Atypical fibroxanthoma histiocytoma A. S. High, W. J. Hume,
of oral mucosa: a variant of malignant fibrous
D. Dyson
Department of Den&l Surgery, Leeds Dental School, University of Leeds and St James’s Hospital, Reckett Street. Leeds
SUMMARY. Atypical fibroxanthoma, a more recently recognised variant of malignant fibrous histiocytoma, is described arising at the site of an earlier squamous cell carcinoma, in a patient treated with radiotherapy 21 years previously. Distinction between atypical fibroxanthoma and a poorly-differentiated squamous cell carcinoma proved to be difficult by ordinary light microscopy and it was only after immunohistochemical staining that the second lesion was confirmed as atypical fibroxanthoma. The natural history, differential diagnosis and histological pitfalls of this poorly characterised mesenchymal lesion are discussed.
unusual sites such as bone and other organs they are less common, so that there is as yet insufficient information on prognoses. Atypical fibroxanthoma occurs in two settings; about the head and neck of the elderly and on the limbs and trunks of young people. Clinically, both forms are characterised by a nodule or ulcer that produces few symptoms, so that diagnosis is often delayed. There is an association between atypical fibroxanthoma and exposure to actinic radiation and a lesswell established link with occupational or therapeutic radiation, with estimates of earlier exposure in up to 50% of cases in different reported series (Enzinger & Weiss, 1983). The interval between irradiation and tumour development is frequently greater than 10 years. It is in relation to this latter link that the current case is presented. Examples of atypical fibroxanthoma involving the oral cavity are few, whilst cases of MFH are better documented (Manni et al., 1986; Hayter et al., 1985; Block et al., 1986; Thompson & Shear, 1984). Accordingly, whereas the latter has a poor prognosis (Thompson & Shear, 1984), the outcome for oral atypical fibroxanthoma, more especially mucosal, is less clear, although it might be expected to behave in a manner similar to those arising in skin and be less aggressive.
INTRODUCTION The term malignant fibrous histiocytoma (MFH) was first introduced by Ozello et al. (1963), and was later discussed by O’Brien and Stout (1964), in reference to a group of soft tissue tumours characteriscd by a storiform growth pattern. Whilst predominantly fibroblastic in appearance, it was thought that MFH was derived from histiocytes which could behave as ‘facultative fibroblasts’, at least in-vitro. Tissue culture explants from these tumours initially showed histiocytic features, including amoeboid movement and phagocytosis, but later developed bipolar shapes resembling fibroblasts studies have both (Ozello et al., 1963). Subsequently, supported and refuted this cellular origin (Weedon & Kerr, 1975; Barr et al., 1977). Malignant fibrous histiocytoma is now generally regarded as arising from primitive mesenchymal cells that retain the capacity for histiocytic and fibroblastic differentiation as evidenced by phagocytosis, collagen production and alpha-l antitrypsin production (Meister & Nathrath, 1980). O’Brien and Stout (1964), felt that behaviour could not be predicted from morphology, but subsequently a clearer understanding of fibrohistiocytic tumours has evolved. Fretzin and Helwig (1973) originally described and classified the atypical fibroxanthoma of skin and more recently all superficial lesions are now classified by Enzinger and Weiss (1983) as atypical fibroxanthomas. These usually arise in skin and, although from a morphological point of view they are identical to MFH, they behave differently by virtue of their superficial location and possible radiation-based aetiology. Thus, they have a more favourable prognosis, with local recurrence but no tendency to metastasisc. Lesions are well characterised and documented in skin, but in more
Case report In 1961, a 54-year-old Caucasian female, developed a painful area in the anterior floor of the mouth. This was biopsied and reported as consisting of mucous glands with a covering of inflamed keratinising squamous epithclium. Although the epithelium was hyperplastic, with pseudoepitheliomatous hyperplasia extending into inflamed subepithelial tissue, there was no evidence of malignancy. Following biopsy, no additional treatment was given. 268
Atypical
Fig. 1 - Clinical presentation of atypical fibroxanthoma as a small raised nodule anterior midline. just lingual to alveolar ridge. ‘l‘hcre is a smaller nodule close-by and the whole area shows mucosal irregularity.
