Atypical Fibroxanthoma and Pleomorphic Dermal Sarcoma 

Atypical Fibroxanthoma and Pleomorphic Dermal Sarcoma – 3 Interesting Facts

Description

1. Atypical fibroxanthoma and pleomorphic dermal sarcoma are rare cutaneous neoplasms distinguished by their depth of cutaneous involvement^(1,2)
   • Atypical fibroxanthoma are limited to dermis or associated with minimal subcutaneous involvement
   • Pleomorphic dermal sarcoma are deeper cutaneous subtypes with more extensive subcutaneous invasion, tumor necrosis, or high-grade histologic features (for example, lymphovascular and perineural invasion and abundant atypical mitoses)

Also Called

• previous terms include^(1,2)
  • superficial malignant fibrous histiocytoma
  • undifferentiated pleomorphic sarcoma

Epidemiology

Who Is Most Affected

• atypical fibroxanthoma and pleomorphic dermal sarcoma typically occur in seventh-to-eighth decade of life (ages 60-79 years)⁽²⁾
• may occur in younger patients with immunosuppression or genetic predisposition for mutations in tumor suppressor genes or gene repair enzymes⁽²⁾
• men more affected than women⁽²⁾

Incidence/Prevalence

• rare, but incidence and prevalence unknown⁽²⁾

Risk Factors

• risk factors include⁽²⁾
  • ultraviolet (UV) exposure
  • ionizing radiation
  • immunosuppression
  • xeroderma pigmentosum

Associated Conditions

• patient often has other premalignant or malignant cutaneous lesions present, such as⁽²⁾
  • actinic keratosis
  • basal cell carcinoma
  • squamous cell carcinoma

Etiology and Pathogenesis

Causes

• exact etiology of atypical fibroxanthoma and pleomorphic dermal sarcoma is unclear^(1,2)
• likely genetic mutations and environmental exposures, particularly ultraviolet (UV) radiation, ionizing radiation, and/or immunosuppression are involved in tumorigenesis^(1,2)

Pathogenesis

• atypical fibroxanthoma show increased gene expression profile involved in epithelial to mesenchymal transition through multiple pathways including⁽¹⁾
  • AKT-phosphatidylinositol 3-kinase (PI3K)
  • RAS (rare)
  • extracellular signal-regulated kinase (ERK)
  • mitogen-activated protein kinase (MAPK)
  • fibroblast growth factor (FGF)
• pleomorphic dermal sarcoma are inflammatory and immunogenic tumors with large numbers of CD8-positive tumor infiltrating lymphocytes⁽²⁾
• genetic alterations in both atypical fibroxanthoma and pleomorphic dermal sarcoma may include
  • TP53 loss of function in nearly all patients^(1,2)
  • CDKN2A^(1,2)
  • FAT1^(1,2)
  • NOTCH1/2^(1,2)
  • COL11A1⁽¹⁾
  • PDGFR^(1,2)
  • TERT^(1,2)
  • DNHD1⁽²⁾
  • GNAS⁽²⁾
  • RTN1⁽²⁾
  • RTL1⁽²⁾
  • ZBTB7A⁽²⁾
  • NCKAP5L⁽²⁾
  • FAM200A⁽²⁾
  • TRAPP12⁽²⁾

History

Chief Concern (CC)

• most commonly presents on older male adults (> 60 years old) as a superficial skin-colored nodule that may be ulcerated or bleeding^(1,2)
• found in areas chronically exposed to sunlight, most frequently on scalp and less often on lower arms and back of hands⁽²⁾
• surrounding skin usually appears sun damaged⁽²⁾

History of Present Illness (HPI)

• tumor generally grows over weeks to months⁽²⁾
• may reach several cm in size prior to presentation⁽²⁾
• generally found in proximity to other skin lesions associated with chronic sun damage, such as, actinic keratoses, basal cell carcinomas, or cutaneous squamous cell carcinoma, suggesting a field cancerization effect⁽²⁾

