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Subcutaneous calcification following chest wall and breast irradiation: a late complication

Departments of ¹ Radiation Oncology and ² Radiodiagnosis, Royal Devon & Exeter Hospital, Barrack Road, Exeter, Devon EX2 5DW, UK

	Abstract

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Subcutaneous calcification as a complication of chest wall irradiation has only been described once before in the literature. Six patients who developed heavy calcification of soft tissue following chest wall and breast irradiation are described here, and relevant literature is reviewed.

	Introduction

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Calcification, a phenomenon often regarded by pathologists as little more than evidence of cell death, is becoming recognized to be important in the dynamics of a variety of diseases from which millions of people suffer. Calcification as a manifestation of late effects of radiation therapy has been reported only once before, in a patient with carcinoma of the left breast [1]. Radiation therapy is the most effective and frequently used local treatment in breast carcinoma. Late complications following radiation therapy can be severe and debilitating in some patients. The incidence of late complications is related to many factors including total dose, fraction size, patient age and extent of disease. Pre-existing abnormalities such as scleroderma are known to result in exaggerated radiation responses, with reported marked fibrosis but not calcification [2]. In the six cases described here, calcification probably developed owing to the larger fraction sizes (greater than 2.0 Gy) and/or the overlap between the glancing and supraclavicular radiotherapy fields resulting in delivery of higher doses of radiation than intended.

	Case reports

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Case 1
A 71-year-old woman underwent left Patey mastectomy in October 1980 for a G2 T2 N1 M0 infiltrating ductal carcinoma of the breast. Post-operatively she was followed-up with radiation therapy to the left chest wall and the draining lymphatics on a telecobalt unit prescribing a mid-plane dose of 42.5 Gy in 15 fractions over 20 days. A four field technique was used. The chest wall was irradiated by using two glancing fields applying a bolus. The axillary and supraclavicular regions were treated with two parallel opposing fields. Follow-up at 1 month showed minimal radiation reaction on the chest wall, and this resolved completely over the ensuing 2–3 weeks. Since then the patient has remained disease free. In February 1988, chest radiography showed loss of volume of the left lung with upper zone fibrosis. In addition there were two irregular calcified lesions, one of which appeared to lie partly outside the rib cage (Figure 1). However, a skeletal isotope scan had shown no areas of abnormal high activity in the rib cage or in the region of calcification. Routine haematological tests and biochemical profile were essentially normal. CT undertaken more recently showed extensive heterotopic calcification centred around the left anterior chest wall (Figure 2).

View larger version (141K): [in this window] [in a new window]   Figure 1. Chest radiograph showing two calcified masses in the left upper zone.

View larger version (96K): [in this window] [in a new window]   Figure 2. CT scan showing heterotopic calcification on the left anterior chest wall.

Case 3
A 63-year-old woman underwent wide local excision of a lump from her left breast in November 1974 for a spheroidal cell carcinoma. No axillary sampling was undertaken. Post-operatively she was followed-up with radiation therapy to her left breast and the draining lymphatics. Her breast was treated by two glancing fields prescribing a mid plane dose of 45.0 Gy in 20 fractions over 26 days. The axilla and supraclavicular regions were treated by using two parallel opposing fields prescribing a mid plane dose of 45.0 Gy in 20 fractions over 26 days. Treatment was undertaken on a telecobalt unit. Following this the patient remained well until August 1981, when she developed pain on her left upper anterior chest wall. Chest radiography showed some early radiation changes in the left upper zone and in the anterior ends of the left 3rd and 4th ribs. However, a skeletal isotope scan had shown no abnormal uptake in the region of the left 3rd and 4th ribs and the rest of the scan was normal. The pain subsided and the patient continued to remain well until October 1990, when she presented following a diagnosis of non-small cell carcinoma of the right lung. Chest radiography showed collapse/consolidation of the medial basal segments of the right lower lobe. In addition there was now a dense area of lobulated calcification in the left upper zone. Chest CT showed considerable loss of volume of the right lower lobe with a right basal effusion. There was also calcification in the intercostal space and deep to the pectoral muscles. The underlying lung parenchyma showed some fibrotic changes. Despite treatment of her lung primary, the patient's condition continued to deteriorate and she died in July 1990. Autopsy was not carried out.

