Therapeutic radiation for cancer is more than 100 years old. Side effects constitute the main limitation to its use. Side effects may be acute or chronic, but these categories overlap. As cancer survival improves, chronic radiation damage becomes more common. The gastrointestinal (GI) tract, particularly the bowel, is particularly vulnerable because of its anatomical location and the rapidity of turnover of many GI epithelial cell types. Severity of radiation damage depends also on patient factors, chemotherapy, radiotherapy regimen, and organ mobility. Histologically, common mucosal changes include ulceration, acute inflammation, eosinophilic infiltrates, and architectural abnormalities. Fibrosis may occur later. Vascular changes are more common in chronic disease, affect deeper layers, and include ectasia, intimal thickening, fibrinoid change, thrombosis, and luminal obliteration. Atypia of epithelium, fibroblasts, and endothelium is common and can mimic neoplasia. Epithelial atypia has a lower nuclear:cytoplasmic ratio than dysplasia and matures towards the mucosal surface, aiding the distinction. Features sometimes resemble viral cytopathic change. Chronic radiation colitis may resemble inflammatory bowel disease, ischaemia, and mucosal prolapse while vascular changes may resemble amyloid. In summary, histological clues to radiation damage include fibrosis, atypical fibroblasts, eosinophilic infiltrates, and vascular changes. Confident diagnosis as radiation damage requires a clinical history but this may be unavailable, especially if decades have elapsed since therapy.
The administration of therapeutic ionising radiation began in 1895, initially to treat a wide variety of benign and malignant lesions. Later, it was used mainly for cancer.1 Approximately 50% of all cancer patients, and up to 70% with some types of cancer, receive radiation therapy during the course of their disease.2–4 There are several forms of radiation therapy:
External beam radiotherapy (the machine aims beams at the cancer)
Radiotherapy implants (brachytherapy)
Radioisotope injections, capsules, or drinks (radioisotope therapy)
Advocates of radiation therapy emphasise its cost effectiveness, i.e. approximately 5% of the total cost of cancer treatment.5 Unfortunately, adverse effects are common and involve many organs. Other causes of exposure to excessive radiation that are associated with tissue damage include nuclear bombs, nuclear accidents, and diagnostic imaging. The gastrointestinal (GI) tract, particularly the bowel, is very vulnerable to radiation damage because of its anatomical location and its relatively rapid epithelial cell turnover. The risk of subsequent cancer also increases, particularly after accidental overdose but also following therapeutic radiation.6 There has been considerable effort to reduce the risk of complications of therapeutic radiation, but side effects remain the main limitation to its use and to the dose.1 Classification of radiation damage as acute (<6 months) or chronic (from 6 months to many decades) is usual, although the distinction is arbitrary and there is much overlap. As cancer survival improves, chronic radiation damage that is sometimes decades in duration becomes increasingly common in the population.
Administration of radiation therapy may be before cancer surgery (neoadjuvant) or after (adjuvant), with the respective aims of reducing tumour bulk or eliminating residual disease. It may be combined with chemotherapy, especially preoperatively, or with immunotherapy.5 Sometimes, surgery is omitted from the management and the tumour is treated with radiotherapy alone or with a combination of radiotherapy and chemotherapy. Radiation therapy may also relieve symptoms in a palliative setting.
