A 54-year-old man who had been irradiated in 1964 for cervical involvement by Hodgkin's disease was admitted in December 1994 to our clinic with strong complaints of dysphagia. The reason was a moderately differentiated squamous cell carcinoma of the proximal esophagus in the previously irradiated region. The patient had no risk factors (abuse of nicotine or alcohol) for the developement of esophageal carcinoma. A reirradiation was performed, but the disease progressed locally and two weeks after the beginning of the therapy the patient developed two tracheoesophagocutaneous fistulae. The radiation therapy was discontinued and the tumor stenosis was bridged by a tube closing the fistulae. A retrospective dose analysis to evaluate the applied doses will be performed. Furthermore, an overview of 66 cases of the literature with radiation-induced esophageal carcinoma analysed concerning applied dose and latent interval will be given. In conclusion the reported case fits the criteria for radiation-induced malignancies (Chudecki Br J Radiol 1972;45:303–4) known from literature: (1) a history of previous irradiation, (2) a cancer occurring within the irradiated area, (3) gross tissue damage due to an excessive dose of radiation, and (4) a long latent interval between irradiation and development of cancer. Esophageal carcinomas belong to the rare secondary malignancies after the therapeutic use of ionizing radiation. Nevertheless in patients with dysphagia they should be suspected as a differential diagnosis even many years after mediastinal irradiation. The treatment of these tumors is very difficult and is associated with a poor prognosis.
The carcinogenic effect of ionizing radiation is well-documented (1–4). As early as six years after the discovery of X-rays the first malignancy induced by ionizing radiation was described. It was a spinocellular carcinoma of the skin of the hand of a 33-year-old technician who regularly worked with X-rays (3,4).
A characteristic of radiation-induced secondary malignancies is the long latency (mostly 10 to 20 years) between radiation exposure and the development of cancer in the irradiated area (3, 5,6). With the recent advances in surgery, radiotherapy and chemotherapy significantly more long-term remissions can be achieved. Therefore the rate of secondary malignancies has also increased (7–9).
The exact incidence of radiation-induced malignancies is not well-defined because of their rarity and their long latency before appearance (10). There are some studies about secondary malignancies after the radiation treatment of Hodgkin's disease. Soft tissue sarcomas and osteosarcomas are the most frequently described solid radiation-induced tumors after radiotherapy of Hodgkin's lymphoma (7–9). On the other hand hematological malignancies, especially acute leukemias, have been observed after radiation exposure. These disorders were particularly found in the atomic bomb survivors of Hiroshima and Nagasaki (1).
The esophagus belongs to the organs of risk of an irradiation of the mediastinal or the sternal region (1,5,6, 11). In most patients different degrees of esophagitis occur (11–13) immediately after mediastinal irradiation. In contrast esophageal carcinomas have been rarely reported in the literature as secondary solid tumors long periods of time after ionizing therapeutic irradiation (10). The majority of cases were diagnosed quite late and are difficult to treat for the radiooncologist (14).
A case of a radiation-induced esophageal carcinoma is now described and discussed in the context of the available literature.
A 54-year-old man was referred to our radiooncological clinic with hoarseness and progredient complaints of dysphagia in December 1994.
In March 1964 the patient was diagnosed to have a Hodgkin's disease stage I with left cervical involvement. He was treated with definitive radiotherapy using a single-field technique at a Cobalt-60 machine with a focus-skin distance of 50 em. Doses of 50 Gy were applied over a left neck field (specified to 4 cm tissue depth), 35 Gy over a mediastinal field (specified to 6 cm) and 25 Gy over a left axillary field (specified to 4 cm). A single dose of 3.0 Gy surface dose was delivered five times a week.
The irradiation set-up was done clinically. Simulation and verifications were not performed, The patient tolerated the radiation therapy without significant early side effects.
Nine years later subcutaneous indurations developed in the previously irradiated left supraclavicular region. The patient complained of severe pain extending from the left shoulder to the left ann. In 1976 for the first time he showed impairments of arm movements and increasing parasthesia as a sign of radiation-induced plexus injury. Further the left cervical fibrosis got more pronounced. In 1983 a microsurgical neurolysis of the left plexus brachialis was performed. But no clear success in pain reduction could be achieved.
