showing an inflamed but otherwise essentially normal dermis (absent for AFX). The epidermis is broadly absent, and there is an acutely inflamed crust. c Immunostain for CD10 of the pretreated AFX. d Immunostain for CD10 of the area after treatment. e Immunostain for CD99 of the pretreated AFX. f Immunostain for CD99 of the area after topical treatment. (a–f, ×40)

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After options were presented to the patient, including Mohs surgery, he chose not to have a surgical procedure. The patient stated he could not afford his deductible or coinsurance amount involved with surgical removal and repair. The patient was presented with a nonsurgical treatment involving tazarotene, imiquimod, and 5-fluorouracil. Per previous treatment regimens detailed for KCs, the patient applied the topical combination for 30 daily applications. The patient was instructed to use this combination 5 days a week for 6 weeks (30 applications within 42 days) but was allowed to extend the treatment phase up to 9.5 weeks (30 applications within 76 days) [4]. Specified amounts of the medications included 1/5 of a packet of imiquimod 5% cream, an equivalent amount of tazarotene 0.1% cream (1/5 of a pea), and one drop of 5-fluorouracil 2% solution. The topical medications were combined on the non-adherent part of a Band-Aid bandage or equivalent for each application and the bandage was placed over the AFX overnight. The application procedure was demonstrated to the patient with a video that detailed the amounts of each medication used.

The patient was allowed to alter his treatment application frequency on the basis of the symptoms that arose, but he applied, as recommended, the combination 5 days/week over 6 weeks. After 2 weeks of application, marked erythema, progressing erosion, pain, crusting, and oozing were present at the site of application on the right temple. The patient did not report any fever, chills, or body aches.

Three weeks after the final application, the patient presented with an erosion (measuring 1.0 cm × 0.9 cm) in a background of erythema over the right temple (Fig. 3). An incisional biopsy (measuring 1.0 cm × 1.0 cm × 0.5 cm) with 90° incision to the skin surface and underlying sharp dissection through the temporal fat was performed to determine if treatment was successful. No signs of an AFX were seen with hematoxylin and eosin staining (Fig. 2b). Immunostains for CD10 (Fig. 2d) and CD99 (Fig. 2f) were also negative. The biopsy site healed well after second intention (Fig. 4). The patient had follow-up evaluation in the post-treatment area every 3 months and had no clinical signs of recurrence. After 1 year from the time of post-treatment, again no clinical signs of the AFX were seen on the right temple and three punch biopsies (2 mm) with histopathology with immunostains for CD10 and CD99 also demonstrated no evidence of the AFX.

Fig. 3
figure 3

Site of previous AFX on the right temple, 3 weeks after last topical application of combination therapy. There is an ulceration in a background of erythema. After this picture was taken, a deep incisional second biopsy was performed to determine if there was complete treatment of the AFX

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Fig. 4
figure 4

Final appearance on the right temple at 1-year follow-up that was previously treated with a combination of tazarotene, 5-fluorouracil, and imiquimod. There was acceptable cosmesis with erythema and minimal scarring

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Discussion

Clinically, histopathologically, genetically, and epigenetically, contemporary perspectives propose that AFX and PDS represent a continuum of a singular pathological entity [1, 5]. Effective therapeutic outcomes can be anticipated following the comprehensive surgical removal of an AFX with Mohs surgery. Although Mohs surgery is the standard of treatment, nonsurgical procedures for treating AFX include cryotherapy, electrocautery, and primary radiation treatments in the form of brachytherapy [2, 6]. Radiation therapy is also used as an adjuvant treatment modality for patients with recurrent or metastatic AFX/PDS [7]. While the available data is not definitive, a study with a restricted patient sample has indicated a non-significant tendency towards decreased local recurrences or metastases in individuals who received adjuvant radiation therapy [8].

There is a dearth of evidence regarding the efficacy of novel medical treatment modalities, with data mainly stemming from a handful of individual case reports. Some of these therapies include chemotherapeutic agents like doxorubicin or a combination of ifosfamide and doxorubicin [3]. Electrochemotherapy has also been explored as a potential treatment avenue. However, the limited body of evidence prevents the establishment of these therapies as the standard of care. For patients presenting with AFX/PDS characterized by elevated levels of tumor-infiltrating lymphocytes and heightened expression of programmed death-ligand 1 (PD-L1) or other immunologic checkpoint molecules, a treatment approach warranting consideration could be off-label use of checkpoint inhibitors, specifically anti-programmed death 1 (PD-1) antibodies. This therapeutic approach leverages the inherent immunological characteristics of the tumor to potentially improve clinical outcomes. A limited number of case reports have indeed suggested that the blockade of the PD-1/PD-L1 pathway may demonstrate efficacy in managing AFX/PDS [9].

AFX and PDS exhibit a significantly elevated mutational load with a UV signature, surpassing other UV-induced skin neoplasms such as cSCC. Investigations into gene mutations and expression profiles have elucidated a striking resemblance between AFX/PDS and cSCC, suggesting the highest degree of genomic commonality between these entities [3]. As such, treatments that target cSCC may have activity against AFX/PDS.