In July 1963 she was again referred by her general dental practitioner because of an area of ‘leukoplakia’ at the site of the previous lesion. She was admitted to hospital and a conservative excision biopsy of the area was carried out. I Iistological examination revealed the presence of supcrficial ulceration involving the terminal portion of the submandibular salivary duct. The ulcer base was reported as being a well-differentiated squamous cell carcinoma. Deep invasion of tissues was limited but, as there was some doubt about the lesion having been excised to normal margins, a decision to carry out radiotherapy as distinct from further surgical treatment was made and she was admitted to the Regional Radiotherapy Ccntre. Over a 6week-period, a total fractionated dose of 67 Gy was administered by external beam therapy. Post-radiotherapy progress was stormy. There was no sign of bone necrosis but she did develop a severe skin reaction, with redness, exfoliation and thickening of the skin of the lower fact and neck and redness of the upper chest wall. Iler lips were bleeding, cracked and ulcerated and she had marked swelling of the tongue, which was covered by a grcyish was exudate. The whole of the mouth and oro-pharynx red, swollen and diffusely ulcerated. Palliative treatment was instituted and the condition slowly improved. She was followed up for 5 trouble-free years and was discharged with a clinically normal floor of mouth, but with prominent atrophicchanges to her lower face resulting from her radiotherapy. There were no further problems until 1982 (14 years later) when, aged 75. she complained of a loose lower denture and soreness in the floor of mouth at the site of her previous carcinoma. Although the alveolar ridge was inflamed, no ulceration was noted. This, and a similar problem 14 months later (1983) were resolved by adjustment of the lower denture. After a further 8 months (1084) she returned, again with soreness at the same site. There was a very small nodule approximately 3 mm in diameter with surrounding puckering of the mucosa in the anterior floor of mouth (Fig. 1). lncisional biopsy was performed and a histological diagnosis of a poorly-differentiated lesion, consistent with a recurrent squamous cell carcinoma was made. She was subsequently reviewed in the Radiotherapy Clinic but it was decided that no further radiation would be advisable and that excision was prcferrable. Under general anaesthesia the anterior floor of mouth was excised. Histological examination confirmed a poorly-differentiated
fihroxanthoma
of oral mucosa
269
lesion and this was diagnosed as probably of squamous cell origin. It appeared to have been completely excised. Good progress was maintained, healing was uneventful and her lower denture was relined. She remained under continuous review. At 8 months postoperatively she returned with a small ‘red spot’ and an adjacent white area on the lingual side of the ridge. The denture was once again eased and the signs and symptoms quickly resolved. Ten months later (1986) she complained of swelling in the floor of mouth. Examination showed a midline sublingual swelling 5 mm in diameter. A biopsy was taken and the histological report was of atypical fibroxanthoma. Following the biopsy, healing appeared to be satisfactory. There were no further problems until 4 months later (1986) when another swelling appeared at the same site. Local excision was performed under local anaesthesia; the histological appearance was again reported as atypical fibroxanthoma. A third histologically identical recurrence was excised, under local anaesthcsia, after a further 16 months (1987). She now continues with a floor of mouth, which is clinically abnormal to naked-eye inspection but with no ulceration or obvious overgrowth of new tissue. The appearance is unchanged over 2 years after her last visit. No regional or distant lymphadenopathy has ever been found.
HISTOYATHOLOGY A review of all the histological material from this case confirmed that the original specimen was, indeed, squamous cell carcinoma (Fig. 2). Characteristic fields of the atypical fibroxanthoma arc shown in Figures 3 and 4. The tissue contained large histiocytic cells and a variety of inflammatory cells in a fibrous and partly necrotic background. Numerous large, plcomorphic cells were seen, many of which were multinucleated. Normal and abnormal mitoses were frequent as were foamy macrophage-like cells and cells with large nuclei, and prominent nucleoli. An interesting feature was the prominent hyahne change with fibrinoid necrosis associated with blood vessels. The lesion was superficial and did not extend to sublingual salivary glands or deep lamina propria. The overlying epithclium was normal. Special stains failed to reveal mucin or glycogen; nor was there evidence of kcratin or squamous cell differentiation. The appearances were consistent with a malignant, histiocytic, soft-tissue lesion and in view of its superficial location a diagnosis of atypical fibroxanthoma seemed more appropriate than malignant fibrous histiocytoma. Immunohistological examinations revealed that the large atypical cells stained strongly positive with the histiocyte markers alpha- I -antitrypsin and alphaI-antichymotrypsin and the vimentin marker-V9 (Dako) which labels mcscnchvmal derived cells. Anti-keratin markers including CAM 5.2 (Becton Dickenson) to keratins 8, 18 and 19 (Makin et al., 1984) and anti-cytokeratin LP34 (Dako, CK-l), active against a range of keratins (Moll et al., 1982), were uniformly negative, whilst appropriate positive controls were satisfactory. Electron microscopy showed no evidence of the
270
Rritish Journal
of Oral and
MaxillofacialSurgery
Fig. 2 - Submucosa showing infiltration by islands of poorlykeratinising squamous cell carcinoma. A dense inflammatory cell infiltrate is present in intervening stroma. (Original magnification ~125. Stain: H & E.)
