British Journal of Radiology 75 (2002),767-771 © 2002 The British Institute of Radiology
Lymphangiolipoma of the lower extremity: 5-year radiological follow-up after radiotherapy treatment
F Bruns, MD
W Steitz, MD
P Schueller, MD
U Schaefer, MD
N Willich, PhD
and
O Micke, MD
Department of Radiation Oncology, University of Muenster, Albert-Schweitzer-Straße 33, D-48129 Muenster, Germany.
Correspondence: Oliver Micke, MD
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Abstract
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This report describes a lymphangiolipoma located in the extremity in a young woman. Radiotherapy effectively controlled recurrent lymphangiolipoma of the left upper leg that had been judged inoperable by limb-sparing surgical resection. In the case presented here, a dose of 50 Gy in 25 fractions over 5 weeks was employed without long-term complications after 5-year follow-up.
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Introduction
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Lymphangiomas of the extremities are uncommon. In combination with lipomas they are exceedingly rare. Only four cases of lymphangiolipoma have been described in the literature, three located in the mesentery and one in the thoracic spine. Surgery is the usual treatment for lymphangioma.
This report describes a lymphangiolipoma located in the left upper leg. After repeated partial resection only radiotherapy was able to achieve long-term local control.
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Case report
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A swelling in the posterolateral region of the left thigh of a 15-month-old girl was found to be a lymphangiolipoma. Angiography showed rich vascularization of soft tissue without any suspicion of malignancy. Conventional radiography of the left femur showed a soft tissue swelling but no cortical bone destruction (Figure 1
). At operation the tumour showed extensive adhesions to the surrounding muscles and only partial resection was possible. Further partial resections of recurrences were necessary at the age of 3 years and 10 years. Histological examination of the last specimen still showed a diffuse muscle-infiltrating tumour that had reached the patellar recess. For this reason, the knee joint had to be opened. After the patient started taking an oral contraceptive at the age of 18 years, considerable swelling and pain in the left upper leg reappeared. These symptoms diminished after the contraceptive pill was discontinued.
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Figure 1. Lymphangiolipoma of the left thigh in a 15-month-old girl. The anteroposterior and lateral radiographs of the lower extremities show a large non-specific soft-tissue mass of the lower two-thirds of the left thigh without cortical destruction. The almost homogeneous mass is limited to the compartment of the quadriceps femoris muscle and contains three rounded areas of calcification.
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In 1992, when 21-years-old, the patient was referred with histologically verified recurrence. Histological examination confirmed lymphangiolipoma with mature adipose cells interspersed with dilated lymphatic vessels, and still showed no sign of malignancy. MRI and CT showed recurrent tumour covering the ventrolateral aspects of the femur without cortical destruction (Figure 2). The patient has experienced increasing swelling and local pain, varying in intensity during the menstrual cycle.
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Figure 2. Recurrent lymphangiolipoma of the left thigh in the same patient aged 21 years. (a) Axial and (b) sagittal T1 weighted (TR/TE, 800/20) spin-echo MR images with gadolinium-DTPA reveal a large, smoothly marginated mass along the group of vastus muscles. The lesion shows mixed signal characteristics containing areas with signal isointense with fat, corresponding to the lipomatous component, and areas slightly hyperintense relative to muscle after application of gadolinium-DTPA, corresponding to the lymphangiomatous component. (c) CT scan (8 mm slice thickness) obtained at 15 cm above the knee joint revealed a heterogeneous, mixed attenuation circumferential lobulated extraosseous mass, a mixture of soft-tissue and fat replacing the normal muscles in the compartment. No periostal reaction was seen. In comparison with the right thigh, there is a loss of volume of thegroup of vastus muscles following repeated resections.
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Local irradiation and, presuming hormone-dependent tumour growth, hormone manipulation were discussed as possible conservative therapy options. The experimental nature of both treatments was highlighted. The patient decided to first attempt a treatment with antioestrogens (Tamoxifen, 20 mg daily) for 6 months. Unfortunately no symptomatic improvement occurred.
From September 1993 to October 1993, local irradiation using a cobalt-60 teletherapy unit was given following the treatment schedule for lymphangiomas, initially with a total dose of 20 Gy. As no symptomatic improvement resulted, the dose was increased to a total of 50 Gy in 25 fractions over 5 weeks, with a daily tumour dose of 2 Gy. Opposed anterior–posterior 25 x 16 cm2 fields covered the region of anomalous lymphatics from the knee to the proximal third of the thigh. During treatment the patient reported only temporary tiredness. Following irradiation the induration in the left upper leg slightly reduced and the pain in the left leg decreased.
