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BRIEF RESEARCH COMMUNICATION
Year : 2016  |  Volume : 9  |  Issue : 4  |  Page : 489-494  

Multiple radiation-induced late changes seen in pelvis in a single patient


Department of Radiation Oncology, Sri Aurobindo Medical College and PG Institute, Indore, Madhya Pradesh, India

Date of Web Publication12-Jul-2016

Correspondence Address:
Virendra Bhandari
401, Samyak Towers, 16/3, Old Palasia, Indore, Madhya Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-2870.186058

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  Abstract 


Background: Radiation sequelae can be early or late depending on the duration of occurrence. Early reactions are temporary, but late reactions tend to be permanent and occur many years after treatment. Late reactions can be seen in skin, subcutaneous tissue, muscle, and bone in the irradiated area. Materials and Methods: We present here a report in which we saw all the late reactions in a single patient, 18 years after radiotherapy to pelvis for cancer cervix. Results: Our patient had bone fracture, new bone formation, bone marrow widening, muscle hypertrophy, subcutaneous fibrosis, and angiokeratoma after 18 years of radiotherapy to pelvic area. Conclusion: All these types of late toxicities are rarely seen in the same patient and we could not find any such reports in the literature.

Keywords: Bone, late radiation toxicity, muscle, skin and pelvis, radiotherapy to pelvic area


How to cite this article:
Naik A, Bhandari V, Gupta K L, Kausar M. Multiple radiation-induced late changes seen in pelvis in a single patient. Med J DY Patil Univ 2016;9:489-94

How to cite this URL:
Naik A, Bhandari V, Gupta K L, Kausar M. Multiple radiation-induced late changes seen in pelvis in a single patient. Med J DY Patil Univ [serial online] 2016 [cited 2022 Oct 5];9:489-94. Available from: https://www.mjdrdypu.org/text.asp?2016/9/4/489/186058




  Introduction Top


Radiation toxicity can be divided into early and late. Nausea, skin reactions, diarrhea, and neutropenia are early temporary effects whereas late effects are connective tissue fibrosis, bone fractures, skin lesions, and secondary malignancy, which occur months or years after radiotherapy. The etiology for long-term sequelae is complex and involves a cascade of cellular, vascular, and cytokine changes induced by radiation. The organs at risk during pelvic radiotherapy are colon, small bowel, bladder, ureters, urethra, genital organs, spinal cord, skin, soft tissue, muscles, bones, vasculature, nerves, and lymphatic system.

One or more late radiation toxicity can be seen in survivors. Here, we present a case where late reactions were seen in all tissues, 18 years after radiotherapy to pelvis. The patient had bone fractures, new bone formation, widening of joint space with fluid, fatty marrow, muscle hypertrophy, subcutaneous fibrosis, and angiokeratoma developing simultaneously. All these late radiation toxicities are rarely seen in the same patient. We could not find any similar case reported in the literature.


  Materials and Methods Top


A 49-year-old female presented with burning micturition, fever, inability to walk, and multiple skin lesions over pelvic area, which were not responding to symptomatic treatment.

In the past, she had squamous cell carcinoma cervix and received external beam radiotherapy (EBRT) 50 Gy/25 fractions with anterior and posterior portals delivered on alternate days on telecobalt unit followed by single fraction of intracavitary brachytherapy 25 Gy at point A on low dose rate (LDR) unit till October 1994. Since then, the patient was on regular follow-up and is loco regionally controlled.

In May 2011, pain in pelvic area started with difficulty in walking. Pelvis X-ray revealed pathological fracture at right superior ischeo-pubic ramus and new bone formation in inferior ischeo-pubic rami [Figure 1]. In June 2011, the patient developed multiple red, firm warty lesions over vulvar and pubic area [Figure 2] with episodes of leucorrhea. The patient was locoregionally controlled. In September 2012, she developed low back pain and progressive difficulty in walking. Her magnetic resonance imaging (MRI) pelvis showed diffuse hyperintense signals in sacral ala and left iliac bone with widening of left sacroiliac joint space and enlargement of psoas muscle along with increased signals in ipsilateral iliacus piriformis and proximal adductor muscles. A loculated cyst was also seen in left iliacus muscle. Fatty marrow changes were evident in all pelvic bones [Figure 3]a and [Figure 3]b. There was no evidence of disease at primary site except for vaginal wall thickening, extensive subcutaneous fibrosis in pelvic region, and lower abdominal muscles, and multiple vulvar lesions A whole body positron emission tomography scan was done, which showed increased uptake (standardized uptake value 8.4) in sclerotic lesions of left sacroiliac joints with increased joint space suggesting inflammatory sacro-ilietis. Fluerodeoxy glucose (FDG) nonavid cortical break was seen in anterior pillar of right acetabulum, inferior pubic ramus, and sacral ala indicating pathological fracture. Soft tissue hypertrophy was seen in left psoas, iliacus, and piriform muscles without uptake. No uptake was seen in the vulvar lesions.
Figure 1: Pathological fracture and new bone formation

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Figure 2: Subcutaneous fibrosis and multiple nodules over vulva

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Figure 3: (A and B) Magnetic resonance imaging showing fatty marrow, diffuse hyperintense signals in sacral ala, and left iliac bone with widening of left sacroiliac joint and muscle changes