Units of radiation include rad and Gray (Gy), 100 rad being equivalent to 1 Gy. There are many different regimens based around radiotherapy. The dose and duration vary according to tumour type, tumour location, tumour histology, patient factors, and local protocols.1 For example, preoperative radiotherapy to the pelvis for colorectal cancer may comprise short-course radiotherapy or long-course chemoradiotherapy. Short-course radiation might consist of 25 Gy (5 Gy in five fractions over 5 days) followed a week later by surgery, while long-course chemoradiotherapy might consist of 50.4 Gy (1.8 Gy in 28 fractions over 5 weeks), combined with chemotherapy, and followed by surgery 4–8 weeks later.7, 8
In general, side effects are more likely with a higher dose and a longer duration of treatment. There is also individual variation. Risk factors for a higher rate of side effects and complications include previous abdominal surgery (particularly if there are adhesions); diseases predisposing to vascular compromise such as diabetes mellitus, vascular disease, and scleroderma; low body mass index (BMI); inflammatory bowel disease (IBD); and tobacco use (Fact Sheet 3.1).2, 9
Low body mass index
Anatomical site of organ
Type of epithelial lining
With or without chemotherapy
Pathogenesis of Radiation Damage to the Gastrointestinal Tract
Radiation can cause direct or indirect damage to cellular DNA,5, 6, 9 causing a diminution in cell division or cell death. Forms of cell death include apoptosis, mitotic cell death/mitotic catastrophe (the two most common), necrosis, senescence, and autophagy (Fact Sheet 3.2). Direct damage comprises single-strand and double-strand DNA breaks. Indirect damage is partly a consequence of the generation of toxic-free radicals that cause oxidative damage. Clusters of DNA damage are characteristic.
Aberrant mitosis with segregation of chromosomes
Giant cells with atypical nuclei or multiple nuclei
Programmed cell death with cell shrinkage and apoptotic bodies
Swelling of cells with disruption of the membrane
Permanent loss of proliferation
A regulated form of programmed cell death
The cell digests itself
Damage does not occur immediately. It may occur after several hours, days, or weeks. Cell death then continues for weeks or months.5 Following apoptosis or other forms of cell death there is inflammation, ulceration, fibrosis, and abnormal vascularisation.10
Underlying changes are not always clear. Levels of interleukin, transforming growth factor, and tumour necrosis factor-α increase after radiation, and their tissue levels may correlate with the dose of radiation and the radiation injury score.11 There are some histological and clinical similarities between IBD and radiation proctocolitis and these may be mirrored by similarities in the mucosal cytokine alterations that play a role in the onset and progression of the changes, e.g. interleukins 2, 6, and 8.12 Microbiota may also be important.10 For example, radiation may alter the gut microbiota, resulting in localised microbial dysbiosis. Radiation-induced changes in microbiota increase the tissue susceptibility to inflammation and to radiation damage and may favour secretion of factors such as interleukin-1β.10
Some tumour types are particularly sensitive to radiation therapy and include cases that have been cured using radiotherapy alone.5 Examples include skin cancer, lymphoma, head and neck carcinomas, prostate carcinoma, and cervical carcinoma.5
In the acute phase, radiation is particularly toxic to rapidly dividing cells, progenitor cells, and stem cells.6, 9 Experts disagree about the causes of chronicity and, in some cases, subsequent progression. Possible contributory factors include continuing epithelial injury and ulceration with epithelial regeneration, or vascular changes and/or fibrosis that continue to progress and contribute to a gradual compromise of tissue perfusion and interference with homeostasis.4, 13 Evidence for an important role for vascular compromise is provided by studies of colectomy specimens that showed a significant reduction in microvascular volume.14
General Features of Radiation Damage to the Gastrointestinal Tract
All parts of the GI tract are vulnerable to damage by radiation. There are some similarities between the effects at different anatomical sites (Fact Sheet 3.3). Changes depend on patient characteristics, time since the administration of treatment, dose, type of therapy, duration of therapy, and the inclusion of chemotherapy in the regimen.
Mucosal architectural changes
Intimal thickening and foam cell proliferation
Fibrinoid degeneration and necrosis
Fibroblast/stromal cell atypia
Endothelial cell atypia and enlargement
The GI tract lining consists mainly of columnar mucosa that has a high rate of cell turnover. Therefore, the lining of the GI tract is more susceptible than many other parts of the body to acute radiation injury.9, 13 Another reason for the vulnerability of the GI tract is its location within the abdomen and pelvis close to the site of a wide variety of tumours that may undergo irradiation. Poor mobility of some GI organs is another factor. The rectum is at particular risk both because of its proximity to common cancers of the lower abdomen and pelvis and because of its relative immobility.
