Atypical fibroxanthoma

Atypical fibroxanthoma (AFX) is a rare neoplastic disease of the skin. Since the term was coined in the early 1960s, the disease has been viewed in many ways. For a long time AFX was regarded as a superficial variant of malignant fibrous histiocytoma (MFH). When the concept of MFH was re-evaluated and the term "undifferentiated pleomorphic sarcoma" (UPS) introduced, the controversy about the nature of AFX increased. The following review aims at providing an understanding of the present status of diagnosis and therapy of AFX based on the historical context and current data.     

Superficial malignant fibrous histiocytoma presenting as recurrent atypical fibroxanthoma

Atypical fibroxanthoma (AFX) and malignant fibrous histiocytoma (MFH) are neoplasms of probable fibrohistiocytic lineage. The precise relationship between AFX and MFH remains controversial. We present two cases in which a lesion was excised from the face of an elderly person and reported as AFX. Both cases recurred within 12 months and were reclassified as MFH. They were excised with slow Mohs' micrographic surgery, with adjuvant radiotherapy in one case. In the other, a further recurrence was treated with orbital exenteration and radiotherapy. We review the difficulties in differentiating between AFX and MFH and the implications for treatment.     

Metastasizing soft tissue tumor of light damaged skin: atypical fibroxanthoma or malignant fibrous histiocytoma?

A 86-year-old female patient presented with a ca. walnut-sized, centrally ulcerated preauricular tumor on the right side as well as a firm submandibular lymph node. Histology disclosed a soft-tissue tumor breaking into the lymph node consisting partly of fibroblast-like and partly of histiocyte-like cells. Clinical and histological criteria speak for both an atypical fibroxanthoma (AFX) as well as a malignant fibrous histiocytoma (MFH). A differentiation into two entities does not appear appropriate in our opinion. As the term "AFX" is classified as a benign tumor, "metastasizing AFX" (mAFX) should be considered a special form of MFH or be diagnosed as such, respectively.     

Atypical fibroxanthoma: DNA ploidy analysis of 14 cases with possible histogenetic implications

The histogenesis of atypical fibroxanthoma (AFX) and its relationship to malignant fibrous histiocytoma (MFH) arc a subject of controversy. Many investigators have proposed that AFX may represent a reactive process, while others contend that it is a true fibrohistiocytic neoplasm, closely related to MFH. In an attempt to determine whether biologic differences between AFX and MFH may be accounted for at the cellular DNA level, we performed ploidy analysis on 14 cases of AFX by flow cytometry and compared our results with previously reported DNA analyses of MFH. Thirteen of the 14 lesions demonstrated diploid distribution of nuclear DNA, and only 1 case had an aneuploid population. This contrasts with prior data on MFH, the vast majority of which are aneuploid. Our results suggest that, despite histologic similarities, AFX may be distinguished from MFH on the basis of DNA content. These findings may be significant in understanding the biologic behavior of AFX.     

CD99 immunoreactivity in atypical fibroxanthoma and pleomorphic malignant fibrous histiocytoma: a useful diagnostic marker

Atypical fibroxanthoma (AFX), a benign lesion, and pleomorphic malignant fibrous histiocytoma (MFH) are thought to represent points along the same neoplastic spectrum but with different prognoses and treatments. Diagnosis based on histology and clinical parameters alone is sometimes difficult, and a reliable cost-effective immunohistochemical marker to help distinguish these lesions would be beneficial. The diagnosis of AFX or MFH was based upon published clinical and microscopic criteria. Formalin-fixed, paraffin-embedded tissues of 17 cases of AFX and 26 cases of MFH were immunostained with monoclonal antibody to CD99. For all cases, CD99 expression was scored on a four-tiered scale: negative, weak (1+), moderate (2+), or strong (3+). Two pathologists blinded to tumor diagnoses and type of immunostain evaluated each case independently. The interobserver correlation coefficient was calculated. Seventeen patients with AFX (16 males and one female; mean age = 79) and 26 patients with MFH (16 males and 10 females; mean age = 60) were included. AFX lesions were from the head and the face, mean size = 1.5 cm, and MFH lesions were from the head, the neck, the trunk, and the upper/lower extremities, mean size = 5.2 cm. The 17 cases of AFX demonstrated moderate or strong (2 to 3+) immunoreactivity with CD99, compared to nine of 26 (35%) MFH cases (chi-square = 18.38; p < 0.001; interobserver correlation coefficient = 0.83). Of these, 16 of 17 (94%) AFX cases stained diffusely with CD99, while only four of 26 (15%) MFH cases stained diffusely. Control slides were adequate. Our study demonstrated that CD99 can help distinguish AFX from MFH, in addition to other immunohistochemistry as well as clinical and histologic criteria.     