Case 4
A 48-year-old woman presented in January 1979 with a lump in her left breast. Excision biopsy showed poorly differentiated adenocarcinoma. The patient underwent simple mastectomy followed by radiation therapy to the chest wall and draining lymphatics. She was treated with a four field technique on a telecobalt unit and was prescribed a dose of 42.5 Gy in 15 fractions over 20 days. Following this the patient remained well until March 1981, when she presented with hyperaesthesia along the inner aspect of the left forearm. The patient demonstrated slight numbness along the C7 distribution. This was not associated with weakness of the arm. It was not until 3 years later that weakness of the muscles of the left hand developed. Over the ensuing 6 years there has been very little progress of the weakness and no sign of recurrence of carcinoma. 1 month ago she presented with a non-productive cough. Chest radiography showed no evidence of pulmonary metastases but there was calcification of soft tissue in the left upper zone extending outside the rib cage.

Case 5
A 57-year-old woman underwent a left simple mastectomy in July 1977 for a G1 T2 N0 M0 carcinoma of the left breast. Post-operatively she commenced tamoxifen, which was followed by radiation to the chest wall and the draining lymphatics. The patient was treated on a telecobalt unit using a four field technique with glancing fields to the chest wall and parallel opposed fields to supraclavicular and axillary regions. She was prescribed a dose of 42.5 Gy in 15 fractions over 20 days. Bolus was used to treat the chest wall. The patient developed a brisk radiation reaction that settled over a period of 6 weeks. Thereafter she remained well until October 1983, when she presented with stiffness of the shoulder. This gradually progressed over the next 6 months, by which time she had developed brachial plexopathy. There was no evidence of recurrence of carcinoma. The patient then presented in 1997 with symptoms of cough and pain in the left side of her chest. Chest radiography had not shown any evidence of pulmonary or pleural metastases but there was evidence of radiation induced fractures of the left 3rd and 4th ribs. Once again there was no evidence of recurrence of carcinoma. The cough resolved without any specific therapy and pain was controlled with analgesics. She then remained well until November 2000, when chest radiography showed a calcified mass in the left upper zone. There was no evidence of recurrence of her treated carcinoma and the brachial plexopathy had not progressed.

Case 6
A 37-year-old woman underwent left simple mastectomy in September 1972 for an infiltrating carcinoma of the left breast. Following this she remained well until May 1974, when carcinoma recurrence developed in the left axilla. This was excised and followed by radiation therapy to the chest wall and draining lymphatics. The patient was treated on a telecobalt unit. The chest wall was treated with glancing fields using bolus, and the axilla and supraclavicular fossa were treated with two parallel opposing fields. The patient was prescribed a mid plane dose of 40.0 Gy in 10 fractions over 23 days. She then remained well until November 1988, when she presented with pain in the neck and left shoulder. Clinical and radiological assessment had shown no sign of recurrent disease. The pain resolved with analgesics. In March 1992 she presented again with pain and swelling over the left shoulder. Clinically there was no evidence of recurrence on her chest wall, but there was a 10.0 cmx10.0 cm swelling overlying the left shoulder joint posteriorly. This was tethered deeply. Chest radiography had shown peripheral calcification in the left upper zone and radiography of the shoulder showed erosion and possible fracture of the neck of the scapula. A bone scan showed focally increased activity in the left scapula. Further investigations were undertaken with CT and MRI. These confirmed a large soft tissue mass invading the soft tissue in the axilla and the chest wall. There was calcification within the mass and along the anterior end of the rib cage (Figure 3). Biopsy of the mass showed spindle cell sarcoma. The tumour was inoperable so treatment consisted of cyclical chemotherapy using cisplatin and adriamycin in combination. Cycles were repeated at 3-weekly intervals. After six cycles there was good regression of the tumour. In December 1992 the patient was considered for forequarter amputation. In April 1993 she developed a small recurrence in the skin graft. CT showed involvement of the chest wall and possibly of the apex of the left lung. Thereafter there was relentless progress of the disease and she died in November 1993.

View larger version (106K): [in this window] [in a new window]   Figure 3. CT scan showing calcification within a mass and along the anterior chest wall.

	Discussion

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Radiation therapy to the breast or the chest wall and the nodal areas often presents a technical problem to match the glancing fields with the axillary and supraclavicular fields. Overlap between these fields will result in underlying tissues receiving a larger dose than intended. In all six cases presented, the area of dense calcification appeared to lie in the region where overlap of the matching fields could have easily occurred in view of a minor position change between fields. It is generally accepted that fraction sizes significantly over 2.0 Gy may lead to increased late side effects. In breast cancer the total dose required to eradicate microscopic disease is 40.0–50.0 Gy in 15–25 fractions. This dose is increased for macroscopic disease or for areas at higher risk of recurrence, such as excision margins after breast conserving surgery. Unwanted side effects of radiation include early acute effects and chronic late effects. Early acute effects occur during or shortly after treatment and are transient. Chronic late effects can occur weeks, months or years after treatment and tend to persist and get worse.