Grading systems may help record the severity of acute or chronic radiation damage to the GI tract. In general, these do not consider histology.1
Chemotherapy also produces a wide variety of mucosal changes macroscopically and histologically. Distinction of the separate effects on the mucosa of chemotherapy and radiotherapy is often difficult. However, the mucosal damage caused by radiotherapy is usually more severe if combined with chemotherapy. For example, the use of chemotherapy in addition to radiotherapy for oesophageal lesions increased the risk of radiation injury by a factor of 12, according to one report. 15 ‘Radiation recall’ refers to an acute inflammatory reaction in previously irradiated areas that appears to be a result of subsequent administration of chemotherapy and most often affects the skin. The reasons for this phenomenon are not clear.16 Radiation recall gastritis may occur, and its main feature in one study was ulceration.17
The prevalence and public health impact of chronic radiation damage to the GI tract in cancer survivors is probably underestimated. The reasons include reluctance of patients to seek medical help, loss of follow-up, removal from follow-up, and, perhaps, low awareness and low prioritisation of radiation-induced disease by health care systems.2, 9 Nevertheless, morbidity caused by radiation damage to the GI tract and other organs is attracting more attention as cancer survivor numbers and follow-up times increase.2, 18 Fortunately, treatment regimens are now more precise, and complication rates should be lower as a result.2
In this chapter, the focus will be on mucosal changes. However, radiation damage involves all layers of the damaged part of the gut. Indeed, the characteristic features are often most obvious in the submucosa and deeper layers, especially in the chronic phase. In addition, involvement of deeper layers plays an important role in the maintenance and progression of chronic changes in all layers.
Radiation damage may be classified as acute or chronic, usually defined respectively as less than 6 months or more than 6 months since cessation of therapy. Some schemes use 3 months as the boundary and some refer to early and late rather than acute and chronic.2, 4 Another scheme refers to acute (less than 6 months), subacute (6 months to 2 years), chronic (2–5 years), and late (more than 5 years). Acute damage typically occurs during therapy and for 4–8 weeks after cessation of treatment, is often subclinical, and is usually self-limiting. Chronic damage occurs in a minority of patients and is sometimes a slowly progressive disease over many years or decades.13
Common acute mucosal changes include ulceration and a neutrophil inflammatory infiltrate. Macroscopically and histologically the ulcers of radiation damage are not distinguishable from many other types of ulcer (Figure 3.1A and B). Mucosal architectural changes may occur, particularly in the large bowel (Figure 3.2).
Figure 3.1(A) Ulceration of oesophageal mucosa several weeks after radiotherapy. There are no specific features.
(B) Ileal mucosal ulceration and submucosal inflammation several years after radiotherapy.
(A) Mild crypt distortion; crypt atrophy with wide spacing of crypts.
(B) Crypt branching, crypt atrophy, vascular dilatation, mild mucosal fibrosis, and Paneth cell metaplasia (arrow). Vascular dilatation, as seen here, is characteristic of radiation damage but is not specific. Crypt changes and Paneth cell metaplasia can mimic chronic idiopathic inflammatory bowel disease.
Eosinophilic infiltration is a feature of radiation damage, and according to some experts is a very useful pointer to the diagnosis (Figure 3.3). Until recently, there has been little documentation of the number and density of eosinophils in the normal GI mucosa.19, 20 Therefore, the threshold above which eosinophilia is a consideration remains difficult to define. However, significant eosinophilic infiltration of the epithelium, eosinophil aggregates, eosinophil crypt abscesses, and extensive eosinophil degranulation are probably abnormal.21 Significant mucosal eosinophilia can occur in various allergic conditions, eosinophilic oesophagitis, eosinophilic gastroenteritis, diverse infections (but particularly parasitic and fungal infections), inflammatory fibroid polyps, gastro-oesophageal reflux, autoimmune gastritis, drug-induced gastroenteritis, IBD, and many other circumstances.21 Accordingly, the presence of eosinophils raises the possibility of a variety of diseases. Therefore, other histological features and the clinical setting require consideration before interpretation of the significance of an eosinophil infiltrate.21
Figure 3.3 An eosinophil crypt abscess, characterised by an eosinophil-rich inflammatory cell population in the lumen of a crypt. According to some authors, eosinophil crypt abscesses and eosinophil cryptitis are highly characteristic of radiation damage to the gastrointestinal mucosa. Nevertheless, both have many other causes.