Aneuploidy in atypical fibroxanthoma: DNA content quantification of 10 cases by image analysis

It has recently been reported that atypical fibroxanthoma (AFX) is a predominantly diploid lesion in contrast to malignant fibrous hystiocytoma (MFH) which is usually aneuploid. To test this hypothesis, DNA content quantification was undertaken on Feulgen-stained cytology and tissue section preparations from 10 cases of AFX by image analysis. The large-atypical cells which characterize AFX were aneuploid in each case. Smaller spindle-shaped cells found in this lesion were diploid. The results suggest that AFX is indistinguishable from MFH by DNA content estimation and highlight an advantage of image analysis over (low cytometry.     

Nucleolar organizer regions in fibrohistiocytic tumors of the skin

Nucleolar organizer regions (NORs) are loops of DNA which are present within the nucleoli of cells that possess ribosomal RNA (rRNA) genes. NORs are associated with proteins which can be visualized by a simple silver staining technique. As the number of NORs appears to reflect cell and nuclear activity its determination in benign, intermediate and malignant conditions could be of help in their differential diagnosis. In this study, we investigated 35 fibrohistiocytic tumors of the skin of benign, intermediate and malignant potential from 32 patients: 15 fibrous histiocytomas (FH), 5 FH with atypia (AFH), 7 atypical fibroxanthomas (AFX), 5 dermatofibrosarcoma protuberans (DFSP) and 3 malignant FH (MFH). A one-step silver technique was used on formalin or Bouin fixed specimens. Ag-NOR counts from benign conditions (FH, AFH) significantly differed from that of their intermediate-risk (AFX, DFSP) and malignant (MFH) counterparts. Furthermore, in 2 cases (one AFX; one MFH) which twice recurred, Ag-NOR counts steadily increased with time. However, a distinction could not be achieved between AFX and MFH. Although Ag-NOR is a simple and valuable technique, it does not allow a definite distinction between malignant and intermediate processes, at least as far as fibrohistiocytic tumors of the skin are concerned.     

Tissue cultures of benign and malignant fibrous histiocytomas: SEM observations

Four dermatofibromas (DF), 2 dermatofibrosarcomata protuberans (DFSP), 2 atypical fibroxanthmas of the skin (AFX), and one malignant fibrous histiocytoma (MFH) were studied by explant culture technique and scanning electron microscopy. Differences in the cellular atypism, phagocytic activity and motility were observed between histiocyte-like cells extending from a DF and DFSP group and an AFX and MFH group. Such cytological characteristics was maintained during in vitro transformation of the cells into fibroblastic cells. It was concluded that culture behaviors of the cells from each tumor group correlated well with in vivo growth and histologic features. We feel that examination of m vitro morphology of fibrous histiocytomas may prove useful in arriving at a correct diagnosis.     

Atypical fibroxanthoma with perineural or intraneural invasion: report of two cases

We report two cases of atypical fibroxanthoma (AFX) that both had the previously unreported feature of neural invasion (one perineural and the other intraneural). AFXs recur in approximately 10% of cases but only rarely metastasize. Features associated with recurrence are inadequate excision and invasion into fat. Features associated with metastasis include recurrence, vascular invasion, deep tissue invasion, and tumor necrosis. Both of these tumors invaded deeply into subcutaneous fat and reached the deep fascia. Some authors would regard such cases as malignant fibrous histiocytoma (MFH) because of such deep extension; however, the concept of AFX as a superficial variant of MFH is outmoded--AFX is a distinct clinicopathologic entity with established clinical, histological, and immunohistochemical features.     

