J Cutan Pathol 2011: 38: 631–635doi: 10.1111/j.1600-0560.2011.01718.xJohn Wiley & Sons. Printed in Singapore

Copyright © 2011 John Wiley & Sons A/S

Journal ofCutaneous Pathology

Diagnostic utility of low-affinity nervegrowth factor receptor (P 75)immunostaining in atypicalfibroxanthoma

Background: Atypical fibroxanthoma (AFX) is a locally destructive,dermal-based, fibrohistiocytic, mesenchymal tumor.Immunohistochemistry helps to differentiate AFX from squamous cellcarcinoma and spindle cell melanoma. Immunomarkers against p75yield positive stains in spindled cell melanomas and negative stains inAFX, suggesting that these may be useful in differentiating these twoentities. However, a recent study concluded that p75 is not a specificmarker of neuroectodermal tumors; furthermore, p75 staining in AFXhas only been evaluated in a few cases.Methods: We stained 20 AFXs for p75 and various other markers.Results: Reactivity was noted for vimentin (20 of 20 cases), CD10(17/20), CD68 (14/20), CD99 (13/20), D2-40 (10/20) and p75 (1/20).Conclusions: We confirmed that CD99 and CD10 are frequentlyexpressed in AFX (65 and 85%, respectively) and that CD31 rarelystains positive (5%). The 50% positivity rate of D2-40, in contrast withpublished evidence for its absence in melanoma, suggests that D2-40may be useful for distinguishing AFX from melanoma. Furthermore,because only one sample was positive for p75, we confirm that p75 isuseful in differentiating AFX from spindle cell melanoma. We advocateadding p75 and D2-40 to assist in differentiating AFX from melanoma.

Keywords: atypical fibroxanthoma, dermatopathology,immunohistochemistry, skin tumors

Bull C, Mirzabeigi M, Laskin W, Dubina M, Traczyc T, Guitart J,Gerami P. Diagnostic utility of low-affinity nerve growth factor receptor(P 75) immunostaining in atypical fibroxanthoma.J Cutan Pathol 2011; 38: 631–635. © 2011 John Wiley & Sons A/S.

Christian Bull1, MarjanMirzabeigi1, William Laskin2,Meghan Dubina1, TomTraczyc1, Joan Guitart1 andPedram Gerami1

1Department of Dermatopathology,Northwestern University, Chicago, IL,USA and2Department of Surgical Pathology,Northwestern University, Chicago, IL, USA

Christian Bull, MD,Department of Dermatology,University Hospital Zurich,Gloriastrasse 31, Zurich 8091,SwitzerlandTel: +41 442551111Fax: +41 442554403e-mail: christian.bull@usz.ch

Accepted for publication February 13, 2011

Atypical fibroxanthoma (AFX) represents a locallydestructive, dermal-based mesenchymal tumor ofpurported ‘fibrohistiocytic’ lineage that most com-monly arises in sun-damaged skin of the head andneck area of elderly patients. Rarely, the processoccurs in younger patients in areas of previous radi-ation. Despite worrisome histopathological features,AFX rarely metastasizes and has been shown tohave a low (5%) local recurrence rate when locallyexcised.1

The clinical presentation and histopathologyof AFX can result in misdiagnosis and inap-propriate treatment.1 Clinically or microscopi-cally, AFX presents in a fashion that cansimulate squamous cell carcinoma, basal cellcarcinoma, desmoplastic melanoma or cuta-neous leiomyosarcoma.1 Histopathologically, AFXpresents as a non-encapsulated, dermal-basedproliferation of cytologically atypical, mitoticallyactive, spindled and epithelioid cells without an

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Table 1. Table with clinical data including patient age and location ofthe lesion

Patient Age Location

1 63 Scalp2 81 Scalp3 48 Nose4 88 Scalp5 75 Scalp6 66 Scalp7 72 Ear8 79 Cheek9 66 Scalp

10 67 Ear11 75 Temple12 82 Cheek13 62 Shoulder14 72 Scalp15 81 Ear16 66 Scalp17 41 Eyebrow18 51 Nose19 86 Cheek20 51 Cheek

intra-epidermal component. Occasional multinucle-ated or foamy cells may also be seen. The architec-tural pattern is typically vaguely whorled, fascicularand storiform.2