Fibrosis is common after radiation injury and suggests chronicity (Figure 3.4), but many types of mucosal injury can induce fibrosis. For example, fibrosis of the large bowel mucosa may result from ischaemia and mucosal prolapse and, less often, diverticular disease and longstanding IBD. In the GI tract generally, other causes of fibrosis include graft-versus-host disease, drug injury (particularly non-steroidal anti-inflammatory drug [NSAID]-induced gastric damage), and chemical injury. The latter includes gastric mucosal damage caused by alcohol. Ulcerated polyps and tumours may also show fibrosis, as may almost any process that can induce erosion, ulceration, severe inflammation, and/or ischaemia. Therefore, fibrosis is characteristic of chronic radiation damage and raises the possibility of this diagnosis in conjunction with other typical features, but is not specific.
Vascular changes include prominence and dilatation of small blood vessels, intimal thickening, intimal expansion by foam cells, mural fibrinoid necrosis, mural hyalinisation, narrowing of the lumen, thrombosis, obliteration, proliferation, vasculitis, arteriolitis, and sclerosis (Figure 3.5).22, 23
(A) Intimal thickening and foamy change.
(B) Mucosal vascular dilatation.
(C) Thrombosis and mild sclerosis.
(D) Narrowing of the lumen and obstruction.
(E) Hyalinisation of the wall.
Vascular abnormalities can occur in any layer of the affected viscus but are often most obvious in the submucosa.
Ulceration also occurs in chronic disease, possibly because of vascular insufficiency (Figure 3.1B). However, blood vessels beneath an ulcer can show a variety of histological changes, regardless of the cause of the ulcer. Accordingly, interpretation of vascular changes beneath an ulcer and their attribution to radiation damage should be cautious.24
At various GI sites, there may be an increase in the number of mucosal endocrine cells following preoperative chemotherapy or radiotherapy, and they may be single or form nests. There are reports of this phenomenon occurring in the non-neoplastic mucosa after radiotherapy for oesophageal adenocarcinoma25 and within the tumour itself in patients with rectal carcinoma following chemotherapy and radiotherapy.26
Epithelial cytological atypia can occur and may be severe, especially if there is acute inflammation or ulceration (Figure 3.6 and Table 3.1). There may be confusion with dysplasia, particularly if the pathologist is unaware of the history of radiotherapy. Both types of atypia show nuclear and cytological pleomorphism. However, radiation-induced epithelial atypia (in common with other forms of regenerative atypia) typically shows maturation of epithelial cells towards the mucosal luminal surface; i.e. the atypical changes become less severe with increasing proximity to the surface, while dysplasia rarely shows this feature. In addition, dysplasia tends to have a higher nuclear/cytoplasmic ratio and more nuclear hyperchromaticity and may have a more monotonous appearance.
(A) Nuclear irregularity, pleomorphism, and hyperchromaticity.
(B) The atypia diminishes in severity towards the mucosal surface and the nuclear/cytoplasmic ratio is relatively low. These features help distinguish radiation-induced epithelial atypia from dysplasia, which typically does not mature towards the surface. However, a clinical history is necessary for accurate interpretation.
|Cell causing concern||May resemble||Comment|
|Atypical epithelial cell||Dysplasia or carcinoma||Maturation towards the surface if not dysplastic|
|Lower nuclear/cytoplasmic ratio than neoplasia|
|Atypical fibroblast||Mesenchymal tumour or carcinoma||Immunohistochemistry may help distinguish from carcinoma|
|Multinucleated cell||Herpes simplex virus (HSV)||Immunohistochemistry very useful|
|Atypical endothelial cell, fibroblast or epithelial cell||May resemble CMV||Rarely has classic owl’s eye appearance|
|Immunohistochemistry very useful|
Atypia of fibroblasts, other stromal cells, and endothelial cells is characteristic of radiation damage to the GI tract (Table 3.1). Fibroblasts may be larger than usual, may have a stellate appearance with cytoplasmic extensions of various lengths and thicknesses, and can show nuclear hyperchromaticity and nuclear enlargement (Figure 3.7). The term ‘radiation fibroblast’ is sometimes used. The fibroblastic credentials of such cells are open to question, and the term ‘fibroblast-like cells’ may be preferable. Indeed, histological distinction between atypical fibroblasts, atypical endothelial cells (Figure 3.8A and B), and other atypical stromal cells in the setting of radiation damage is not always possible (Figure 3.8C). Atypical fibroblasts can be numerous and can mimic carcinoma or mesenchymal neoplasia (Figure 3.9).