Previous studies have detailed a treatment regimen for cSCC using tretinoin, imiquimod, and 5-fluorouracil [4]. In the authors’ experience with treating cSCCs, patients treated with tazarotene in a triple combination with imiquimod and 5-fluorouracil had greater success than those using tretinoin in combination. Also, in the authors’ experience, when combined, tazarotene had greater treatment efficacy in patients who had recalcitrant tumors, invasive tumors, or smoked heavily. Moreover, imiquimod has extensive activity against cSCC [10, 11]. Also, 5-fluorouracil and tazarotene have activity against cSCC [12,13,14].

Imiquimod has the ability to modulate both innate and adaptive immunity [11]. Intrinsically, imiquimod can activate the innate immunity that may potentiate the anti-tumor activity of 5-fluorouracil and tazarotene in treating AFX. This is achieved through its direct binding to Toll-like receptors 7 and 8, found on macrophages, monocytes, and dendritic cells, which leads to the induction of apoptosis [15, 16]. Additionally, imiquimod indirectly affects immune cells by releasing cytokines [17]. The drug is also known to enhance antigen presentation by Langerhans cells and promote T cell activation in lymph nodes [17]. Imiquimod can treat skin cancers, as it triggers apoptosis via the intrinsic pathway [16]. This results in the release of pro-apoptotic factors and the activation of caspase-9 [18]. Furthermore, imiquimod is known to upregulate Bcl-2 family pro-apoptotic proteins, which promotes cancer cell death [18]. Imiquimod also elicits a cell-mediated immune response, which is beneficial in anti-tumor activity. This is achieved through the release of cytokines such as interleukin-12, tumor necrosis factor alpha, and interferon-γ [16]. These cytokines increase cytotoxic T cells and natural killer cells while inhibiting angiogenesis [16].

5-Fluorouracil’s chemotherapeutic properties are based on its facilitated cellular entry, conversion to fluorodeoxyuridine monophosphate, and subsequent interaction with thymidylate synthase [19]. This interaction inhibits the production of deoxythymidine monophosphate (dTMP), which is a crucial precursor for DNA replication and repair [20]. The depletion of dTMP leads to an imbalance in intracellular nucleotides, ultimately resulting in double-stranded DNA breaks mediated by endonuclease activity [21]. Furthermore, 5-fluorouracil is a pyrimidine analogue that misincorporates into RNA and DNA, substituting for uracil or thymine [22]. This erroneous incorporation significantly damages DNA repair machinery, ultimately leading to the demise of rapidly proliferating cells [23]. Notably, the topical application of 5-fluorouracil demonstrates remarkable selectivity for actinic skin lesions while sparing normal skin. This selectivity is proposed to arise from the preferential inhibition of thymidylate synthase in actinic skin, with only partial inhibition observed in normal skin [24].

Local adverse effects commonly occur with the use of topical tazarotene. Approximately 10–30% of patients report skin peeling, dryness, redness, and a burning sensation, while a smaller proportion of users, ranging from 1% to 5%, may encounter itching, facial pain, irritation, and a stinging sensation [25,26,27,28]. These side effects are largely attributed to compromised barrier function, leading to increased transepidermal water loss, which is often coupled with temporary heightened exfoliation, such as peeling, and mild irritation [28, 29]. This diminished skin barrier is thought to lead to enhanced cutaneous penetration of other topical medications, such as 5-fluorouracil and imiquimod [30].

Tazarotene has also been found to induce apoptosis in immortalized keratinocytes. This process is primarily facilitated through the transcriptional upregulation of p73, a homolog of p53, a well-known tumor suppressor gene that plays a significant role in the apoptotic pathway and cellular response to DNA damage [31]. This mechanism highlights the potential therapeutic applications of tazarotene in targeting abnormal proliferation, particularly relevant in skin cancer treatment and prevention [32].

Tazarotene-induced gene-3 (TIG-3) is thought to act as a tumor suppressor and is upregulated by all retinoic acid receptor-selective retinoids, including tazarotene, and is inducible in keratinocytes and HaCaT cell lines [33]. Loss of TIG-3 expression could result in epidermal malignancies. Aggressive cutaneous tumors were found to have no TIG-3 mRNA staining. TIG-3 protein, as shown by immunohistochemistry, is highest in the suprabasal epidermis of normal skin, just under the stratum corneum, and is decreased in both basal cell carcinomas and SCCs [33].

This case report is significant for several reasons. It marks the first recorded instance of successful topical treatment for AFX, offering a new option beyond surgical intervention like Mohs surgery, especially for patients unable or unwilling to undergo surgery because of factors like financial constraints or medical conditions. This case adds to the limited literature on nonsurgical approaches for AFX management, providing valuable clinical evidence that can inform future research and clinical practice in dermatology and oncology. It also highlights avenues for further exploration of molecular mechanisms and potential drug development, emphasizing the importance of personalized treatment strategies for patients with AFX.

Conclusion

Here, we report on the first case involving a successful topical medical treatment for an AFX that may benefit those patients who choose not to undergo surgery. This case advances our understanding of AFX treatment by demonstrating successful nonsurgical options and underscores the need for ongoing research to refine treatment approaches and enhance outcomes for patients with an AFX.