Fig. 3 - Normal epithehum covers lamina propria containing large atypical cells throughout. These are seen in more detail in Figure 4. hut the complctc absence of epithelial involvement in this figure is noteworthy. (Original magnification x250. Stain: H & E.)
cells all showed features of histiocytes, including numerous lysosomes and vacuoles, surrounded by a tri-laminar membrane, containing occasional myelin figures and dense bodies. Delicate finger-like cytoplasmic projections were numerous around the cell margins. Rough endoplasmic reticulum in cisternae and small mitochondria were prominent. Many reactive inflammatory cells were also identified and extracellular bundles of loose collagen were prominent. After the diagnosis of atypical fibroxanthoma was made, the material from 1984, reported as a poorlydifferentiated lesion of probable squamous origin, was reviewed using immunohistological techniques. The histological appearances resembled the more recent biopsies, and the atypical cells also stained positively with alpha-l-antitrypsin, alpha-l-antichymotrypsin (Fig. 5) and anti-vimentin, but were ncgative with CAM 5.2. anti-cytokeratin CK-1 (Fig. 6) and epithelial membrane antigen (EMA Dako) which is known to stain a wide variety of normal and neoplastic epithelia. These findings support a diagnosis of atypical fibroxanthoma rather than poorly-differentiated squamous carcinoma. Of the even earlier specimens, both the hyperplastic epithelium (1961) and the invasive tumour cells (1963) stained heavily with anticytokeratin CK-1 and EMA, as expected from the diagnosis of squamous cell carcinoma, whilst CAM 5.2 appeared negative in the surface, hyperplastic and malignant epithelia (although salivary epithelium in the same section was strongly positive). This is often the case, in that hyperplastic and well differentiated squamous carcinomas usually express low levels of keratins 8 and 18. The final diagnosis is of a superficial variant of MFH, the atypical fibroxanthoma, which has now recurred three times since 1984, but which shows no evidence of aggressive local growth nor of metastatic spread. DISCUSSION
Fig. 4 - A vcsscl (off centre) is seen, containing polymorphs. It is surrounded by a hyaline rim-often seen as a post-radiotherapy change, and large atypical, often multinucleate cells, as well as a more diffuse polymorph infiltrate. (Original magnification x400. Stain: H & E.)
tonotilaments or desmosomes which could have supported an epithelial origin, nor were melanosomes or dense core granules seen, so that malignant melanoma was also discounted. The large, atypical
This case has demonstrated the difficult& involved in establishing a diagnosis of atypical fibroxanthoma from poorly-differentiated squamous cell carcinoma and has shown the important contributions of immunohistology and electron microscopy. The patient, who presented originally with a welldifferentiated squamous cell carcinoma of the floor of mouth, was treated with radiotherapy. An atypical fibroxanthoma arose at the same site 21 years later (1984) and recurred three times in 4 years. The long interval between radiotherapy and the appearance of atypical fibroxanthoma is well rccogniscd and is consistent with the accepted interval for a radiationinduced tumour. On reviewing the material from 1984, a diagnosis of poorly differentiated carcinoma was revised to atypical fibroxanthoma on immunohistological findings. This was further supported by electron microscopic findings. Diagnosis of atypical fibroxanthoma can be difficult and in this case was initially confused with a poorly differentiated lesion
Atypical tibroxanthoma of oral mucosa
Fig. 5 - Note the diffuse cytoplasmic staining of all the large
atypical cells (arrows), one of which shows a tripolar mitosis. The small inflammatory cells appear dark due to condensed nuclear chromatin and the counterstain (methyl green). By contrast, the nuclei of the large cells have stained very poorly. (Original magnifcation x400. Stain: Peroxidase labelled alphaI-antichymotrypsin.)
