Order from chaos: Conceptualizing atypical fibroxanthomas, pleomorphic dermal sarcomas, and undifferentiated pleomorphic dermal sarcomas
By Warren R. Heymann, MD
June 26, 2019
Vol. 1, No. 16
The classification of fibrohistiocytic tumors is ambiguous and controversial. This has been compounded by the evolving nomenclature as understanding of the genetic and molecular basis of these tumors improved. Previously, fibrohistiocytic tumors encompassed the superficial AFX [atypical fibroxanthoma] and its deep dermal/subcutaneous version, the malignant fibrous histiocytoma (MFH). Since 2002, the World Health Organization (WHO) has started dismantling the term MFH due to the heterogeneity of these tumors, most of which are better aligned under other classifications. The term MFH has been completely eliminated from the 2013 WHO classification of sarcomas. (1)
So much for dismantling. If you PubMed search MFH today, you will see that the term is alive and well. Perhaps it will never be expunged from the pathology lexicon — regardless, the key to proper communication between a pathologist and clinician is a common understanding of a disease process and its implications.
I will begin with a conclusion — although controversies continue about their pathogenesis and relationship to each other, I think it is appropriate that these tumors be considered as part of a spectrum. An AFX is a superficial lesion of the dermis that may extend into the subcutaneous tissue. Deeper lesions with greater subcutaneous invasion, tumor necrosis, or high grade histological features (i.e., abundant atypical mitoses, lymphovascular and/or perineural invasion) are considered pleomorphic dermal sarcomas (PDS). (2) The term undifferentiated pleomorphic sarcoma (UPS) was introduced early this century; many cases called UPS are really PDS. The diagnosis of UPS should be limited to sarcomas arising from deeper tissues, other organs, and the retroperitoneum.
Clinically, both AFX and PDS mostly affect elderly men with photodamaged skin, with a strong predilection for the scalp. Lesions demonstrate rapid growth, ulceration and bleeding. Histologically, AFXs are well-circumscribed growths, confined to the dermis. They contain pleomorphic, epithelioid, spindle and multinucleated giant tumor cells. (3)
The diagnosis of these tumors is one of exclusion — other malignancies such as squamous cell carcinoma or melanoma must be ruled out by appropriate immunoperoxidase stains (keratin, S100, respectively). There is no reliable marker to differentiate AFX from PDS; however, CD10 and or procollagen-1 are relatively specific for AFX. (2)
The pathogenesis of AFX and PDS is unknown, although ultraviolet light, immunosuppression, and trauma have been implicated. (1) AFX is considered of myofibrocytic origin. (2) Molecular studies display similar features in both, including mutations in the p53 tumor suppressor gene and in the CCND1/CDK4/6/RB1 signaling pathway. (4) Amplification of BRAF, KIT, or PDGFRA and/or losses of CDKN2A may be poor prognostic markers. (5)
Winchester et al performed a retrospective study of 319 cases of UPS (equating AFX and PDS as superficial UPS, but classifying deep UPS as those lesions arising deep to the superficial fascia). The authors observed that lesions with aggressive behavior demonstrated invasion beyond subcutaneous fat and tumor size >2 cm. They proposed the subcategorization of superficial and deep UPS. They also acknowledge that the current standard of care is surgical — either by wide local excision (WLE) or Mohs micrographic surgery (MMS). (6) In their meta-analysis of 23 publications encompassing 907 patients with 914 tumors, Tolkachjov et al presented data substantiating the reports of lower recurrence rates of AFXs removed by MMS compared to WLE. (7) Regarding the use of sentinel lymph node biopsies, if an approximate 10% risk of regional metastasis is used as a cutoff for performing the procedure (as for melanoma or squamous cell carcinoma), it would not be helpful for AFXs, but could be of benefit for PDSs or UPSs in selected cases. (2)
Dermatologists can be excused for being confused by these lesions, given the lack of agreement in nomenclature in the literature. At the risk of being over-simplistic, my recommendation is to think of AFX-PDS-UPS as a spectrum — the deeper the extension, the deeper the trouble.
Point to remember: AFX, PDS, and UPS are likely part of tumor spectrum from essentially benign to potentially fatal.
Our expert’s viewpoint
Ashley B. Decker, MD
Assistant Professor of Medicine
Cooper University Health Center
As mentioned in the excellent commentary by Dr. Heymann, the jury is still out on whether AFX and PDS are different variants of the same tumor versus distinct clinical entities. For the sake of simplicity, I also prefer to think of them as on a continuum. However, distinguishing between the two is imperative as tumors with histological features of PDS are more likely to recur and metastasize. It is important to remember the initial biopsy may transect the lesion at the base leading to the incorrect diagnosis of the more superficial AFX. Complete margin assessment with MMS is recommended for both tumor extirpation and histological evaluation to delineate AFX vs. PDS. Due to the aggressive clinical nature of PDS, additional imaging should be considered. With either entity, close clinical follow up is recommended.
2. Soleymani T, Hollmig ST. Conception and management of a poorly understood spectrum of dermatological neoplasms: Atypical fibroxanthoma, pleomorphic dermal sarcoma, and undifferentiated pleomorphic sarcoma. Curr Treat Options Oncol 2017; 18: 50.
3. Sharma SR, et al. Uncommon skin cancer: Pleomophic dermal sarcoma. BMJ Case Rep 2018; Mar 5: 2018.
4. Kohlmeyer J, et al. Cutaneous sarcomas. J Dtsch Dermatol Ges. 2017; 15: 630-648.
5. Helbig D, et al. Copy number variations in atypical fibroxanthomas and pleomorphic dermal sarcomas. Oncotarget 2017; 8: 109457-67.
6. Winchester D, et al. Undifferentiated pleomorphic sarcoma: Factors predictive of adverse outcomes. J Am Acad Dermatol 2018; 79: 853-9.
7. Tolkachjov S, et al. Atypical fibroxanthoma: Systematic review and met-analysis of treatment with Mohs micrographic surgery. J Am Acad Dermatol 2018; Jul 4 [Epub ahead of print].
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