Physical

Skin

• atypical fibroxanthomas (AFX) and pleomorphic dermal sarcomas (PDS) typically present as superficial skin-colored nodules that are ulcerated with bleeding or crusting^(1,2)
• atypical fibroxanthoma often appears as a well-circumscribed lesion, while pleomorphic dermal sarcoma may show less clear demarcation with normal skin, suggesting more aggressive, infiltrative growth⁽²⁾
• these lesions are typically found on the head, neck, scalp or ears (Australas J Dermatol 2018 Nov;59(4):309)
• perform full body skin examination to evaluate for other skin cancers⁽¹⁾
• AFX and PDS may be found in areas with other signs of chronic actinic damage, such as field cancerization with visibly sun-damaged skin showing telangiectasia, pigmentation abnormalities, sandpaper-like texture, actinic keratoses, basal cell carcinoma and/or cutaneous squamous cell carcinoma⁽²⁾
• dermoscopic features of atypical fibroxanthoma may help distinguish it from cutaneous squamous cell skin cancer (level 2 [mid-level] evidence)
  •  based on case control study
  • dermoscopic features were compared among 40 atypical fibroxanthoma, 61 basal cell carcinoma, and 61 squamous cell cancers
  • most common features of atypical fibroxanthoma
    • red structureless areas in 83%
    • white structureless areas in 70%
    • irregular linear vessels in 43%
    • central keratin mass in 33%
    • white lines from crystalline structures in 33%
    • opaque, yellowish-white scales in 30%
  • all features were also seen in patients with basal cell carcinoma and squamous cell carcinoma except for white circles, which were not seen in basal cell carcinoma patients
  • no individual feature was significantly predictive of atypical fibroxanthoma when compared to basal cell carcinoma
  • some features were significantly more likely in atypical fibroxanthoma than in squamous cell carcinoma
    • presence of red structureless areas (odds ratio [OR] 14.8, 95% CI 2.5-87.8)
    • absence of opaque yellowish-white scales (OR 0.15, 95% CI 0.03-0.87)
    •  absence of white circles (OR 0.04, 95% CI 0.01-0.2)
  • Reference – Australas J Dermatol 2018 Nov;59(4):309
• perform regional nodal physical examination for signs of metastatic disease⁽¹⁾

Diagnosis

Making the Diagnosis

• suspect atypical fibroxanthoma and pleomorphic dermal sarcoma in areas chronically exposed to sunlight, most frequently on scalp, in older male adults (> 60 years old)⁽²⁾
• diagnosis of atypical fibroxanthoma and pleomorphic dermal sarcoma generally made after exclusion of other more common diagnoses^(1,2)
• diagnosis must be confirmed with histopathology and immunohistochemistry of biopsy
• imaging studies typically not required unless locoregional metastases or deep infiltration

Differential Diagnosis

• Common differential diagnoses
  • Cutaneous squamous cell carcinoma⁽¹⁾
  • Cutaneous basal cell carcinoma⁽²⁾
  • Melanoma⁽¹⁾
  • Leiomyosarcoma^(1,2)
  • Angiosarcoma⁽¹⁾
  • Dermatofibrosarcoma protuberans^(1,2)
  • Reticulohistiocytomas⁽²⁾
  • Myofibrosarcomas⁽²⁾

Testing Overview

• Biopsy of lesion needed to identify histopathology
• Immunohistochemical staining may be helpful in distinguishing between atypical fibroxanthoma and pleomorphic dermal sarcoma and other cutaneous tumors
• Imaging may be needed if deep invasion or metastases suspected

Imaging Studies

• imaging typically not performed for superficial atypical fibroxanthoma tumors with minimal high-risk histologic features but may be useful if depth of local infiltration involves bone or critical anatomic structures⁽¹⁾
• locoregional lymph node sonography performed only if locoregional metastases suspected⁽²⁾
• locoregional cross-sectional imaging indicated only if nonmovable tumors or deep infiltration⁽²⁾

Biopsy and Pathology

Histopathology

• superficial biopsy likely not sufficient to exclude pleomorphic dermal sarcoma; elliptical biopsy generally needed⁽²⁾
• histopathology not unique for either atypical fibroxanthoma and pleomorphic dermal sarcoma and immunohistochemistry needed to distinguish these from other spindle-celled neoplasms and desmoplastic melanomas^(1,2)
• histologic features include^(1,2)
  • dense cellularity with haphazardly arranged, large, pleomorphic, and atypical appearing spindle-shaped cells
  •  hyperchromatic, irregular nuclei, and bizarre multinucleated giant cells
• histopathology similar between atypical fibroxanthoma and pleomorphic dermal sarcoma, however atypical fibroxanthoma limited to the dermis^(1,2)
• pleomorphic dermal sarcoma characterized by the following^(1,2)
  • deeper subcutaneous tissue invasion, such as, perineural invasion, and/or lymphovascular invasion
  • tumor necrosis (seen in 50% of cases)
  • abundant atypical mitoses
• pleomorphic dermal sarcoma may extend into deep subcutaneous adipose tissue, skeletal muscle, fascia, and galea of scalp^(1,2)