Because of dysphagic complaints esophagoscopy with biopsy was carried out in January 1995 (Fig. 1). A poorly differentiated squamous cell carcinoma (G3) of the upper thoracic esophagus (21 to 25 em) could be proven (Fig. 2). An infiltration of the trachea was suspected by Cl-scan. Additionally paraesophageal lymph nodes have been detected. There were no distant metastasis. According to the TNM-c1assification of the VICC (1992) a clinical stage T4 N1 M0 resulted.
The patient had no evidence for typical risk factors (abuse of nicotine or alcohol) for developing esophageal carcinoma. Surgical resection was not possible, because of the tumor localization. An MRI of the chest was carried out for determination of tumor extent and radiation therapy treatment planning (Fig. 3).
There was no further option for percutaneous irradiation due to the preirradiation and the marked subcutaneous fibrosis. For palliation of the pronounced dysphagia endoesophageal High-Dose-Rate-brachytherapy with Iridium-192-afterloading was performed using an bougie-applicator with a diameter of 1 cm. During radiation therapy the tumor locally progressed two weeks after the beginning of therapy and two applications of 5 Gy two tumorous tracheoesophagocutaneous fistulas arose (Fig. 4). The radiation treatment was then discontinued. The tumor stenosis of the esophagus was endoscopically bridged by a tube which closed the fistulas. One month later the patient died from aspiration pneumonia.
Retrospective Dose Analysis
Having no sufficient documentation of the former irradiation, we tried to reconstruct the set-up using an actual CT-scan of the neck and mediastinum aided by a modem computer assisted treatment planning system (Cadplan®, Varian).
We assumed that the diameter and the contours of the patients body have not significantly changed.
Doses of 35 Gy specified to 6 cm tissue depth were applied over an anterior mediastinal field in which the radiation-induced esophageal carcinoma developed. The retrospective dose analysis resulted in a cumulative dose of 34 to 35 Gy at the upper thoracic esophagus (Fig. 5). Possible field overlaps resulting from the historically used single field irradiation technique could retrospectively not be evaluated. Of course it could not be excluded that areas of inadequate field matches could have caused considerable overdosage zones. One can speculate that from overlapping portals cumulative doses from over 65 Gy could result.
Retrospective Case Analysis
A review of the literature of the cases describing radiation-induced esophageal cancer will be presented (Table 1). They will be analysed concerning the relationship between applied dose and latent interval. So far 66 patients including the patient in this study have been reported. Most patients were female. The reported patients received doses between 18.6 and 68 Gy (median dose: 40 Gy) as primary treatment. The interval between radiation exposure and occurrence of the secondary esophageal carcinoma had a median of 15 years (ranging from 2 to 63 years). Most cases were moderately or poorly differentiated squamous cell carcinomas.
We statistically analysed the data of applied doses and latent interval from the literature overview including our own results using a linear regression model. The result of the analysis was statistically tendentially significant with P =0.0738 (Fig. 6).
In 43 of the 66 retrospectively analysed patients details about treatment of the radiation-induced esophageal carcinoma and the final outcome were available. Most patients (n =26) received a surgical resection, 14 patients were treated with radiotherapy, two with chemotherapy and one patient received hyperthermic chemotherapy. Eleven of the 26 surgically treated patients (42.3%) achieved a long-term curation from surgical intervention. None of the patients treated with radiotherapy or chemotherapy could be cured. Only the patient who received hyperthermic chemotherapy had a long-term remission.
The reported case fits the criteria for radiation-induced malignancies of the esophagus known from literature reported by Chudecki in 1972 (5):
A history of previous irradiation.
A cancer occurring within the irradiated area.
Gross tissue damage due to an excessive dose of radiation.
A long latent interval between irradiation and development of cancer.
There is a close correlation between the spontaneous development of esophageal carcinoma and special nutritional factors as well as the abuse of nicotine and alcohol. Therefore the absence of these risk factors connected with a marked radiation exposure of the esophagus is a clear indication for a radiation-induced esophageal carcinoma (15).
