None of the present adjuvant treatment regimens for desmoid tumours has been evaluated in a randomised trial or is based on convincing clinical or experimental data. In contrast to the widely held belief, but in agreement with other published immunohistochemical series, our present study proves that desmoid tumours should be regarded as oestrogen receptor α and c-KIT negative tumours.
Throughout the literature, desmoid tumours in general are thought to be hormonally sensitive, because young fertile women are often affected. Therefore, antioestrogens have been used as an adjuvant treatment successfully4
or without benefit.5,6
This treatment is based mainly on seven reports on the expression of oestrogen receptor α in 20 of 38 desmoid tumours.2,7,8,9,10,11,12,13
In contrast, no positive staining for oestrogen receptor α was found in three large series with 72, 24, and 23 patients each,6,14,15
or in five smaller reports with a total of 11 cases.16–20
In addition, Chaudhuri and colleagues21
reported negative oestrogen receptor findings in 17 fibrosarcomas, including a not specified number of desmoid tumours.
Oestrogen receptor negativity does not necessarily mean that the tumour is insensitive to oestrogen and is not affected by antioestrogens, such as tamoxifen.17
Even some patients with oestrogen receptor negative breast cancer are known to respond to antioestrogens, although the response is much lower than that seen in oestrogen receptor positive patients.22
An explanation for the sporadically reported effect of tamoxifen has been proposed by Lim and colleagues,7
who found that four desmoid tumours that were oestrogen receptor negative had high numbers of antioestrogen binding sites in the subcellular fraction. However, this does not explain the conflicting results. In our present series, to rule out false negativity because of lack of sensitivity, the desmoid tumour samples were processed by an individual who has been in charge of breast cancer samples for many years.
Another enigma is the role of the newly established oestrogen receptor β, which has never been tested in desmoid tumours. The physiological role of oestrogen receptor β has not been extensively defined, so that the impact on treatment of a positive finding in a desmoid tumour is uncertain. Concerning sensitivity, seven different antibodies to oestrogen receptor β were tested by Skliris and colleagues,23
and the one used in our present study provided the best nuclear immunoreactivity.23
Five small and one larger series reported immunostaining for the progesterone receptor, four with positive results in seven of 15 cases (including four juvenile fibromatoses),8,9,10,11
two with negative results in eight cases,18,24
and one with negative findings in 24 cases,15
a finding that was confirmed in our series.
“Oestrogen receptor negativity does not necessarily mean that the tumour is insensitive to oestrogen and is not affected by antioestrogens, such as tamoxifen”
To our knowledge, the androgen receptor has been examined in only two cases (one positive) in a report focusing mainly on soft tissue sarcomas.18
In our present series, six of 46 extra-abdominal desmoid tumours showed a weak positive signal.
De Pas and colleagues25
retrospectively analysed 10 desmoid tumour samples for somatostatin receptor subtype 2, and found that two samples were positive. In our present series, nine of 80 samples were positive for somatostatin. The benefit of treatment with peptide receptor radiotherapy using a somatostatin analogue, as proposed by De Pas and colleagues,25
Overexpression of HER2 has been shown to be associated with tumorigenesis and enhanced tumorigenicity, and was proposed as a prognostic factor in osteosarcoma.26
However, our negative results are not surprising, because desmoid tumours do not dedifferentiate or metastasise.
Take home messages
- We analysed 80 desmoid tumours immunohistochemically for oestrogen receptor α and β, HER2, the progesterone receptor, somatostatin, cathepsin D, and c-KIT
- All samples were negative for oestrogen receptor α and only one sample was positive for c-KIT
- These data show that the published effects of antioestrogens and imatinib mesylate in the treatment of aggressive fibromatoses may not be attributable to oestrogen receptor α or c-KIT expression
Cathepsin D is a lysosomal acidic protease that may also stimulate tumour cell proliferation.16
Its expression was previously reported in one intra-abdominal desmoid tumour.16
Cathepsin D expression, which we found in all samples, might in part reflect the infiltrative growth behaviour of desmoid tumours.
Contrary to two negative reports in a total of 42 patients,27,28
but in agreement with one series where 10 of 25 patients were positive,29
and one case report,20
we found that 20 of our 80 cases were positive for Ki-67. These discrepancies might result from the different cutoff values used: positive results with a cutoff value of 5%,29
negative results with a cutoff value of 20%,28
or not stated.27
In our present series, using a cutoff value of 5%, only two of 20 positive samples had more than 10% positive cells. Brueckl and colleagues29
found Ki-67 expression in 10 of 25 desmoid tumours, and also found it a useful predictive marker of disease free survival in patients with desmoid tumours. In our present series, it was impossible to validate this result because the samples tested originated from patients treated at 18 different institutions using different treatment regimens.
c-KIT is a transmembrane protein with tyrosine kinase activity. The pathogenetic role of c-KIT in the growth of several tumour types, such as gastrointestinal stromal tumours, has been demonstrated by expression analyses and mutational analyses,30
and imatinib mesylate, a c-KIT tyrosine kinase inhibitor, has been used successfully in the treatment of gastrointestinal stromal tumours.30
This new agent has been used in two patients with aggressive fibromatosis with, according to the authors, encouraging preliminary results.31
However, data from previous studies on c-KIT immunoreactivity in aggressive fibromatoses are contradictory, with positive reports in 15 of 21 cases in two series,31,32
negative ones in a total of 52 patients,20,33–35
and one report on focal weak staining in only one of 20 desmoid tumours.36
and Hornick and Fletcher36
questioned whether the positive report by Yantiss32
might be a false positive. In our present series only one abdominal desmoid tumour showed weak positive immunostaining, unlike the strong expression seen in the positive controls (gastrointestinal stromal tumours). However, these differences might be explained in part by different c-KIT antibodies or the different dilutions used, as has been demonstrated by Lucas et al
In our present study, the dilution used was higher (1/1000) than the one recommended by Lucas and colleagues (1/250)33
; contrary to their report, we used a heat induced epitope retrieval method, which resulted in the gastrointestinal stromal tumours remaining highly positive and a reduction in the background staining. Whether the reported effects of imatinib mesylate in two patients31
are attributable to platelet derived growth factor receptor tyrosine kinase activity inhibition remains uncertain. Initially, we had planned to screen for platelet derived growth factor receptor also, but dismissed this idea because at present antibodies against platelet derived growth factor receptor remain inadequate.
In conclusion, the immunohistochemical analysis of tumour specimens from 80 patients with desmoid tumours showed that this tumour is oestrogen receptor α and c-KIT negative. Therefore, the published effects of antioestrogens and imatinib mesylate in the treatment of aggressive fibromatoses may not be attributable to oestrogen receptor α or c-KIT expression.