Immunohistochemistry

• no single known immunohistochemistry marker helps distinguish atypical fibroxanthoma and pleomorphic dermal sarcoma⁽¹⁾
• initial immunohistochemistry panel should include
  • ≥ 2 melanocytic markers (SOX-10, S100), which are associated with melanoma and melanocytic tumors, and are nearly always negative with atypical fibroxanthoma and pleomorphic dermal sarcoma^(1,2)
  • 2 cytokeratin markers (AE1/3, MNF116, KL1, or CAM5.2), which are associated with spindle cell squamous cell carcinomas, and are negative with atypical fibroxanthoma and pleomorphic dermal sarcoma (⁽²⁾, J Cutan Pathol 2010 Mar;37(3):301)
  • 1 muscle marker (desmin/caldesmon), which is associated with leiomyosarcomas and is negative with atypical fibroxanthoma and pleomorphic dermal sarcoma^(1,2)
• additional markers may be necessary, such as
  • CD10 strongly positive with atypical fibroxanthoma and pleomorphic dermal sarcoma (weakly positive in 50% of cutaneous squamous cell carcinoma, and 33% in multiple myeloma)^(1,2)
  • vascular markers (CD34, ERG) that are negative with atypical fibroxanthoma and pleomorphic dermal sarcoma⁽²⁾
  • procollagen-1 that is mostly positive in atypical fibroxanthoma, not commonly reactive in cutaneous squamous cell carcinoma, and weak-to-moderate expression in desmoplastic multiple myeloma^(1,2)
  • myocytic markers (alpha smooth actin, alpha-SMA) that may be focally positive in atypical fibroxanthoma and pleomorphic dermal sarcoma⁽²⁾
  • PDGFRB that is positive in 100% of pleomorphic dermal sarcoma but also strongly associated with advanced squamous cell carcinoma⁽²⁾
  • CD99 that is mostly positive in atypical fibroxanthoma, negative in cutaneous squamous cell carcinoma, and 10% positive in multiple myeloma⁽²⁾
  • CD68 that is rarely positive in macrophages and mostly negative in tumor cells⁽²⁾

Management

Management Overview

• for both atypical fibroxanthoma and pleomorphic dermal sarcoma, complete surgical excision is mainstay of treatment
  • Mohs micrographic surgery (MMS) is preferred modality if available
  • wide local excision is an alternative option, but recurrence rates reported as higher than with MMS
• adjuvant radiation therapy often advised for unresectable, recurrent, or metastatic disease, but limited data to evaluate its efficacy
• immunotherapy reported to induce complete remission in a few case reports of adults with recurrent or metastatic disease (level 3 [lacking direct] evidence)
• follow-up after treatment, every 6 months in first 1-2 years for atypical fibroxanthoma and every 3 months in first 1-2 years for pleomorphic dermal sarcoma for recurrence or metastasis

