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J Clin Pathol. 2007 October; 60(10): 1162–1164.
PMCID: PMC2014836

Dermatofibrosarcoma protuberans in a patient with X‐linked agammaglobulinaemia

This is the first case report of dermatofibrosarcoma protuberans (DFSP) arising in a patient with X‐linked agammaglobulinaemia (XLA). XLA is the prototypic genetic disorder resulting in a lack of antibody production. Mutations are found in the Btk gene, which results in arrest of B cell development from pro B cells to pre B cells and subsequently to mature B lymphocytes.1 These patients are prone to recurrent infections without replacement immunoglobulin but are generally not at increased risk of malignancy. DFSP is a slow growing cutaneous tumour that has been reported previously with HIV infection and post‐renal transplantation, but not with antibody deficiency.

Case report

A 46‐year‐old man, known to have XLA, presented in 2001 with a painless cystic subcutaneous swelling over the proximal interphalangeal joint of his right little finger. The swelling had gradually been increasing in size over the previous year. Plain radiographs of the area were normal. The lesion was excised and histology showed a subcutaneous nodule composed of densely packed spindle cells with tapering nuclei. Collagen was focally seen between the cells but there were no giant cells or foamy histiocytes, although mitoses were identified. The findings were those of a DFSP, which had been incompletely excised. Subsequent immunohistochemical staining demonstrated the tumour was CD34 positive and factor XIIa negative.

The lesion recurred 4 months later and was re‐excised. However, histology, showed widespread recurrence and the finger was subsequently amputated with clear resection margins.

This man had originally been diagnosed with antibody deficiency at the age of 11 years and had been treated with intramuscular immunoglobulin injections initially. The diagnosis of XLA was made by demonstrating absence of the Bruton's tyrosine kinase (Btk) protein on Western blotting. Investigations showed absent circulating B cells with normal T cell numbers on flow cytometric analysis. Levels of serum immunoglobulin G, A and M were markedly reduced. Subsequent genetic analysis showed a four‐base pair (TTTG) deletion between codons 1581 and 1584. This deletion results in a frameshift mutation leading to a stop codon, one codon downstream of the deletion, thus confirming the diagnosis of XLA. Prior to the diagnosis of DFSP, he had been diagnosed with bronchiectasis, presumed to be due to a delay in starting immunoglobulin replacement; however, this had been stable on replacement intravenous immunoglobulin treatment.

At present, 5 years after amputation of the affected finger, he continues to remain well with no recurrence of DFSP and there has been no evidence of metastases or other malignancy.

Discussion

DFSP is a rare monoclonal cutaneous soft tissue sarcoma accounting for approximately 1.8% of all soft tissue sarcomas in one series.2 About 85–90% of DFSPs are low‐grade lesions, although the remainder contain a high grade fibrosarcomatous component. It is an indolent tumour with a mean symptom duration of 6.4 years at presentation.3 Treatment of DFSP is wide local excision of the tumour, and the probability of controlling the tumour with this exceeds 90% although there is a less than 5% chance of distant metastases.2 Radiotherapy has been used in the event of local disease that cannot be resected.

Patients with XLA typically suffer from recurrent sino‐pulmonary infections with encapsulated bacteria. In addition, they are also prone to infections with giardia and enteroviruses.1 The incidence of malignancy in patients with XLA is not clearly defined as no formal epidemiological studies have been performed. However, the frequencies reported in four large studies were 4 of 201, 0 of 73, 2 of 96 and 0 of 44.1,4,5,6 It should be noted that only the first two studies confirmed the diagnosis of XLA on a molecular basis. The other two studies were published prior to the description of Btk mutations in XLA and it has been suggested that some of the patients in these series might have had common variable immunodeficiency—a condition more frequently associated with malignancy.4 There have been case reports describing gastric adenocarcinoma,7 squamous cell carcinoma of the lung8 and lymphoreticular malignancy1 in patients with XLA. In addition, the European Society for Immunodeficiencies (http://www.esid.org) XLA sub‐registry was launched at the most recent biennial meeting in October 2006, and it will be interesting to see the data on the incidence of malignancy when it is available.

Conventionally, tumour immunity has been thought to be cell‐mediated and DFSP has been described in the setting of immunodeficiency in two patients with the acquired immunodeficiency syndrome9 and three patients after renal transplantation,10 suggesting that T‐cell‐mediated immunity is likely to play a role in this tumour. However, although there might be a possible link with T cell immunocompromise, overall very few cases of DFSP have been reported in this setting.

The mutation in XLA, however, primarily affects antibody production. In the cases of

patients with gastric and lung carcinomas, infection with Helicobacter pylori and chronic infection with bronchiectasis, respectively, were thought to play a role in the development of malignancy. It is also possible that in lymphoreticular malignancy, recurrent infection results in chronic stimulation of lymphocytes, accumulation of mutations and subsequent malignancy. Hence, the lack of antibody production is thought to increase the risk of chronic infections that can subsequently predispose to malignancy.

Btk is also expressed in non‐lymphocytic cells and may have roles there. In addition to its role in B cell survival, there is data to suggest that Btk can mediate apoptosis as well.11 DFSP is thought to arise from dermal fibroblasts but Btk is not known to be expressed in this cell lineage. Hence, it is unlikely that a Btk deficiency results in excess tumour survival in DFSP. However, Btk is also expressed in myeloid cells, including monocytes/macrophages and dendritic cells, and plays a role in the activation of these cells. It is important in NFκB activation and stimulation via toll‐like receptors 2 and 4,12,13 although there is some conflicting data.14 Hence, there might be subtle defects in these antigen‐presenting cells that might predispose towards a reduction in tumour immunity.

In our patient with XLA, there was no evidence of chronic cutaneous or soft tissue infection at the site of the tumour. Consequently, it is unclear why XLA should predispose to development of DFSP. The possibilities are that antibody or B cell (as antigen presenting cell) deficiency in some way contributes to tumour immunity, lack of Btk might result in subtle myeloid/antigen presenting cell defects or that this is a chance finding (although both XLA and DFSP are very rare).

Conclusion

This is the first case report of DFSP in a patient with XLA. Apart from bronchiectasis, our patient has remained well with no other malignancy. It is possible that in addition to T cells, other factors resulting from a Btk mutation might have a role in immunity against cutaneous sarcomatous tumours, although further evidence would be required to confirm this. As the number of surviving patients with XLA increases because of better treatment, it is possible that more patients with this association might be seen in the future.

Take‐home messages

  • This is the first published case of dermatofibrosarcoma protuberans in X‐linked agammaglobulinaemia.
  • Antibody deficiency or other subtle defects secondary to Btk mutation in non‐lymphoid cells might possibly contribute to increased susceptibility to tumours, although further work needs to be done to evaluate this.

Footnotes

Competing interests: None.

References

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