Late complications following radiation therapy can be severe and debilitating in some patients. The incidence of late complications is related to many factors including total dose, fraction size, patient age, extent of disease and pre-existing abnormalities. The main delayed toxicities are atrophy, telangiectasia, dyspigmentation and, rarely, necrosis of the skin. With modern megavoltage machines the maximum dose lies beneath the skin and severe late skin changes are unusual, but subcutaneous fibrosis is fairly common. Severe fibrosis in the axilla can obstruct the lymphatic or venous drainage. Calcification of soft tissue following irradiation is an extremely rare sequela. So far only one case has been reported in the literature [1]. This patient was treated on an orthovoltage unit, whilst the above six patients were treated on a megavoltage (telecobalt) unit. The breast and the chest wall were irradiated by tangential fields and the lymph nodes were treated by parallel opposing fields of equal sizes. Due care was taken to match the fields, using a gap of 1.0 cm to prevent any overlap of the upper edge of the beam of the chest wall and breast tangents and the lower edge of the beam of the anterior cervico–axillary or supraclavicular fields. However, a penumbra trimmer was not used in any of the above six patients. All fields were treated at each treatment session. Three patients were prescribed 42.5 Gy in 15 fractions over 20 days, two patients were prescribed 45.0 Gy in 20 fractions over 26 days and one patient was prescribed 40.0 Gy in 10 fractions over 23 days.

The pathogenesis of the formation of calcium deposits in the soft tissue remains poorly understood. However, pathological calcification can be subdivided into metastatic, occurring in undamaged tissues when extracellular calcium and phosphate concentrations are increased, and dystrophic, occurring in injured tissue when extracellular calcium and phosphate concentrations are normal [3]. A cellular mechanism for calcification has been suggested [4]. In the presence of hypoxia, the equilibrium of extracellular calcium fails and there is an influx of calcium into the cell, resulting in calcium phosphate deposition, which in a stable micro-environment may eventually be converted into calcium hydroxyapatite. Crystal proliferation then follows with the extension of calcification into the extracellular space. Calcification therefore follows cell death. It is promoted by the presence of alkaline phosphatase, which is most effective in an alkaline milieu [5]. Radiation leads to vascular damage, thereby causing thickening of the vessel walls and proliferation of intimal and subintimal cells. Later, circulatory efficiency is compromized by fibrotic and sclerotic changes of the vessels. It is possible that hypoxia created by the late effects of radiation cause calcification by a cellular mechanism as suggested by White et al [6]. Necrotic or degenerative tissues are likely to be alkaline owing to their low metabolic rate and, hence, reduced carbon dioxide production. Conversely, it has been suggested that loss of calcification can indicate accelerated growth of malignant tumours [7].

Benign conditions of calcification include bleeding, infarcts, metabolic disorders or parasites. Calcification of metastases can also be observed following radiation [3, 8]. Interestingly, all six cases described here, and that described by Cowie and Jones [1], had developed dense calcification following radiation to left sided breast lesions. The significance of this will not be known until more cases are reported.

	Acknowledgments

 
We wish to thank Neal Amin for typing the manuscript.

Received for publication July 25, 2001. Accepted for publication November 9, 2001.

	References

Top Abstract Introduction Case reports Discussion References

 

1. Cowie R, Jones R. Subcutaneous calcification as a late effect of orthovoltage chest wall irradiation. Clin Oncol 1999;11:196–7.
2. Robertson JM, Clarke DH, Pevzner MM, et al. Breast conservation therapy. Severe breast fibrosis after radiation therapy in patients with collagen vascular disease. Cancer 1991;68:502–8.[Medline]
3. Anderson HC. Calcific lesions: a concept. Arch Pathol Lab Med 1983;107:341–8.[Medline]
4. Yoon K, Golub E, Rodon GA. Alkaline phosphatase cDNA transfected cells promote calcification and phosphate deposition. Connect Tissue Res 1989;22:17–25.[Medline]
5. Halpin S, Kingsley D. Disappearance of cerebral calcification as a sign of tumour growth. Neuroradiol 1993;14:119–22.
6. White BC, Wiegenstein JG, Winegar B. Brain ischemic anoxia. Mechanism of injury. JAMA 1984;251:1586–90.[Abstract/Free Full Text]
7. Peretti-Viton P, Margain D, Murayama N, et al. Metastases cerebrales. J Neuroradiol 1991;18:161–72.[Medline]
8. Ricke J, Baum K, Hosten N. Calcified brain metastases from ovarian carcinoma. Neuroradiol 1996;38:460–1.[Medline]

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