British Journal of Radiology 75 (2002),460-463 © 2002 The British Institute of Radiology
Heterotopic calcification as a late radiation effect: report of 15 cases
U M Carl, MD1 and
K A Hartmann, MD2
1 Department of Radiation Oncology, Diakoniekrankenhaus Rotenburg, Postfach 1211, D-27342 Rotenburg and 2 Department of Radiation Oncology, University of Duesseldorf, Moorenstrasse 5, D-40225 Duesseldorf, Germany
Correspondence: K Axel Hartmann, MD
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Abstract
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The LENT-SOMA scoring system for reporting late tissue effects following therapeutic radiation does not include heterotopic calcification as an end-point. Here we report on 15 long-term radiotherapy survivors with significant heterotopic calcifications. In all cases heterotopic calcification was linked to other radiation sequelae, e.g. ulceration, bone necrosis, nerve damage and fibrosis. The median time interval between radiotherapy and the occurrence of heterotopic calcification was 19 years (range 2–31 years). All patients received doses in excess of 40 Gy; overlap of adjacent fields played a role in some cases. It appears that heterotopic calcification can be regarded as end-stage damage following high dose radiotherapy. Heterotopic calcification in conjunction with local tissue breakdown is highly suggestive of previous radiation treatment.
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Introduction
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Necrosis, ulceration and fibrosis are well known end-points of therapeutic radiation. The LENT-SOMA scoring system for reporting late tissue effects following therapeutic radiation in various organs or tissues includes these items as possible end-points [1]. The occurrence of heterotopic calcification, however, is not included in the LENT-SOMA scoring system. It appears from the literature that two distinct types of calcifications exist, e.g. in previously malignant tissues following tumour shrinkage and in normal tissues and organs as late radiation damage. Heterotopic calcification developing in previously normal tissue that is incidentally irradiated occurs infrequently and reports in the literature are scarce. Here we report on long-term radiotherapy survivors with significant heterotopic calcification in normal tissues or organs. Contributing factors such as radiation dose, field arrangements, the time course of treatment and pathophysiology are discussed.
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Materials and methods
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From 1997 to 1999 over 200 patients with late radiation sequelae were referred to the Department of Radiation Oncology at the University Clinic Düsseldorf to identify candidates for hyperbaric oxygen treatment. At admission, patients had a general work-up to assess the severity of radiation damage and the relationship to previous radiation treatment. CT of the treated regions was performed in patients with severe radiation damage in whom a clinical examination alone was felt insufficient to define the extent of the lesion. 15 patients with heterotopic calcifications were identified. Basic information regarding the previous radiation treatment were available for all patients. However, the applied dose per fraction was not available for all patients. Whenever possible, the biologically effective dose (BED), as proposed by Fowler [2], was calculated using: 
where D is the total dose and d is the dose per fraction. For 
/ß we assumed a range between 2 Gy and 4 Gy. BED is given for an /ß value of 3 Gy, with the calculated values for /ß=2 Gy and /ß=4 Gy in parentheses (see Table 1). For Patient 6, who received a post-operative neutron treatment of a lower limb sarcoma, BED calculations were performed as proposed by Dale and Jones [3]:
where RBEmax was taken as 4.
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Results
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Patient and treatment characteristics are outlined in Table 1
. The median time interval between radiotherapy and heterotopic calcification was 19 years (range 2–31 years). All patients received radiation doses in excess of 40 Gy. The BED for six patients (Patients 4 and 11–15) is in the range where no severe side effects would be expected. For these patients, radiation damage is probably owing to the applied field arrangement rather than the total dose and dose per fraction. Most patients in this series were treated during the era when no simulation or CT scans were available, making field overlap as the possible cause of radiation damage likely, in particular when multiple fields were used. Patients with low BED but where late complications occurred at a site of possible field overlap are indicated in the table. Heterotopic calcification was linked to severe radiation side effects of surrounding organs or tissues. Ulceration of the skin was the most frequent co-existing radiation damage in 11 of 15 patients. Figures 1a,b show an example of Patient 5 (Table 1) treated for breast carcinoma and exhibiting necrosis, ulceration and heterotopic calcification.
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Figure 1. (a) Patient irradiated for invasive breast cancer showing rib necrosis, ulceration and heterotopic calcification (Patient 5 in Table 1). (b) Thoracic CT of the same patient showing heterotopic calcification in the axillary region.
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Discussion
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Heterotopic tissue calcification as a consequence of radiation therapy occurs infrequently. From a clinical point of view, two distinct types of calcification exist, e.g. in previously malignant tissues following tumour shrinkage or in normal tissue and organs as late radiation damage. Strickland [4] reports four instances where calcification occurred in previously involved lymph nodes in Hodgkin's disease following direct radiation. Dalinka et al [5] decribe a case of an undifferentiated intraabdominal sarcoma with calcifications after radiotherapy. In a case with multiple brain metastases from ovarian carcinoma, calcification indicated long-term survival [6].
There is evidence in the literature that calcification can occur in previously normal tissue without gross tumour involvement prior to radiation therapy. 17 of 190 patients surviving for 5 years following treatment with parametrial injection of 198Au colloid had soft tissue calcification in the pelvis [7]. Other sites of heterotopic tissue calcification in previously normal tissue incidentally irradiated are pre-sternal soft tissue [8], the perivesical region [9], the brain [10, 11] and the chest wall [12]. Heterotopic calcification generally develops no sooner than 1 year after therapy. In our report, the median time interval between radiotherapy and calcification was 19 years. Heterotopic calcification was generally associated with ulceration, fibrosis and other severe radiation damage following high radiation doses. Patient 4 received only 40 Gy but, because of the co-existing bronchoalveolar fistula and bone necrosis, a field overlap overdose is considered to be the most likely cause. In conclusion, heterotopic calcification can be regarded as a possible end-point for long-term survivors after high radiation doses. In this series, calcification was preceded by various other radiation late effects and did occur at a very late stage of tissue breakdown. Because heterotopic calcification is a rare phenomenon, the presently used LENT-SOMA scoring system for radiation late effects has not included it as an end-point.
Generally, aetiological factors for heterotopic tissue calcification are hypercalcaemia, ischaemia, trauma, inflammatory metabolic disorders, infection and hereditary factors [13]. Small haemorrhages from radiation-induced vascular damage are also a possible cause of calcification. Calcification is caused by active metabolic processes. Mitochondria regulate the calcium concentration and therefore play a major role in intracellular calcification, whereas extracellular deposits are initiated by membranous organelles producing hydroxyapatite. It is assumed that reperfusion of necrotic tissue causes calcification after myocardial infarction, and that this is mediated by mitochondria. It is possible although unproven that similar processes occur in irradiated tissue as a consequence of damage to the vasculature by irradiation. At present, the aetiology of heterotopic calcification following radiotherapy remains unclear.
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Conclusions
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Heterotopic calcification as a consequence of radiation therapy can occur both in regions with previous malignant involvement and in previously normal tissue as a late radiation effect. Heterotopic calcification in previously normal tissue can be regarded as end-stage tissue damage following high dose radiotherapy. Local tissue breakdown in conjunction with heterotopic calcification is highly suggestive of previous radiation treatment.
Received for publication July 16, 2001.
Revision received January 24, 2002.
Accepted for publication January 28, 2002.
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References
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Abstract
Introduction