1 year post treatment the initial problems of pain and swelling still persisted but were less severe. MRI examination did not show any change in the size of the tumour at that time. However, MRI scans performed 2 years and 5 years after radiotherapy showed significant tumour regression (Figure 3). At the last examination in November 1998, swelling and pain had completely disappeared. Late radiation side effects could not be detected. The knee joint still has limited mobility, however, since the third operation involved opening the joint.
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Figure 3. Follow-up imaging after radiotherapy. (a) After 2 years, the axial T1 weighted (TR/TE, 800/20) spin-echo MR image with gadolinium-DTPA shows a distinct regression of the lymphangiomatous component in all involved muscles. Subcutaneous fibrosis-like structural changes are due to surgical scars. (b) After 5 years, the axial T1 weighted (TR/TE, 800/20) spin-echo MR image with gadolinium-DTPA shows nearly complete regression of the lymphangiomatous component, whereas the lipomatous component persists.
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Discussion
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Lymphangiolipomas were first described as a separate entity by Schnabel [1] in 1971. There have been only three further reports of this disease in the world literature since. In three of these cases the tumour was located in the mesentery, and in one case in the thoracic spine. All of these cases were successfully treated by surgery [1–4]. Experience with radiation therapy for lymphangiolipoma has not been previously published. In the case described above, symptoms were probably caused by the lymphangioma component and the treatment was analogous to that of lymphangiomas.
Tumours of the lymph vessels, i.e. lymphangioma and lymphangiosarcoma, are much less common than their vascular counterparts, haemangioma and angiosarcoma. Lymphangiomas are pathologically benign and can occur in any lymphatic area. The cervicofacial region is the most common location (60% of cases), and the extremities are involved in only 6.5% of cases [5–7].
Lymphangiomas are considered to be developmental lymphatic malformations (LM) and consist of thin-walled lymphatic vessels and a supporting network of connective tissue. Unlike congenital haemangiomas, these lesions rarely undergo spontaneous involution, but their growth becomes less noticeable beyond the late teens. Most LMs are evident at birth or detected before the age of 2 years; they may grow slowly and remain asymptomatic for a long time but occasionally cause severe complications. At times, lymphangiomatous enlargement of soft tissues may be caused by localized gigantism, the pattern of enlargement often reflecting the peripheral sensory nerve distribution to that region. Lymphatic malformations may expand due to intralesional haemorrhage, fluid accumulation or cellulitis, and can often infiltrate diffusely into the surrounding tissue, causing, for example, bone destruction [6–8].
Takahashi et al [9] redefined the precise biologic characteristics of the various phases of haemangiomas (proliferation, involuting, involuted) with the aid of immunohistochemistry. They demonstrated that during the proliferating phase a number of growth factors, such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), proteases that are able to degrade the extracellular matrix (type IV collagenase, urokinase), as well as the adhesion molecule E-selectin, are involved. During the involuting process, tissue inhibitors of metalloproteinases are produced and, later in the life cycle of haemangiomas, apoptosis of endothelial cells announces the switch from uncontrolled growth to spontaneous resorption of the tumour [9, 10]. These experimental discoveries were of clinical significance in that elevated bFGF levels can be measured in urine samples as a marker for abnormal vascular proliferation in tumour patients, but also as a useful marker to objectively follow the clinical course of haemangioma therapy [11]. The molecular basis and cellular mechanisms of lymphangiomas and other lymphatic pathology, such as lymphoedemas, are unfortunately still not very well understood [12]. Despite the fact that the histological structure of lymphatic vessels is widely different from that of blood vessels, both have, in particular, at least a single layer of endothelial cells and a reticular fibrous network as extracellular matrix around the vessel. Therefore it is highly probable that the pathological mechanisms of lymphangiomas are similar to those of haemangiomas. However, increased understanding of vascular anomalies and angiogenesis has lead to the development of new therapeutic drugs [10].
Standard treatment for lymphangiomas is staged surgical resection of involved soft tissues. However, when lesions are incompletely excised, recurrence is common. Occasionally, repeated surgical procedures are not successful in controlling these lesions, or lesions are located in a site where complete excision is not possible. Other treatment modalities include cryotherapy, injection of sclerosing agents and radiotherapy, but each therapy has its associated problems. In addition, since the late 1990s, antiangiogenic agents have become available as a new therapeutic modality. Cryotherapy has been tried in lymphangiomas, but with benefit only in those patients with superficial tumours. The use of sclerosing agents is limited to the treatment of small tumour cysts and can produce fibrous thickening. This in turn causes greater problems and may necessitate later excision ending in a disappointing cosmetic result.
The radiosensitivity of lymphangiomas is unknown; some even regard them as radioresistant. Moreover, radiotherapy in children may lead to growth retardation or malignant transformation [7, 13].