of probable squamous cell origin following radiotherapy. However, using conventional light microscopy, immunohistological methods and electron microscopy we were unable to demonstrate any squamous cell features, whilst features consistent with a histiocyte origin were positively identified in all biopsies from 1984 onwards. It is important to note that there is prominent site variation in keratin expression within the oral cavity (Morgan et al., 1987a). Anti-keratin antibodies should therefore be chosen carefully so that they can be directed at those keratins which are normal to the region in which the tumour has arisen (Morgan et al., 1987b). As Enzinger and Weiss (1983) pointed out, it is important to distinguish atypical fibroxanthoma from MFH because of their disparate prognoses. The natural history of atypical fibroxanthoma in this instance is of a benign lesion and lends support to the idea that oral lesions will behave more like superficial atypical fibroxanthoma of skin than MFH and therefore have a favourable prognosis. Acknowledgements The authors
would like to thank Dr M. Harris, Consultant Histopathologist at the Christic Hospital and Holt Radium Institute, Manchester and Dr Carl Gray, Consultant Histopathologist, Leeds General Infirmary for assistance with this case.
References Barr, R. J., Wuerker, R. B. & Graham, J. H. (1977). Ultrastructure of atypical libroxanthoma. Cancer, 40, 736. Block, M. S., Cade, J. E. & Rodriguez, F. H. Jr. (1986). Malignant fibrous histiocytoma in the maxilla. The British Journal of Orul and Maxillofacial Surgery, 44, 404. Enzinger, F. M. & Weiss, S. W. (1983). Sofr Tissue Tu~~KY,
pp. 166-199. St Louis: C. V. Mosby. Fretzin, D. F. & Hclwig, E. B. (1973). Atypical fibroxanthoma of the skin. Cancer, 31, 1541. Hayter, J. P., Williams, D. M., Cannell, H. & Hope-Stone, H. (1985). Malignant fibrous histiocytoma of the maxilla. Journal of Cranio-Maxillo-Facial Surgery, 13, 167. Makin, C. A., Bobrow, L. G. & Bodmer, W. F. (1984). Monoclonal antibody to cytokeratin for routine use in
271
Fig. 6 - Note the granular, cytoplasmic, positive staining in the covering epithelium top left, whilst the large atypical cells seen throughout the lamina propria show only light counterstaining, being completely negative for any peroxidase deposition (arrows). (Original magnification Xm. Stain: Peroxidase labclled anticytokcratin LP34.) histopathology. Journal of Clinical Pathology, 37,975. Manni, J. J., van den Broek, P., van Haelst, U. J. G. M., Slooff, J. P. & Bruaset, I. (1986). Malignant fibrous histiocytoma of the tongue. Journal of CranbMaxillo-Facial Surgery, 14, 103.
Meistcr, P. & Nathrath, W. (1980). Immunohistochcmical markers of histiocytic turnours. Human Pathology, II, 300. Mall, R., Franke, W. W. & Schillcr, D. L. (1982). The catalogue of human cytokcratins: patterns of expression in normal epithelia, tumours and cultured cells. Cell, 31, 11. Morgan, P. R., Leigh, I. M., Purkis, P. E., Gardner, I. D., van Muijen, G. N. P. & Lane, E. B. (1987a). Site variation in keratin expression in human oral epithelia-an immunocytochemical study of individual keratins. Epitheliu, l(l), 31. Morgan, P. R., Shirlaw, P. J., Johnson, N. W., Leigh, I. M. & Lane, E. B. (1987b). Potential applications of anti-keratin antibodies in oral diagnosis. Journal of Oral Pathology, 16, 212.
O’Brien, J. E. & Stout, A. P. (1964). Malignant fibrous xanthomas. Cuncer, 17, 1445. OzclIo, L., Stout, A. P. & Murray, M. R. (1963). Cultural characteristics of malignant histiocytomas and fibrous xanthomas. Cancer, 16, 331. Thompson, S. H. & Shear, M. (1984). Fibrous histiocytomas of the oral and maxillofacial regions. Journal of Oral Purhology, 13, 282. Wecdon, D. & Kerr, J. F. R. (1975). Atypical fibroxanthoma of the skin. An electron microscopic study. Pathology, 7, 173.