As its immunophenotype is somewhat variable,AFX often remains a diagnosis of exclusion.1– 10

However, through the use of specific immuno-histochemical markers, AFX can be differentiatedfrom its mimics, which have a relatively more spe-cific immunoprofile. It is known that AFX cellsexpress vimentin3 and the majority express thelysosomal marker CD68.3,4 Recently, it has beenshown that the majority of AFXs also express CD10and CD99.6,8,10,11 In contrast, squamous cell carci-noma and melanoma typically lack CD10 and CD99expression.6– 11 With respect to the differential diag-nosis of AFX, keratin markers are typically expressedin squamous carcinoma,4 but may be absent insome examples of spindled squamous carcinoma.5

Recently, p63 has been identified as a marker of use inrecognizing epithelial differentiation in dermal-basedtumors and was reported to be generally negative inAFX6,7 and melanoma.6– 11

Melanocytic markers, especially S-100 proteins,are commonly used to differentiate AFX frommelanoma,2,4 but melanoma (including desmoplasticmelanoma) can occasionally lack expression of thissensitive melanocyte-related determinant.12 In thecontext of S100-negative desmoplastic melanoma,assessment of expression of the low-affinity nervegrowth factor receptor, p75, has reported to bepositive in spindle cell melanoma and negative inAFX.13– 15 It has been postulated that p75 may beuseful in differentiating these two entities. Interest-ingly, a study of 1150 neural and non-neural tumors

Table 2. Immunostain-map for patient samples. 20 samples were immunostained for a range of markers and characterized as being positive(black) or negative (white). The percentage of positive patient samples are indicated at the bottom

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concluded that p75 is not a specific marker of neu-roectodermal lineage16 and to date p75 staining inAFX has only been evaluated in a limited numberof cases. In a study by Kanik et al.,13 two examplesof AFX lacked p75 expression. Our goal was to testp75 immunoexpression in larger series of AFX.

Materials and methodsAfter approval from the Northwestern UniversityCancer Center Institutional Review Board, 20 micro-scopically confirmed cases of AFX were gatheredfrom the Northwestern University Dermatopathol-ogy files. All cases were evaluated by two der-matopathologists and one surgical pathologist withover 20 years of experience, specializing in soft tissuetumors. Inclusion criteria required that all casesrepresent atypical spindle cell tumors based on thedermis. All biopsies or excision specimens needed tobe sufficiently deep to confirm a dermal base. All caseslacked any evidence of a concurrent intra-epithelialmelanocytic proliferation and required a lack of sig-nificant immunohistochemical staining with S100,Mart-1, p63 or AE1/AE3.

All cases were immunohistochemically tested,after appropriate pre-treatment, with antibodiesfrom various suppliers that had been diluted permanufacturer instructions. The antibody panelincluded p75, CD99, CD10, CD68, CD31,AE1/AE3, MNF-116, MART-1, MITF, S-100,vimentin, p63 and D2-40. Tissue sections werestained in the Dako Autostainer using Dako Envisiondual link horse radish peroxidase (HRP) detectionsystem followed by Dako’s 3′ 3′ diaminobenzidene(DAB) chromagen kit and a Dako hematoxylincounter stain; positive and negative control tissueslides were stained with each batch. Tumors with lessthan 5% staining of the cells were called negative.Staining of 5–10% of cells was called focally positive

Fig. 1. p75 stain at 10X. Of note is the strong staining of the wholetumor lesion.

and staining of >10% of cells was called positive.Clinical information (i.e. patient age, tumor locationand size, duration of the lesion, surgical treatmentand follow-up data) was retrieved from the clinicaldatabase of the Department of Dermatology.

ResultsThe study cohort included tumors from 19 malesand 1 female. The patients ranged in age from 41 to88 years, with a mean of 69 years. All tumors werelocated in the dermis of the head and neck region(Table 1). Prior to this study, subjects had been man-aged with complete surgical excision of the tumor.All tumors showed the typical histopathology of AFXand lacked specific melanocytic or epithelial differ-entiation. The immunoperoxidase staining resultsare summarized in Table 2. Immunohistochemically,reactivity was noted for vimentin (20 of 20 cases),CD10 (17/20), CD68 (14/20), CD99 (13/20), D2-40(10/20) and CD31 (1/20). All cases stained negative

Fig. 2. H&E at 10X. Overview of the p75-positive dermal-basedtumor.