In the older literature, irradiation of lymphangiomas is generally described as disappointing. Nevertheless, in individual cases it has been performed successfully, as Bachmann et al [5] showed, referring to a review of 1000 cases from the literature. Unfortunately no details were provided about radiation doses. Lindén [7] reports on 52 patients with benign lymphangiomas treated with irradiation between 1936 and 1962, 19 of them in combination with surgery. Using short-distance therapy (60 kV) the total dose ranged from 500 R to 8000 R (mean 2300 R); the total orthovoltage dose administered per field varied from 500 R to 8000 R (mean 1300 R). The therapeutic result was excellent in 38% of cases, some improvement in 46% of cases and no benefit in 6% of cases [7]. Other authors also reported that low doses in the range 1.5–2.0 Gy appeared to be well tolerated, effective and resulted in few long-term complications. Some studies, however, report considerably better results for higher radiation doses. Schild et al [14] reported 13 patients with large, symptomatic, unresectable or partially resected haemangiomas in different sites. A decrease in tumour size was noted in 82% of cases. Objective (measurable) complete responses occurred in two (50%) of the four patients irradiated with doses of 30 Gy or more, compared with only two (29%) of seven patients who had received lower doses. In 10 patients (77%) there was complete resolution of symptoms. Because the majority of patients responded to a variety of dose levels, no firm dose-response relationship was evident [14]. From the literature review, a common dose for haemangiomas within or surrounded by bowel is 25–40 Gy. Similar doses have been used for haemolymphangiomas and lymphangiomas. In vertebral haemangiomas, radiotherapy after subtotal resection to a total dose of between 26 Gy and 45 Gy prevented recurrence [15].
However, the biological rationale for using local external beam radiation therapy in benign vascular tumours, which are characterized by endothelial overproliferation, is based on the radiosensitivity of the proliferating vascular endothelial cells. Ionizing radiation directly damages their DNA, inducing them to undergo programmed cell death (apoptosis).
Furthermore, recent advances in angiogenesis research have shown that radiation-induced phenotypic alterations within the cellular matrix also inhibit autocrine and paracrine signals from the proliferating endothelial cells [16]. So, there is a basic biological reason for the use of radiotherapy.
We now know that growing endothelial cells in benign vascular tumours may initiate angiogenesis through multiple mechanisms. For infantile haemangiomas, the most direct mechanism is the production and secretion of angiogenic factors like VEGF and bFGF, which then stimulates endothelial cell proliferation. It is not surprising that the use of antiangiogenic drugs, such as interferon-alpha-2b or Pingyangmycin, was successful in the management of complicated haemangiomas, and clinical regression during therapy was associated with decreased urinary bFGF excretion [11, 17].
The use of antiangiogenic agents in lymphangiomas was first reported by Reinhardt et al [18] in 1997. In two cases of infantile lymphangioma they achieved a favourable response to interferon-alpha, suggesting that this is also an effective and well-tolerated treatment for lymphangiomas in children. The same therapy schedule for adults, however, leads to no objective response, suggesting that age related differences in response to interferon-alpha may possibly represent a distinct biology of lymphangiomas in children and adolescents as compared with adults [18]. Further known antiangiogenic drugs, including thalidomide, AGM-1470, endostatin and combretastatin, have not been used so far in patients with benign vascular tumours. Some of these drugs are particularly interesting in this context because of their potentially positive interaction with radiotherapy [19]. Reasons for the restrictive use of other antiangiogenic drugs in benign vascular tumours include the possible severe side effects of these substances, such as growth impairment for children and severe impairment of fertility in women of childbearing age. Furthermore, the scientific world is currently more focused on malignant tumours, which still constitute an unsolved and often urgent puzzle for the clinician.
In the case presented here, progressive diffuse muscular lymphangiolipomatosis recurring after three previously unsuccessful attempts at surgical removal precluded any chance of complete limb sparing surgical resection. A relatively high radiation dose was justified by the size of the tumour, previous surgery and initial poor response. A delayed but complete regression of palpable tumour was achieved, with corresponding involution of the lymphangiomatous features on MRI and a subsequent disappearance of symptoms. In view of recent advances in the field of angiogenesis and its inhibitions, with encouraging results also in the therapy of benign vascular tumours, medical management should be attempted for patients with inoperable lymphangiolipoma first if possible. However, in cases of inoperability, recurrence or insufficient response to medical treatment, the use of radiotherapy can be appropriate with minimal adverse sequelae, but the choice of alternative treatment must be made according to the specific circumstances of the clinical situation.
Received for publication August 3, 2001.
Revision received March 25, 2002.
Accepted for publication May 8, 2002.
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References
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Abstract
Introduction