The Authors A. S. High BDS, FDSRCS, MRCPath
Lecturer W. J. Hume PhD, BDS, FDSRCPS, MRCPath Professor Department of Dental Surgery Leeds Dental School University of Leeds Leeds LS2 9LU D. Dyson BChD, FDSRCS Consultant Dental Surgeon St James’s Hospital Beckett Street Leeds LS9 7TF Correspondence
and requests
Paper received 20 April 1989 Accepted 14 October 1989
for offprints
to
Mr A. S. Wh.
of oral mucosa: a variant of malignant fibrous
D. Dyson
Department of Den&l Surgery, Leeds Dental School, University of Leeds and St James’s Hospital, Reckett Street. Leeds
SUMMARY. Atypical fibroxanthoma, a more recently recognised variant of malignant fibrous histiocytoma, is described arising at the site of an earlier squamous cell carcinoma, in a patient treated with radiotherapy 21 years previously. Distinction between atypical fibroxanthoma and a poorly-differentiated squamous cell carcinoma proved to be difficult by ordinary light microscopy and it was only after immunohistochemical staining that the second lesion was confirmed as atypical fibroxanthoma. The natural history, differential diagnosis and histological pitfalls of this poorly characterised mesenchymal lesion are discussed.
unusual sites such as bone and other organs they are less common, so that there is as yet insufficient information on prognoses. Atypical fibroxanthoma occurs in two settings; about the head and neck of the elderly and on the limbs and trunks of young people. Clinically, both forms are characterised by a nodule or ulcer that produces few symptoms, so that diagnosis is often delayed. There is an association between atypical fibroxanthoma and exposure to actinic radiation and a lesswell established link with occupational or therapeutic radiation, with estimates of earlier exposure in up to 50% of cases in different reported series (Enzinger & Weiss, 1983). The interval between irradiation and tumour development is frequently greater than 10 years. It is in relation to this latter link that the current case is presented. Examples of atypical fibroxanthoma involving the oral cavity are few, whilst cases of MFH are better documented (Manni et al., 1986; Hayter et al., 1985; Block et al., 1986; Thompson & Shear, 1984). Accordingly, whereas the latter has a poor prognosis (Thompson & Shear, 1984), the outcome for oral atypical fibroxanthoma, more especially mucosal, is less clear, although it might be expected to behave in a manner similar to those arising in skin and be less aggressive.
INTRODUCTION The term malignant fibrous histiocytoma (MFH) was first introduced by Ozello et al. (1963), and was later discussed by O’Brien and Stout (1964), in reference to a group of soft tissue tumours characteriscd by a storiform growth pattern. Whilst predominantly fibroblastic in appearance, it was thought that MFH was derived from histiocytes which could behave as ‘facultative fibroblasts’, at least in-vitro. Tissue culture explants from these tumours initially showed histiocytic features, including amoeboid movement and phagocytosis, but later developed bipolar shapes resembling fibroblasts studies have both (Ozello et al., 1963). Subsequently, supported and refuted this cellular origin (Weedon & Kerr, 1975; Barr et al., 1977). Malignant fibrous histiocytoma is now generally regarded as arising from primitive mesenchymal cells that retain the capacity for histiocytic and fibroblastic differentiation as evidenced by phagocytosis, collagen production and alpha-l antitrypsin production (Meister & Nathrath, 1980). O’Brien and Stout (1964), felt that behaviour could not be predicted from morphology, but subsequently a clearer understanding of fibrohistiocytic tumours has evolved. Fretzin and Helwig (1973) originally described and classified the atypical fibroxanthoma of skin and more recently all superficial lesions are now classified by Enzinger and Weiss (1983) as atypical fibroxanthomas. These usually arise in skin and, although from a morphological point of view they are identical to MFH, they behave differently by virtue of their superficial location and possible radiation-based aetiology. Thus, they have a more favourable prognosis, with local recurrence but no tendency to metastasisc. Lesions are well characterised and documented in skin, but in more
Case report In 1961, a 54-year-old Caucasian female, developed a painful area in the anterior floor of the mouth. This was biopsied and reported as consisting of mucous glands with a covering of inflamed keratinising squamous epithclium. Although the epithelium was hyperplastic, with pseudoepitheliomatous hyperplasia extending into inflamed subepithelial tissue, there was no evidence of malignancy. Following biopsy, no additional treatment was given. 268
Atypical
Fig. 1 - Clinical presentation of atypical fibroxanthoma as a small raised nodule anterior midline. just lingual to alveolar ridge. ‘l‘hcre is a smaller nodule close-by and the whole area shows mucosal irregularity.