S100A6 expression in fibrohistiocytic lesions

BACKGROUND: S100A6, an S100 calcium-binding protein, has been found in a variety of cutaneous and extracutaneous lesions including: melanocytic nevi, melanoma, some salivary gland and epithelial tumors, and malignant fibrous histiocytoma (MFH). Dermal dendrocytes (DD) in the papillary dermis of skin also express S100A6 protein. We evaluated a variety of cutaneous fibrohistiocytic lesions to determine if the immunophenotype of S100A6 positivity can be expanded to include some or all of these lesions. METHODS: Formalin-fixed, paraffin-embedded tissues from fibrous papules (FP, 20), dermatofibromas (DF, 20), dermatofibrosarcoma protuberans (DFSP, 5), atypical fibroxanthomas (AFX, 5), oral fibromas (3), digital fibroma (1), and dermatomyofibroma (1) were evaluated with antibodies to S100A6, S100B, factor XIIIa, and MAC387 using a one-hour capillary action-based immunohistochemical procedure. RESULTS: DD in 20/20 FP, 19/20 DF, and 4/4 fibromas stained positively with anti-S100A6 in a pattern similar to anti-factor XIIIa. No DFSP cases stained with anti-S100A6. Anti-S100A6 showed superior staining to anti-factor XIIIa in 4/5 AFX cases. CONCLUSIONS: The immunophenotypes of some fibrohistiocytic lesions can be expanded to include S100A6 protein. With the exception of AFX, the use of anti-S100A6 does not appear to offer added benefit over anti-factor XIIIa in the differential diagnosis of fibrohistiocytic lesions.     

The role of CD10 in distinguishing atypical fibroxanthoma from sarcomatoid (spindle cell) squamous cell carcinoma

Background: The role of CD10 needs clarification in a broader immunohistochemical battery for distinguishing atypical fibroxanthoma (AFX) from spindle cell squamous cell carcinoma (sSCC). Methods: We retrospectively reviewed 23 cutaneous spindle cell tumors previously classified as AFX (n = 11) or as sSCC (n = 12). Each tumor was stained with CD10, S‐100, p63 and two or more cytokeratin stains. Defining AFX as a diagnosis of exclusion based on multiple negative cytokeratin stains and negative p63 staining, we reclassified four squamous cell carcinomas (SCCs) as AFX. CD10 staining was reviewed and graded in all tumors. Results: Fifteen tumors were classified as AFX. Strongly positive CD10 staining was observed in all 15 AFXs, as well as four (50%) of the eight SCCs. Expression of p63 was seen in six sSCCs (75%). Conclusions: CD10 is consistently expressed by AFX. However, CD10 is also often strongly expressed by sSCC. Positive staining with p63 favors a diagnosis of sSCC. An immunohistochemical battery useful for distinguishing AFX from sSCC may include CD10, p63 and two cytokeratin markers. However, CD10 alone should not be relied upon in the distinction of these entities. Wieland CN, Dyck R, Weenig RH, Comfere NI. The role of CD10 in distinguishing atypical fibroxanthoma from sarcomatoid (spindle cell) squamous cell carcinoma.     

Atypical fibroxanthoma of the skin and the lower lip in xeroderma pigmentosum

Xeroderma pigmentosum (XP) is a rare, usually autosomal recessive disorder related to DNA repair defects. Atypical fibroxanthoma (AFX) is a pleomorphic tumour that occurs infrequently on the limbs and trunk in children. We report a child with XP who presented with AFX of the facial skin and the lower lip. The diagnosis of AFX was confirmed using histological and immunohistochemical techniques. We discuss the possibility that ultraviolet-induced damage might be implicated in the pathogenesis of AFX.     