(A) An enlarged, stellate fibroblast-like cell with cytoplasmic extensions.
(B) Nuclear hyperchromaticity and nuclear enlargement.
(A) Atypical endothelial cells and fibroblasts in the oesophageal lamina propria 21 months after radiation therapy for oesophageal carcinoma. Note the hyperchromatic enlarged nuclei.
(B) Atypical endothelial cells in the small bowel submucosa, several decades after radiation therapy.
(C) Atypical cell of uncertain type, possibly a fibroblast, adjacent to a ganglion in the ileal submucosa.
Figure 3.9(A) Atypical stromal cells in the oesophageal lamina propria 21 months after radiation therapy for oesophageal squamous cell carcinoma. In addition, there is fibrosis and vascular ectasia of the lamina propria. Distinction between radiation-induced stromal cell atypia and recurrent carcinoma is difficult.
(B) Immunohistochemistry for an epithelial cell marker is negative, suggesting radiation-induced stromal cell atypia rather than carcinoma. The patient remains alive, with persistent oesophageal ulceration, 5 years after the date of the biopsy.
Atypia, nuclear enlargement, and cytological enlargement of endothelial, stromal, or epithelial cells resulting from radiation damage may resemble the changes of cytomegalovirus (CMV) infection (Figure 3.10). The classic ‘owl’s eye’ inclusion surrounded by a clear halo may occur rarely.13 However, genuine CMV inclusions also often lack the classical features. Therefore, pathologists should have a low threshold for considering CMV because some patients may have an underlying disease that causes immunosuppression. Immunohistochemistry is a reliable way to confirm or exclude CMV.
Figure 3.10 A stromal cell in the lamina propria of the oesophagus after radiotherapy with an atypical enlarged nucleus. The features resemble a cytomegalovirus (CMV) inclusion. Immunohistochemistry for CMV is a reliable and specific test that will help distinguish between CMV and radiation effect.
Multinucleation of squamous cells in the oesophagus, or of other types of cell, might also cause confusion with herpes simplex virus (HSV) infection (Figure 3.11). The cells in HSV typically have ground glass nuclei and Cowdry A inclusions. Nuclear immunohistochemical positivity is useful for confirmation of HSV.
Figure 3.11 Atypical stromal cell in radiation-damaged small bowel wall, showing multinucleation reminiscent of herpes simplex virus (HSV) infection. Immunohistochemistry can help confirm or refute the possible diagnosis of HSV.
Diagnosing Radiation Damage
Unfortunately, no histological change is specific for radiation damage. A combination of characteristic abnormalities such as radiation fibroblasts, eosinophils, vascular abnormalities, and fibrosis might raise the possibility of radiation damage, but a confident histological diagnosis is impossible if there is no clinical history. Even with a clinical history, a confident diagnosis is often difficult, as there are many clinical and histological mimics. Indeed, patients with an underlying diagnosis of cancer are at risk of other types of GI mucosal injury and can develop any other GI disease, including reflux oesophagitis, Helicobacter-associated gastritis, chemical/reactive gastropathy/gastritis, and IBD, and all of these have the potential to overlap with radiation damage histologically.
Residual, recurrent, or new malignancy is an important clinical consideration. Symptoms resembling those of cancer, even if they probably reflect radiation damage, are an indication for endoscopy. If a lesion is apparent at endoscopy, and particularly if the lesion could be a tumour, the endoscopist will take a biopsy.7 Ulceration in particular raises the possibility of neoplasia in this setting and is likely to lead to a biopsy.4
Clinically, confident attribution of symptoms and signs to the effects of radiotherapy can be difficult. In particular, radiation may not necessarily be responsible for symptoms if there is known or possible residual cancer in the affected area. Also, endoscopic features of radiation effect and neoplasia overlap considerably. For example, mucosal ulceration occurs in both. Similarly, pathologists should be aware that the histological features of radiation damage are not always easy to distinguish from those of cancer and in turn should not allow the clinical impression to influence their assessment so strongly that they overdiagnose or underdiagnose cancer (Practice Points 3.1).