In July 1963 she was again referred by her general dental practitioner because of an area of ‘leukoplakia’ at the site of the previous lesion. She was admitted to hospital and a conservative excision biopsy of the area was carried out. I Iistological examination revealed the presence of supcrficial ulceration involving the terminal portion of the submandibular salivary duct. The ulcer base was reported as being a well-differentiated squamous cell carcinoma. Deep invasion of tissues was limited but, as there was some doubt about the lesion having been excised to normal margins, a decision to carry out radiotherapy as distinct from further surgical treatment was made and she was admitted to the Regional Radiotherapy Ccntre. Over a 6week-period, a total fractionated dose of 67 Gy was administered by external beam therapy. Post-radiotherapy progress was stormy. There was no sign of bone necrosis but she did develop a severe skin reaction, with redness, exfoliation and thickening of the skin of the lower fact and neck and redness of the upper chest wall. Iler lips were bleeding, cracked and ulcerated and she had marked swelling of the tongue, which was covered by a grcyish was exudate. The whole of the mouth and oro-pharynx red, swollen and diffusely ulcerated. Palliative treatment was instituted and the condition slowly improved. She was followed up for 5 trouble-free years and was discharged with a clinically normal floor of mouth, but with prominent atrophicchanges to her lower face resulting from her radiotherapy. There were no further problems until 1982 (14 years later) when, aged 75. she complained of a loose lower denture and soreness in the floor of mouth at the site of her previous carcinoma. Although the alveolar ridge was inflamed, no ulceration was noted. This, and a similar problem 14 months later (1983) were resolved by adjustment of the lower denture. After a further 8 months (1084) she returned, again with soreness at the same site. There was a very small nodule approximately 3 mm in diameter with surrounding puckering of the mucosa in the anterior floor of mouth (Fig. 1). lncisional biopsy was performed and a histological diagnosis of a poorly-differentiated lesion, consistent with a recurrent squamous cell carcinoma was made. She was subsequently reviewed in the Radiotherapy Clinic but it was decided that no further radiation would be advisable and that excision was prcferrable. Under general anaesthesia the anterior floor of mouth was excised. Histological examination confirmed a poorly-differentiated
fihroxanthoma
of oral mucosa
269
lesion and this was diagnosed as probably of squamous cell origin. It appeared to have been completely excised. Good progress was maintained, healing was uneventful and her lower denture was relined. She remained under continuous review. At 8 months postoperatively she returned with a small ‘red spot’ and an adjacent white area on the lingual side of the ridge. The denture was once again eased and the signs and symptoms quickly resolved. Ten months later (1986) she complained of swelling in the floor of mouth. Examination showed a midline sublingual swelling 5 mm in diameter. A biopsy was taken and the histological report was of atypical fibroxanthoma. Following the biopsy, healing appeared to be satisfactory. There were no further problems until 4 months later (1986) when another swelling appeared at the same site. Local excision was performed under local anaesthesia; the histological appearance was again reported as atypical fibroxanthoma. A third histologically identical recurrence was excised, under local anaesthcsia, after a further 16 months (1987). She now continues with a floor of mouth, which is clinically abnormal to naked-eye inspection but with no ulceration or obvious overgrowth of new tissue. The appearance is unchanged over 2 years after her last visit. No regional or distant lymphadenopathy has ever been found.