CD163 is not a sensitive marker for identification of atypical fibroxanthoma

The histopathological features of atypical fibroxanthoma (AFX) overlap with those of poorly differentiated carcinoma, melanoma and leiomyosarcoma in the skin. As there are no specific stains to identify AFX, the diagnosis is essentially one of exclusion and requires completion of a panel of immunostains. Recently, it has been suggested that the macrophage/monocyte-specific marker CD163 is of value in identifying AFX. To investigate this claim, 57 AFX were stained for CD163. Only 21 of 57 (37%) of AFX stained positively, and intratumoral macrophages confounded interpretation of the stain at times. In four cases, it was not possible to definitively interpret the tumor staining reaction because of this effect. While a lack of stainable CD163 antigenicity may indicate that AFX is not of histiocytic lineage, it is conceivable that expression of the antigen has been lost for some reason in cells that are in fact of macrophage lineage. In summary, CD163 only stains a minority of AFX and staining results can be difficult to interpret. CD163 is therefore of very limited value in the diagnosis of AFX. Beer TW. CD163 is not a sensitive marker for identification of atypical fibroxanthoma.     

Diagnostic utility of low-affinity nerve growth factor receptor (P 75) immunostaining in atypical fibroxanthoma

Background: Atypical fibroxanthoma (AFX) is a locally destructive, dermal‐based, fibrohistiocytic, mesenchymal tumor. Immunohistochemistry helps to differentiate AFX from squamous cell carcinoma and spindle cell melanoma. Immunomarkers against p75 yield positive stains in spindled cell melanomas and negative stains in AFX, suggesting that these may be useful in differentiating these two entities. However, a recent study concluded that p75 is not a specific marker of neuroectodermal tumors; furthermore, p75 staining in AFX has 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 frequently expressed in AFX (65 and 85%, respectively) and that CD31 rarely stains positive (5%). The 50% positivity rate of D2‐40, in contrast with published evidence for its absence in melanoma, suggests that D2‐40 may be useful for distinguishing AFX from melanoma. Furthermore, because only one sample was positive for p75, we confirm that p75 is useful in differentiating AFX from spindle cell melanoma. We advocate adding p75 and D2‐40 to assist in differentiating AFX from melanoma. 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.     

CD117 immunoreactivity in atypical fibroxanthoma

Atypical fibroxanthoma (AFX) is a spindle cell neoplasm of the skin seen typically on sun-damaged skin of the elderly. Though described as a benign entity, local recurrence and distant metastasis have been reported. This study aims to investigate the potential pathogenic role of CD117, the c-kit receptor in AFX. CD117 was detected in 15 of the 16 cases (94%). The percentage of positive cells for CD117 expression among all tumors was approximately 30%. CD117 proved to be a very sensitive marker of AFX. This antibody may be a useful diagnostic adjunct in AFX.     

Utility of p63 in the differential diagnosis of atypical fibroxanthoma and spindle cell squamous cell carcinoma

Atypical fibroxanthoma (AFX), spindle cell squamous cell carcinoma (SCSCC) and spindle cell melanoma are the primary entities in the differential diagnosis of a cytologically atypical spindle cell tumor arising on sun-damaged skin. AFX is generally regarded as a diagnosis of exclusion in this context: in the absence of S100 or keratin reactivity, a diagnosis of AFX is favored. However, keratin reactivity may be focal or even absent in SCSCC, and although numerous positive markers of AFX have been proposed, none has shown sufficient sensitivity and specificity for routine diagnostic use. We evaluated 20 AFX and 10 SCSCC with a panel of cytokeratins and p63 to assess the utility of the latter antibody in this differential diagnosis. All 10 SCSCC showed strong expression of p63, whereas all 20 AFX were p63 negative. Two additional cases (excluded from the study) were negative for keratins and S100 on initial shave biopsies, resulting in a favored diagnosis of AFX, but p63 stains performed retrospectively were positive. However, review of the excision specimens in both cases revealed deep subcutaneous extension, excluding AFX. p63 reactivity argues against the diagnosis of AFX and is therefore a useful addition to the standard immunohistochemical panel for cutaneous spindle cell neoplasms.     