Seek histological features that support a clinical diagnosis of radiation damage.
Consider other non-neoplastic causes of symptoms:
Consider the possibility of radiation damage if the combination of histological features is particularly suggestive.
The oesophagus is at risk of damage when there is irradiation of cancers of the upper body, e.g. lung, oesophagus, and breast. Genetic factors modify the risk.22 Chemotherapy increases the likelihood of radiation damage. Overall, the histological and endoscopic features of oesophageal radiation damage are often even less specific than those at other GI sites such as the rectum.22
Oesophagus: Acute Radiation Damage
Symptoms of acute radiation oesophagitis are rare, occurring in only about 1% of patients, and are not specific.22 They include dysphagia, a burning sensation, and other symptoms of oesophagitis.4 Symptomatic patients may have no endoscopic abnormalities, while histological abnormalities may be discrepant with endoscopic changes.22, 27 Investigation of oesophagitis is less likely if there is a known history of oesophageal cancer than if the cancer was at another site because clinicians may attribute symptoms to the known oesophageal cancer. Macroscopically, acute changes of radiation damage include ulceration, perforation, and fistulas.22
Histologically, early acute changes include apoptosis of epithelial cells, particularly basal cells; necrosis of epithelial cells; vacuolisation of the epithelium; a reduction in mitotic figures; and loss of underlying mucous glands. After at least a week, the epithelium starts to recover and shows basal cell hyperplasia and thickening (Figure 3.12). In mice, there was vacuolisation of epithelial cells and disappearance of mitotic figures in the basal layer on day 3, with thinning of the epithelium. From days 7 to 14 there was evidence of regeneration as well as focal denudation, and after 21 days there was recovery with basal cell and upper layer hyperplasia.23 Confusingly, these changes may occur in parallel with ongoing mucosal damage.23 Acute pathological features in humans are probably similar.23, 27 In the first few weeks, usually more than 2 weeks after therapy, there may be ulceration and erosion (Figure 3.1A).
Oesophagus: Chronic Radiation Damage
Chronic radiation-induced changes in the muscularis propria and submucosa are more obvious than mucosal changes (Fact Sheet 3.4).23 Vascular changes in the deeper layers include obliterative vasculitis, arteriolitis, sclerosis, fibrinoid necrosis, and intimal expansion by foam cells.22 Dilatation, proliferation, and narrowing of blood vessels also occur.23. In general, vascular changes are less severe than in the bowel. Chronic changes also include fibrosis of the submucosa and underlying muscularis propria and adventitia, which can cause symptomatic stricturing22 and luminal narrowing. Fibrosis is often not apparent in mucosal biopsies,4 but there may be well-developed collagenisation of the lamina propria beneath the epithelium with atypical fibroblasts and ectasia of small blood vessels (Figure 3.9).23 Submucosal glands may be lost.
Atrophic, normal, or hyperplastic epithelium
Mucosa possibly arranged in multiple folds
Possible occurrence of parakeratosis, hyperkeratosis, and epithelial vacuolisation
Mucosal bridges occur rarely
Ulceration, especially after high-dose radiation
Atypical fibroblasts and atypical epithelial cells
May mimic carcinoma on biopsy and cytology
Degenerative cytological changes
Collagenisation of the lamina propria
Ectasia of small blood vessels
In the chronic phase, the mucosa may be atrophic. More often it regenerates and is then either normal or thickened, may be arranged in multiple folds, and may show parakeratosis, hyperkeratosis, and/or vacuolation (Figure 3.13).4 Mucosal bridges overlying a chronically inflamed lamina propria have been reported.28 Ulcers can occur in the chronic phase (Figure 3.1A).4 High-dose radiation in particular can cause persistent ulceration.