Of course one is not able to confirm the diagnosis of a radiation-induced esophageal carcinoma unequivocally, because radiation-induced carcinomas do not differ histologically from spontaneously developed carcinomas (5,10,16).
The esophagus belongs to the less radiation-sensitive organs (2,11,13). The most important acute side effect is esophagitis of different degrees (13). Fibroses and scarred esophageal strictures are found as chronic radiation reactions (2,11,13). Radiation-induced esophageal carcinomas have been seldom described in the literature. The first scientific report is from the late 1950s (17). Radiation-induced tumors account for less than 1% of all carcinomas of the esophagus (18).
The development of radiation-induced esophageal carcinomas after the therapeutic application of ionizing radiation could be proven by experimental data in animal models (19). In a population-based retrospective cohort study Ahsan et al. (20) described a 5.42-fold increased risk for esophageal squamous cell carcinoma in women who had received radiation therapy for breast cancer compared to unirradiated breast cancer patients.
According to the literature, the therapy of choice in radiationinduced esophageal carcinomas is complete surgical resection (16,21,22). Frequently, a radical surgical approach is not possible because of tumor extension, the radiation damage or a reduced performance status of the patient. In these cases reirradiation alone or palliative chemotherapy can be carried out (21), because radiation-induced malignancies are not less sensitive to radio- and chemotherapy than their spontaneously developed counterparts (14). External beam reirradiation is seldom possible because of overlapping with the former portals. Endoluminal brachytherapy can provide an alternative (21).
Retrospective Dose Analysis
The retrospective dose analysis resulted in a cumulative dose of 34 to 35 Gy at the upper thoracic esophagus. This is a dose which is in the range of doses reported in the literature.
Using a single field irradiation technique it could not be concluded that areas of inadequate field matches could have resulted in marked overdosage zones with doses of above 65 Gy.
Whether this phenomenon supported the induction of a secondary malignancy must remain unclear. The marked plexus injury the patient consecutively developed could have resulted from those incalculable overdosage zones. Emami et al. (2) reported a TD5/5 of 60 Gy and a TD50/5 of 75 Gy for developing brachial plexopathy. The speculated overdosage zones may be in this range, that the plexus injury can be assumed to be radiation-induced.
Further it should be taken into account that an increased daily dose had been applied with a surface dose of 3 Gy corresponding to a treatment target volume dose of about 2.5 Gy. It is well known from the literature that the incidence of radiation-induced plexus injuries is higher after increased single doses (23,24).
Retrospective Case Analysis
The relationship between applied dose and time interval between treatment and the occurrence of the secondary malignancy has been controversially discussed in literature. Some authors stated that higher doses shortened the latent interval (3,4,25,26). Experimental data from animal models could prove a time-dose relationship (26). Other authors could not find this correlation (10,27). Therefore we statistically analysed the data from the overview of literature including our own results using a linear regression model. The result of the analysis was statistically tendentially significant with P = 0.0738 (Fig. 6) supporting a time-dose relationship.
Taal et al. (22) reported the largest series of eight patients with radiation-induced esophageal carcinomas treated with reirradiation. As in our case report not all patients were eligible for full dose radiotherapy. The reported survival in this series ranged between 2 and 13 months. Our reported patient survived only one month after the end of radiation treatment. The use of endoesophageal HDR-brachytherapy as a palliative treatment of radiation-induced esophageal carcinoma has not been described in the literature so far.
Esophageal carcinomas belong to the rare secondary malignancies after the therapeutic use of ionizing radiation. Nevertheless, they should be suspected in patients with dysphagia as a differential diagnosis even many years after mediastinal irradiation (28). The treatment of these tumors seems to be difficult and their overall prognosis is poor.
- radiation therapy
- squamous cell carcinoma
- deglutition disorders
- pathologic fistula
- hodgkin's disease
- constriction, pathologic
- diagnosis, differential
- neoplasm metastasis
- radiation, ionizing
- esophageal carcinoma
- therapeutic uses
- tissue damage