Surgery and Procedures

• Mohs micrographic surgery (MMS) preferred over wide local excision (WLE) as standard treatment for both atypical fibroxanthoma and pleomorphic dermal sarcoma because of reported higher success in producing negative margins^(1,2)
  • MMS involves repeated excision and complete circumferential and deep microscopic analysis of en face fresh frozen sections with intraoperative pathologic analysis and continued removal of tissue until margins are tumor free
  • for WLE, advised optimal surgical margins include⁽²⁾
    • for atypical fibroxanthoma, safety margin of 0.5 cm
    • for pleomorphic dermal sarcoma, 2-cm safety margin
  • MMS reported to have 2% recurrence rate and WLE reported to have 8.7% recurrence rate in adults with atypical fibroxanthoma or pleomorphic dermal sarcoma (level 3 [lacking direct] evidence)
    •  based on systematic review of observational studies with indirect comparisons
    • systematic review of 23 observational studies on MMS and WLE in 907 adults (mean age 74 years) with 914 atypical fibroxanthoma or pleomorphic dermal sarcoma
    • 175 patients were treated with MMS and 732 with WLE
    • majority of tumors were located in head and neck
    • mean follow-up of 41.6 months
    • MMS had
      • recurrence rate 2% (95% CI 0%-4.1%) in 5 tumors in 7 studies with 175 tumors
      • metastatic rate 1.9% (95% CI 0.1%-3.8%) in 7 studies with 175 patients
    • WLE had
      • recurrence rate 8.7% (95% CI 5%-12.3%) in 68 tumors in 16 studies with 732 tumors (associated with statistical heterogeneity among studies, p < 0.001)
      • metastatic rate 1% (95% CI 0.2%-1.9%) in 16 studies with 732 patients
    • Reference – J Am Acad Dermatol 2018 Nov;79(5):929
  • surgical safety margin < 2 cm associated with increased risk of relapse in adults with pleomorphic dermal sarcoma
    •  based on retrospective cohort study
    • 92 adults (median age 81 years, 87% male) with pleomorphic dermal sarcoma were evaluated
    • median follow-up was 18 months
    • majority of tumors located on scalp (82%)
    • 26 patients (28.3%) developed relapse including lymph node metastasis in 3 patients and distant metastasis in 5 patients
    • factors associated with increased risk of relapse include
      • surgical safety margin < 2 cm (hazard ratio 4.48, 95% CI 1.54-13.06)
      • no ulceration (hazard ratio for ulceration 0.4, 95% CI 0.17-0.9)
    • Reference – J Eur Acad Dermatol Venereol 2019 Aug;33(8):1577
• adjuvant radiation therapy
  • radiation therapy may be advised in patients with unresectable, recurrent, or metastatic disease, but limited data regarding efficacy^(1,2)
  • limited data to evaluate adjuvant radiation therapy for pleomorphic dermal sarcoma in adults (level 2 [mid-level] evidence)
    •  based on retrospective cohort study
    • 92 adults (median age 81 years, 87% male) with pleomorphic dermal sarcoma were evaluated
    • median follow-up was 18 months
    • majority of tumors located on scalp (82%)
    • 26 patients (28.3%) developed relapse including lymph node metastasis in 3 patients and distant metastasis in 5 patients
    • adjuvant radiation therapy given to 11 patients (12%)
    • adjuvant radiation therapy not associated with improved progression-free survival
      • hazard ratio 0.775 (95% CI 0.231-2.593)
    • Reference – J Eur Acad Dermatol Venereol 2019 Aug;33(8):1577
• adjuvant chemotherapy
  • immunotherapy has been used in patients with unresectable, recurrent, or metastatic disease but limited data regarding efficacy^(1,2)
    • pembrolizumab with or without radiation therapy reported to induce complete remission in 2 patients with relapsed or metastatic pleomorphic dermal sarcoma in case series (Oncoimmunology 2019;8(12):e1665977full-text)
    • pembrolizumab reported to induce complete remission in 87-year-old male individual with metastatic pleomorphic dermal sarcoma in case report (Br J Dermatol 2020 Dec;183(6):e189)
  • traditional chemotherapy has not been effective in treatment of metastatic disease⁽¹⁾

Follow-Up

• risk for recurrence may be increased in patients with any of the following
  • pleomorphic dermal sarcoma (as opposed to atypical fibroxanthoma)⁽²⁾
  • thick pleomorphic dermal sarcoma with deep infiltration⁽²⁾
  • positive margins after resection⁽²⁾
  • underlying immunosuppressive condition⁽²⁾
• for atypical fibroxanthoma, consider follow-up⁽²⁾
  • every 6 months in years 1-2
  • every year in years 3-5
• for pleomorphic dermal sarcoma, consider follow-up, which should include palpation of regional lymph nodes⁽²⁾
  • every 3 months in years 1-2
  • every 6 months in years 3-5
  • within first 5 years of diagnosis, ultrasound of scar and regional lymph nodes every 6 months
  • computed tomography (CT) or magnetic resonance imaging (MRI) cross-sectional imaging indicated if recurrence or metastasized tumors