Role of the EGF +61A>G polymorphism in melanoma pathogenesis: an experience on a large series of Italian cases and controls

Background

Atypical fibroxanthoma (AFX) histologically mimics high-grade sarcoma in the skin, although it follows a benign clinical course. AFX occurs in the sun-exposed skin and for this reason, an association with ultraviolet light has long been suspected. Bax and Gadd45 are p53 effector proteins. Bax is a programmed cell death protein and belongs to the Bcl-2 family. Gadd45 is a multifunctional DNA damage-inducible gene associated with the process of DNA damage.

Methods

Immunohistochemical expression of Bax was analyzed in 7 cases of AFX, and in 7 cases of benign fibrous histiocytoma (BFH) used as a comparison. The expression pattern of Bax was compared to previously reported p53 and Gadd45 expressions in a correspondent series. Mutation of the Gadd45 gene at exon 4 was also analyzed in AFX.

Results

AFX and BFH showed immunoreactivities respectively for Bax (3/7, 0/7), Gadd45 (4/7, 1/7) and p53 (2/7, 0/7). There was no exact correlation between p53 expression and Bax or Gadd45 expression. However, the pattern of expression between Bax and Gadd45 was also the same, with the exception of one case. No mutation of the Gadd45 gene at exon 4 was observed in a series of 6 AFX cases where DNA was available (0/6).

Conclusion

These results suggest a possible association between Bax and Gadd45 in AFX, and may refute any possibility of dysfunction of Gadd45 in terms of gene mutation, at least at exon 4 of the Gadd45 gene.     

Atypical fibroxanthoma on a bald scalp

We present the clinical, histopathological and immunohistochemical findings of an atypical fibroxanthoma (AFX) on the bald scalp of an 81-year-old French man who had worked at a private high school in Japan as a janitor for over 40 years. The patient had a history of basal cell carcinoma on the nape, and chronic solar radiation seemed to be a predisposing factor in the pathogenesis of this association. This case showed the typical clinical and histopathological characteristics of AFX, and the immunohistochemical results suggested differentiation of histiocytes and myofibroblasts. The AFX was completely resected, and the patient has not had tumor recurrence or metastasis for over four postoperative years. This case therefore provides further support to the theory that AFX displays a clinically benign course, even though it is essentially a malignant tumor histologically located in the dermis. Therefore, we must excise AFX completely with great care and perform regular physical examinations for several years after operation.     

Atypical fibroxanthoma presenting in a patient with stage III mycosis fungoides

The association of atypical fibroxanthoma (AFX) and mycosis fungoides (MF) has never been reported. We report a 77-year-old female who was referred for Mohs micrographic surgery (MMS) of an AFX on the right hand. At the time of presentation, this patient had stage III MF, with erythroderma and palpable lymph nodes. Our patient's AFX measured 1.5x2.8 cm. The tumor was removed by MMS with clear margins. The pathologic specimen revealed a relatively well-circumscribed neoplasm in the upper dermis composed of atypical spindle cells with pleomorphism, hyperchromatic nuclei, and brisk mitotic activity. Immunohistochemical stains were focally positive for CD68, and negative for S-100, Melan-A, desmin, smooth muscle actin and neurofilament. Perilesional skin revealed epidermal hyperplasia, parakeratosis, and multiple epidermotropic lymphocytes with enlarged and hyperchromatic nuclei. One year after the initial MMS, our patient developed another tumor on the right hand, which measured 4x6 mm. This neoplasm underwent a fusiform excision with clear margins. Histological examination revealed evidence of MF and an AFX. To our knowledge, this is the first report of an AFX arising in a patient with MF.     

Melanoma simulating atypical fibroxanthoma

Melanoma may present with a wide variety of clinicopathological presentations, among those very rarely lesions imitating atypical fibroxanthoma (AFX). While AFX usually is cured by complete excision, melanoma simulating AFX has a much more serious prognosis, and thus is important to be recognized correctly. The present series describes 4 cases of such melanomas in 3 patients whose exact diagnosis was (markedly) delayed due to unusual clinicopathological presentations including negative immunohistochemistry for melanocytic markers (S100 protein, MelanA/MART1, HMB45).