HISTOYATHOLOGY A review of all the histological material from this case confirmed that the original specimen was, indeed, squamous cell carcinoma (Fig. 2). Characteristic fields of the atypical fibroxanthoma arc shown in Figures 3 and 4. The tissue contained large histiocytic cells and a variety of inflammatory cells in a fibrous and partly necrotic background. Numerous large, plcomorphic cells were seen, many of which were multinucleated. Normal and abnormal mitoses were frequent as were foamy macrophage-like cells and cells with large nuclei, and prominent nucleoli. An interesting feature was the prominent hyahne change with fibrinoid necrosis associated with blood vessels. The lesion was superficial and did not extend to sublingual salivary glands or deep lamina propria. The overlying epithclium was normal. Special stains failed to reveal mucin or glycogen; nor was there evidence of kcratin or squamous cell differentiation. The appearances were consistent with a malignant, histiocytic, soft-tissue lesion and in view of its superficial location a diagnosis of atypical fibroxanthoma seemed more appropriate than malignant fibrous histiocytoma. Immunohistological examinations revealed that the large atypical cells stained strongly positive with the histiocyte markers alpha- I -antitrypsin and alphaI-antichymotrypsin and the vimentin marker-V9 (Dako) which labels mcscnchvmal derived cells. Anti-keratin markers including CAM 5.2 (Becton Dickenson) to keratins 8, 18 and 19 (Makin et al., 1984) and anti-cytokeratin LP34 (Dako, CK-l), active against a range of keratins (Moll et al., 1982), were uniformly negative, whilst appropriate positive controls were satisfactory. Electron microscopy showed no evidence of the
270
Rritish Journal
of Oral and
MaxillofacialSurgery
Fig. 2 - Submucosa showing infiltration by islands of poorlykeratinising squamous cell carcinoma. A dense inflammatory cell infiltrate is present in intervening stroma. (Original magnification ~125. Stain: H & E.)
Fig. 3 - Normal epithehum covers lamina propria containing large atypical cells throughout. These are seen in more detail in Figure 4. hut the complctc absence of epithelial involvement in this figure is noteworthy. (Original magnification x250. Stain: H & E.)
cells all showed features of histiocytes, including numerous lysosomes and vacuoles, surrounded by a tri-laminar membrane, containing occasional myelin figures and dense bodies. Delicate finger-like cytoplasmic projections were numerous around the cell margins. Rough endoplasmic reticulum in cisternae and small mitochondria were prominent. Many reactive inflammatory cells were also identified and extracellular bundles of loose collagen were prominent. After the diagnosis of atypical fibroxanthoma was made, the material from 1984, reported as a poorlydifferentiated lesion of probable squamous origin, was reviewed using immunohistological techniques. The histological appearances resembled the more recent biopsies, and the atypical cells also stained positively with alpha-l-antitrypsin, alpha-l-antichymotrypsin (Fig. 5) and anti-vimentin, but were ncgative with CAM 5.2. anti-cytokeratin CK-1 (Fig. 6) and epithelial membrane antigen (EMA Dako) which is known to stain a wide variety of normal and neoplastic epithelia. These findings support a diagnosis of atypical fibroxanthoma rather than poorly-differentiated squamous carcinoma. Of the even earlier specimens, both the hyperplastic epithelium (1961) and the invasive tumour cells (1963) stained heavily with anticytokeratin CK-1 and EMA, as expected from the diagnosis of squamous cell carcinoma, whilst CAM 5.2 appeared negative in the surface, hyperplastic and malignant epithelia (although salivary epithelium in the same section was strongly positive). This is often the case, in that hyperplastic and well differentiated squamous carcinomas usually express low levels of keratins 8 and 18. The final diagnosis is of a superficial variant of MFH, the atypical fibroxanthoma, which has now recurred three times since 1984, but which shows no evidence of aggressive local growth nor of metastatic spread. DISCUSSION
Fig. 4 - A vcsscl (off centre) is seen, containing polymorphs. It is surrounded by a hyaline rim-often seen as a post-radiotherapy change, and large atypical, often multinucleate cells, as well as a more diffuse polymorph infiltrate. (Original magnification x400. Stain: H & E.)
tonotilaments or desmosomes which could have supported an epithelial origin, nor were melanosomes or dense core granules seen, so that malignant melanoma was also discounted. The large, atypical
This case has demonstrated the difficult& involved in establishing a diagnosis of atypical fibroxanthoma from poorly-differentiated squamous cell carcinoma and has shown the important contributions of immunohistology and electron microscopy. The patient, who presented originally with a welldifferentiated squamous cell carcinoma of the floor of mouth, was treated with radiotherapy. An atypical fibroxanthoma arose at the same site 21 years later (1984) and recurred three times in 4 years. The long interval between radiotherapy and the appearance of atypical fibroxanthoma is well rccogniscd and is consistent with the accepted interval for a radiationinduced tumour. On reviewing the material from 1984, a diagnosis of poorly differentiated carcinoma was revised to atypical fibroxanthoma on immunohistological findings. This was further supported by electron microscopic findings. Diagnosis of atypical fibroxanthoma can be difficult and in this case was initially confused with a poorly differentiated lesion
Atypical tibroxanthoma of oral mucosa
Fig. 5 - Note the diffuse cytoplasmic staining of all the large
atypical cells (arrows), one of which shows a tripolar mitosis. The small inflammatory cells appear dark due to condensed nuclear chromatin and the counterstain (methyl green). By contrast, the nuclei of the large cells have stained very poorly. (Original magnifcation x400. Stain: Peroxidase labelled alphaI-antichymotrypsin.)
