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Radiotherapy in multilocalized lymphedema-associated angiosarcoma

European Journal of Dermatology. Volume 15, Number 6, 474-7, November-December 2005, Therapy

Summary

Author(s) : Beate Danz, Andrea Hellmann, Volker Stadie, Jürgen Dunst, Christine Richter, Wolfgang Ch Marsch, Peter Helmbold , Department of Dermatology Martin Luther University Halle-Wittenberg, Klinik und Poliklinik für Hautkrankheiten Ernst-Kromayer-Str. 5 D-06097 Halle (Saale), GermanyFax: (+49)-345/5573978., Department of Radiotherapy, Martin Luther University Halle-Wittenberg, 06097 Halle (Saale), Germany.

Summary : We report an 80-year-old woman, suffering from a recurrence of a multilocalized lymphedema-associated angiosarcoma of the right arm. The tumor consisted of solid tumor cell formations and “classical” spongiform tumor complexes. In the tumor periphery, pathological endothelial cell proliferates on pre-existing dilated lymphatic capillaries were detectable, which, together with immunohistology (CD 31+/Desmoplakin-1-2.17+/CD 34–), supported the diagnosis of lymphangiosarcoma. Complete remission was achieved under radioimmunotherapy (54 Gy/Interferon β). A further recurrence 3 months later outside the primary therapy fields was successfully treated with radiotherapy alone. During a follow-up observation period of 3 years, there was neither local recurrence nor metastasis. This case demonstrates for the first time the long-lasting efficacy of photon radiation in a case of histologically-defined lymphangiosarcoma. Further studies should elucidate the suitability of radio monotherapy as first-line therapy in lymphedema-associated angiosarcoma with lymphatic endothelium-like immunohistology.

Keywords : interferon β, lymphangiosarcoma, lymphedema, radiotherapy, Stewart Treves Syndrome

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ARTICLE

Auteur(s) : Beate Danz¹, Andrea Hellmann¹, Volker Stadie¹, Jürgen Dunst², Christine Richter², Wolfgang Ch Marsch¹, Peter Helmbold¹

¹Department of Dermatology Martin Luther University Halle-Wittenberg, Klinik und Poliklinik für Hautkrankheiten Ernst-Kromayer-Str. 5 D-06097 Halle (Saale), GermanyFax: (+49)-345/5573978.
²Department of Radiotherapy, Martin Luther University Halle-Wittenberg, 06097 Halle (Saale), Germany

accepté le 25 Juillet 2005

In 1948, Stewart and Treves described the development of angiosarcomas with chronic persistent lymphedemas after combination of mastectomy and radiotherapy (“Stewart Treves Syndrome”, STS) [1]. STS arises typically 10 to 20 years after therapy and can develop multicentrically [2]. Apparently, some of the reported cases that were classified as STS in the literature were lymphangiosarcomas, but others were hemangiosarcomas [3].The differentiation between the two types of angiosarcoma is, however, often uncertain. The prognosis of angiosarcomas is poor [4]. So far, radiotherapy alone is not considered as the first-line therapy [5, 6].

Clinical observations

Anamnesis

An 80-year-old woman presented first with a rapidly growing tumor of the right arm ( (figure 1) ). It had doubled in size compared to findings photographically recorded 8 weeks earlier. The patient had undergone a mastectomy with axillary lymphadenectomy because of breast cancer (pT2, pN0, M0) 16 years earlier. Radiation of the pectoral region and right axilla was performed postoperatively (Deep X-ray therapy, 40 Gy, fractions of 2 Gy). A moderate lymphedema arose consecutively. Eleven years after mastectomy, an angiosarcoma (3 cm in size) was excised elsewhere from the extensor side of the upper right arm, whereby incision margins were within healthy tissue. Five years later, there was recurrence of a proliferating, this time multilocal tumorous process.

Clinical findings

Clinical examination revealed a vulnerable and spongy tumor conglomerate on the right arm, which consisted of confluent, burgundy-red coarse nodes and was partly covered with crusts. It reached from the proximal extensor side of the lower arm to the upper arm circumferentially at a size of 12 × 10 cm ( (figure 1B, C) ). Peripheral to this conglomerate were multiple pinhead- to 3 cm-large livid-red maculae, papulae and plaques of the same morphology, affecting a total area of 40 × 30 cm.

Histology

Biopsies showed two different histological patterns ( (figure 2) ): solid tumor cell formations consisting of small cells with pleomorphic nuclei and some atypical mitoses, and “classical” spongiform tumor complexes forming endothelial-lined lumina, which were partly filled with lymphocytes. In the tumor periphery, pathological endothelial cell proliferates on pre-existing dilated lymphatic capillaries, identifiable by lymphatic vessel-typical valves, were detectable in the upper corium ( (figure 2D) ).

Immunohistology: Tumor cells expressed vimentin, CD 31, and Desmoplakin-1 2.17. They were negative in respect to CD 34, desmin, smooth muscle alpha-actin, and cytokeratins (MNF116, LP34). The tumor cell stroma expressed discrete collagen IV spots but no laminin.