Fig. 3. H&E at 40X. Appreciate the atypical epitheloid cells of thep75-positive tumor.

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for the epithelial-related markers, keratins AE1/AE3and MNF-116, and the melanocyte-related markers,Mart-1, MITF and S-100, as well as p63. Only oneAFX specimen out of 20 biopsies expressed p75; thistumor showed no expression of CD10 and CD99.

DiscussionAFX, a dermal mesenchymal neoplasm composed ofa variable mixture of pleomorphic spindled, epithe-lioid and multinucleated cells, typically shows markedcytological atypicality but paradoxically rarely metas-tasizes. Therefore, separating this curious tumorfrom neoplasms with greater biological aggressive-ness, especially spindle cell melanoma, is impera-tive. In our immunohistochemical analysis of 20bonafide examples of AFX, we confirmed previousobservations6– 11 that CD99 and CD10 are com-monly expressed, as positivity was observed in 65and 85% of cases, respectively. Our study also sup-ports the fact that CD31 rarely labels AFX,17 as onlyone of our cases showed positivity.

Kanner et al.6 evaluated CD99, CD10 andp63 immunostaining in AFX and melanoma andreported that CD10 was the only immunomarker ofthe three that was relatively specific for AFX. Othershave shown the benefits of using CD10 in con-junction with procollagen immunostaining. AlthoughCD10 is more sensitive, procollagen has even greaterspecificity.18 To optimize efficiency and to minimizecosts, an algorithmic approach to the diagnosis ofAFX has been forwarded.19 In such an approach,CD10 and procollagen along with S100 and keratinshould be utilized initially. Absence of S100 andkeratin expression with co-expression of CD10 andprocollagen then highly supports the diagnosis ofAFX. If initial immunostaining proves inconclusive,then additional immunomarkers could subsequentlybe introduced.19

D2-40, an immunomarker directed againstpodoplanin, is expressed by the majority of fibroushistiocytomas but not by dermatofibrosarcomaprotuberans.20 In our data, 50% (10/20) of tumorsexpressed this immunomarker. To our knowledge,we are the first to report D2-40 immunoexpressionby AFX. In a recent study, D2-40 expression was

detected in only 1 of 10 spindle cell melanomasand absent in all conventional melanomas tested.21

This data, coupled with our results, indicates thatD2-40 merits further evaluation for its potential asan additional adjunct marker to distinguish AFXfrom melanoma.

The low-affinity nerve growth factor, p75, has beenreported to label spindled melanoma cells, especiallythe cells of desmoplastic melanoma, but AFX has notbeen formally analyzed for p75 expression. We foundthat only one AFX in our study group expressed p75(Fig. 1). This single tumor showed histopathologicalattributes of AFX (Figs. 2 and 3), lacked expres-sion of S-100 protein and epithelial determinantsand followed a benign clinical course for more than2 years. However, the tumor also lacked both CD10and CD99 expression and thus may not represent aclassical AFX. Notwithstanding this one p75-positivecase and the limited number of cases in our study, webelieve that p75 has potential value for distinguishingAFX from spindled and conventional melanomas.

Further analysis will be necessary to determineif atypical spindle cell tumors occurring in sun-damaged skin that express p75 but lack S100 expres-sion behave similarly to S100-positive desmoplasticmelanoma or instead follow a less aggressive courselike that of AFX. Furthermore, our analysis is lessthan optimal because only the stains listed in Table 2were assessed and these stains were not applied tocontrol cases of carcinoma and melanoma. For prac-tical reasons, we utilized data from the literature forcomparison with our AFX staining results.

In conclusion, the diagnosis and distinction of AFXand spindle cell melanoma, including desmoplasticmelanoma, remains challenging. The diagnosis ofAFX is difficult because of its microscopical andimmunohistochemical diversities. On the basis ofour immunohistochemical results from 20 examplesof AFX, we suggest that p75 and D2-40 can beconsidered as components of a battery of immunos-tains, including other determinants such as CD10and procollagen, to assist in differentiating AFXfrom melanoma. This use of p75 and D2-40 maybe especially valuable if the spindle cell tumor lacksS100 expression.

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