of probable squamous cell origin following radiotherapy. However, using conventional light microscopy, immunohistological methods and electron microscopy we were unable to demonstrate any squamous cell features, whilst features consistent with a histiocyte origin were positively identified in all biopsies from 1984 onwards. It is important to note that there is prominent site variation in keratin expression within the oral cavity (Morgan et al., 1987a). Anti-keratin antibodies should therefore be chosen carefully so that they can be directed at those keratins which are normal to the region in which the tumour has arisen (Morgan et al., 1987b). As Enzinger and Weiss (1983) pointed out, it is important to distinguish atypical fibroxanthoma from MFH because of their disparate prognoses. The natural history of atypical fibroxanthoma in this instance is of a benign lesion and lends support to the idea that oral lesions will behave more like superficial atypical fibroxanthoma of skin than MFH and therefore have a favourable prognosis. Acknowledgements The authors
would like to thank Dr M. Harris, Consultant Histopathologist at the Christic Hospital and Holt Radium Institute, Manchester and Dr Carl Gray, Consultant Histopathologist, Leeds General Infirmary for assistance with this case.
References Barr, R. J., Wuerker, R. B. & Graham, J. H. (1977). Ultrastructure of atypical libroxanthoma. Cancer, 40, 736. Block, M. S., Cade, J. E. & Rodriguez, F. H. Jr. (1986). Malignant fibrous histiocytoma in the maxilla. The British Journal of Orul and Maxillofacial Surgery, 44, 404. Enzinger, F. M. & Weiss, S. W. (1983). Sofr Tissue Tu~~KY,
pp. 166-199. St Louis: C. V. Mosby. Fretzin, D. F. & Hclwig, E. B. (1973). Atypical fibroxanthoma of the skin. Cancer, 31, 1541. Hayter, J. P., Williams, D. M., Cannell, H. & Hope-Stone, H. (1985). Malignant fibrous histiocytoma of the maxilla. Journal of Cranio-Maxillo-Facial Surgery, 13, 167. Makin, C. A., Bobrow, L. G. & Bodmer, W. F. (1984). Monoclonal antibody to cytokeratin for routine use in
271
Fig. 6 - Note the granular, cytoplasmic, positive staining in the covering epithelium top left, whilst the large atypical cells seen throughout the lamina propria show only light counterstaining, being completely negative for any peroxidase deposition (arrows). (Original magnification Xm. Stain: Peroxidase labclled anticytokcratin LP34.) histopathology. Journal of Clinical Pathology, 37,975. Manni, J. J., van den Broek, P., van Haelst, U. J. G. M., Slooff, J. P. & Bruaset, I. (1986). Malignant fibrous histiocytoma of the tongue. Journal of CranbMaxillo-Facial Surgery, 14, 103.
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O’Brien, J. E. & Stout, A. P. (1964). Malignant fibrous xanthomas. Cuncer, 17, 1445. OzclIo, L., Stout, A. P. & Murray, M. R. (1963). Cultural characteristics of malignant histiocytomas and fibrous xanthomas. Cancer, 16, 331. Thompson, S. H. & Shear, M. (1984). Fibrous histiocytomas of the oral and maxillofacial regions. Journal of Oral Purhology, 13, 282. Wecdon, D. & Kerr, J. F. R. (1975). Atypical fibroxanthoma of the skin. An electron microscopic study. Pathology, 7, 173.
The Authors A. S. High BDS, FDSRCS, MRCPath
Lecturer W. J. Hume PhD, BDS, FDSRCPS, MRCPath Professor Department of Dental Surgery Leeds Dental School University of Leeds Leeds LS2 9LU D. Dyson BChD, FDSRCS Consultant Dental Surgeon St James’s Hospital Beckett Street Leeds LS9 7TF Correspondence
and requests
Paper received 20 April 1989 Accepted 14 October 1989
for offprints
to
Mr A. S. Wh.