Prognosis

• curative rate for atypical fibroxanthoma and pleomorphic dermal sarcoma is typically high after complete excision^(1,2)
• metastasis rare and often associated with thick or incompletely excised tumors^(1,2)
• atypical fibroxanthoma^(1,2)
  • rare metastatic potential
  • reported metastasis rate of 1%-5% (may not be accurate as these reports may be regarded as pleomorphic dermal sarcoma)
• reported metastasis rate 10%-28% for pleomorphic dermal sarcoma⁽¹⁾
• poor prognostic factors for atypical fibroxanthoma and pleomorphic dermal sarcoma are similar to squamous cell carcinoma and may include^(1,2)
  • perineural invasion
  • poor histologic differentiation
  • deeper depth of invasion
• older age, history of immunosuppression, preoperative tumor size > 2 cm, and lymphatic or vascular invasion each associated with increased mortality in adults with atypical fibroxanthoma or pleomorphic dermal sarcoma
  •  based on retrospective cohort study
  • 319 adults (median age 72 years, 81% male) with undifferentiated pleomorphic sarcoma were evaluated and followed for average of 4.1 years
  • undifferentiated pleomorphic sarcoma includes atypical fibroxanthoma, malignant fibrous histiocytoma, pleomorphic dermal sarcoma, and subfascial undifferentiated pleomorphic sarcoma
  • 14.1% had local recurrence and 10.3% had distant metastatic disease
  • factors associated with poorer survival include
    • older age (hazard ratio [HR] 1.07, 95% CI 1.05-1.1)
    • history of immunosuppression (HR 2.58, 95% CI 1.65-4.02)
    • preoperative tumor size > 2 cm (HR 1.06, 95% CI 1.01-1.12)
    • lymphatic or vascular invasion (HR 5.59, 95% CI 2.03-15.35)
  • factors associated with increased risk of metastasis include
    • trunk and extremities as treatment site (HR 5.15, 95% CI 2.53-10.5)
    • depth of invasion beyond subcutaneous fat (HR 24.9, 95% CI 5.85-106)
    • lymphatic or vascular invasion (HR 8.22, 95% CI 2.48-27.22)
  • factors associated with increased risk of recurrence include
    • preoperative tumor size > 2 cm (HR 1.09, 95% CI 1.01-1.18)
    • depth of invasion beyond subcutaneous fat (HR 3.3, 95% CI 1.55-7.1)
  • Reference – J Am Acad Dermatol 2018 Nov;79(5):853

Prevention and Screening

• not applicable

Guidelines

• National Comprehensive Cancer Network (NCCN) statement on mitigating the impacts of anticancer drug shortages can be found at NCCN 2023 Jun 7 PDF
• American Society of Clinical Oncology (ASCO) position on prioritization of antineoplastic agents in limited supply for first intervention can be found at ASCO, accessed 2023 Jun 13
• Working Group Dermatological Oncology (ADO) of the German Cancer Society/German Dermatological Society (DKG/DDG) S1 guideline on atypical fibroxanthoma and pleomorphic dermal sarcoma can be found in J Dtsch Dermatol Ges 2022 Feb;20(2):235

Review Articles

• review of atypical fibroxanthoma can be found in
  • Semin Cutan Med Surg 2019 Mar 1;38(1):E65
  • Surg Pathol Clin 2017 Jun;10(2):319
• review of updates on classification and management of atypical fibroxanthoma and pleomorphic dermal sarcoma can be found in Dermatol Clin 2019 Jul;37(3):253
• review of management of atypical fibroxanthoma can be found in Australas J Dermatol 2018 Feb;59(1):10
• review of histopathologic features of atypical fibroxanthoma and pleomorphic dermal sarcoma can be found in Actas Dermosifiliogr (Engl Ed) 2021 May;112(5):392full-text
• review of management of atypical fibroxanthoma and pleomorphic dermal sarcoma can be found in Curr Treat Options Oncol 2017 Aug;18(8):50
• review of radiation therapy for cutaneous malignancies can be found in J Am Acad Dermatol 2021 Sep;85(3):551
• case report of atypical fibroxanthoma can be found in Cesk Patol 2019 Fall;55(3):182

MEDLINE Search

• to search MEDLINE for (Atypical Fibroxanthoma OR Pleomorphic Dermal Sarcoma) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis

Patient Information

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References

General References Used

1. Soleymani T, Aasi SZ, Novoa R, Hollmig ST. Atypical Fibroxanthoma and Pleomorphic Dermal Sarcoma: Updates on Classification and Management. Dermatol Clin. 2019 Jul;37(3):253-259.
2. Helbig D, Ziemer M, Dippel E, et al. S1-guideline atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS). J Dtsch Dermatol Ges. 2022 Feb;20(2):235-243.