Ultrastructurally: undifferentiated cell proliferates without Weibel-Palade bodies were evident.

Apparative diagnostics

General examinations (abdominal sonography, chest X-ray, CT-Thorax and CTAbdomen) did not reveal any metastasis. MRI of the tumor showed a plate-like area 4 cm thick with radii extending to triceps musculature.

Therapy and course

We decided on treatment with radio-immunotherapy of the largest tumor conglomerate. Radiotherapy alone was applied simultaneously at the smaller “scattered foci” and at a 3-cm distal tumor part ( (figure 1) ). Both areas were treated with fractioned photon radiation on 5 days per week. A total cumulative dose of 54 Gy was applied in single doses of 2 Gy. 1-2 h before radiotherapy, the larger tumor conglomerate was treated with intratumoral injections of human interferon β (alternating 5 or 10 Mio. IU, Fiblaferon^®, Biosyn, Fellbach, Germany, total dose: 160 Mio. IU).

Regression of the tumor was visible with grey coloration and dry necrosis after 12 fractions (24 Gy). At the end of radiation, histologically-confirmed complete remission was achieved ( (figure 1E, F) ). Three months later, a recurrence with small nodules of histologically-proven lymphangiosarcoma became manifest on the shoulder up to 4 cm outside the radiation area. We treated with radiotherapy, using a total dose of 40 Gy in 20 fractions, this time, however, not in combination with β-Interferon. Complete remission could again be achieved. During a 3-year post-therapy observation period, there were no further local recurrences or metastases. The patient died after this period of an acute myocardial infarction.

Discussion

In the present case, we report a lymphedema-associated angiosarcoma. We ascribed this tumor histologically to lymphangiosarcoma because of:

– pleomorphous endothelial cell proliferates on pre-existing lymphatic capillaries;
– manifestation in the upper corium (by contrast, hemangiosarcomas start rather at the corium-subcutis border [3]), and;
– a lymphatic endothelium-like immunohistology (expression of Desmoplakin-1 2.17, CD 34-negativity [7]).

At the time of primary examination of the patient, the following therapy alternatives were possible:

1. Surgical therapy (amputation);
2. Attempt at radiotherapy with locally-applied immunotherapy;
3. Hyperthermic extremity perfusion with Melphalan/tumor necrosis factor alpha [8, 9];
4. Systemic therapy with pegylated microsomal encapsulated doxorubicin (effective treatment of micrometastases when already established in the lymphatics and venules);
5. Local or systemic treatment with tretinoin (recently established in Kaposi sarcoma, little experience in other angiosarcomas) [10, 11];
6. Anti-angiogenic therapies (i.e. bevacizumab) in combination with radiation (or similar experimental options).

The patient declined amputation or systemic chemotherapy. Due to the extensive, relatively inoperable tumor and the patient’s generally debilitated condition, we decided on radiotherapy in combination with local immunotherapy with the intention of increasing local radiation sensitivity [12]. In an “intra-patient” controlled approach, we treated part of the tumor with radiation alone and part with radioimmunotherapy. The therapy effect was equal in both treatment areas, resulting in complete remission. We therefore assume that the main effect was achieved by the radiotherapy. This hypothesis could be confirmed by the success of radiation therapy of a recurrence. The derivation of effect of immunotherapy with interferon β based on results of sarcomas with different sizes, as in this case, can only be tentatively interpreted. Thus, the effects of immunological drugs for treating angiosarcoma remain controversial [13].

The pathogenesis of lymphangiosarcoma is not clear. Chronic lymphedema may play a key role by weakening the local immune defence and stimulating neo-angiogenesis [14]. Interestingly, the therapy effects were soon noticeable (24 Gy). Furthermore, because of the patient’s poor general condition, we were not able to fully apply curative doses.

These aspects suggest radiation influence on sarcoma-associated growth factor expression in this case [3, 15].

There is a complete lack of controlled therapy studies in lymphangiosarcoma. Many studies have summarized angiosarcoma with other soft tissue sarcomas. The preferred procedure is resection combined with postoperative radiation, and preoperative radiotherapy, hyperthermic extremity perfusion (Melphalan, TNF-alpha) or systemic approaches (e.g. microsomal encapsulated doxorubicin) have been reported [5, 6].

According to our results, it could be valuable to differentiate angiosarcomas according to (immmuno-) histological criteria. Further studies are necessary to find out if radiation should be taken into consideration as a first-line therapy in lymphedema-associated angiosarcomas with lymphatic endothelium-like immunohistology.

References

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12 Ulrich J, Krause M, Brachmann A, Franke I, Gollnick H. Successful treatment of angiosarcoma of the scalp by intralesional cytokine therapy and surface irradiation. J Eur Acad Dermatol Venereol 2000; 14: 412-5.

13 Ohguri T, Imada H, Nomoto S, Yahara K, Hisaoka M, Hashimoto H, et al. Angiosarcoma of the scalp treated with curative radiotherapy plus recombinant interleukin-2 immunotherapy. Int J Radiat Oncol Biol Phys 2005; 61: 1446-53.

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15 Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 1997; 276: 1423-5.