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Biopsy done from one warty lesion over pubis showed hyperplastic epidermis with focal hyperkeratosis and papillary dermis showing numerous dilated vascular spaces forming angiomatous mass confirming radiation-induced angiokeratoma [Figure 4]a and [Figure 4]b. On follow-up on last month, she had increased pain in pelvis, inability to walk, increased number of vulvar lesions, and bilateral lower limb edema.
Figure 4: (A and B) Hyperplastic epidermis with focal hyperkeratosis and papillary dermis showing numerous dilated vascular spaces forming angiomatous

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  Discussion Top


Radiation therapy remains to be a mainstay of treatment in various malignant conditions. The frequency of radiation-induced adverse effect has decreased significantly with the advent of newer technologies of radiation delivery, which allows more conformity of the target tissue and homogenous dose distribution and also because of increased knowledge of tissue response to radiation.

Effects of radiation on living tissue can be divided into early and late effects, which show huge variation in terms of different patterns of response to fractionations and dose-response relations. Acute damage may be completely reversible and is rapidly repaired by rapid proliferation of stem cells.[1] Only after a delay of months or years late, effects appear and these can be seen predominantly in slowly proliferating tissues, such as lung, kidney, heart, liver, and central nervous system. Late damage may improve, but it is never completely repaired and these late changes might result from a combination of vascular damage and loss of parenchymal cells.[1]

Musculoskeletal complication of radiotherapy are often discovered incidentally when radiographic investigations are ordered to check the presence of recurrence or metastatic disease. Radiation doses which are used routinely for the treatment for cervical cancer (CaCx) or carcinoma prostate do not result in acute injury to bone. Therefore, late radiation-induced changes in bones are characteristic and a long latent period is usually present before these changes are detected because of slow metabolic turnover of bones.[2] These late effects include damage to osteoblasts, decreased matrix formation, and osteopenia along with osteoradionecrosis, pathologic fractures, and radiation-induced neoplasms, which are usually seen years after radiation.[2] The threshold of radiation-induced changes in the bone is thought to be 3000 cGy, with death of cells usually occurring at 5000 cGy.[3],[4]

Repair of damaged bone takes place with deposition of bone on unresorbed trabeculae, which can be seen as focal areas of increased opacity in close proximity to areas of mottled bone with osteopenia on radiographs and the patient can be initially asymptomatic, but ultimately symptoms appear due to osteonecrosis or stress insufficiency fractures.[5] These changes can be attributed to the decrease in bone blood flow. This reduction in bone vascularity combined with impaired bone formation from irradiated osteoblasts results in decrease in bone density and thus resulting in fracture. Radiation can lead to obliteration endartitis and endothelial cell cytoplasmic vacuolization,[6] which in turn leads to luminal narrowing in the haversian system resulting in decreased blood flow. Also, the fact that osteoblast proliferation is affected by radiation resulting in decreased bone matrix formation and bone atrophy. Thus as an end result of radiation injury, osteoclast bone resorption can continue without concomitant bone formation resulting in decrease in bone density and thus fractures.[7],[8] Risk factors for radiation-induced pathologic factors of bones include total radiation dose, dose given per fraction, area of bone receiving radiation, size of radiation portals periosteal stripping of bone, female gender, older age, postmenopausal women, osteoporosis, and use of chemotherapy.[9],[10],[11]

The bony structures of pelvis are frequently included in radiation portals while treating CaCx or other gynecological malignancy. Radiation-induced changes in pelvis usually include osteopenia, increased bone density and widening and irregularity of the sacroiliac joints, and pelvic insufficiency fractures (PIFs). These can be detected on radiographic imaging and it is important to differentiate these radiation-induced changes from metastatic disease. On routine X-rays, typical pattern of osteopenia is seen along with patchy areas of sclerosis and increased bone densities.[12] Sacroiliac joints may also appear widened and irregular with sclerosis.[4] PIFs are common in patients who have received prior radiation to pelvis. PIF usually occurs near the areas of radiation osteitis and in close proximity to the weight bearing joints, especially adjacent to sacroiliac joints. Computed tomography scans or MRI pelvis has a higher sensitivity for the detection of PIFs.[13],[14],[15],[16] The 5-year incidence of PIF in patients who have been previously irradiated patients is found to be 2.1-13%.[15],[16],[17] Usually, patients having PIF are asymptomatic, but these may present with new onset of pain. These painful lesions may persist for months to years in symptomatic patients. Risk factors for PIF include dose >50 Gy, osteopenia, corticosteroid use, and older age.[16],[18],[19] Clinical presentation of our patient along with changes seen on X-rays and MRI, and the presence of risk factors for PIF favors our diagnosis of radiation-induced late changes.

EBRT delivered by conventional fractionation cause no damage or very little damage to mature muscle fibers.[20],[21] Dose fractionation schedule is an important determinant of muscle injury. Karasek et al.[22] noted that the most important determinant of delayed late muscle morbidity in patient of soft tissue sarcoma after radiotherapy is the volume of tissue receiving more than 55 Gy. Withers et al.[21] performed a retrospective analysis on 676 patients treated with EBRT for carcinoma tonsil and reported that 66% of late muscle complications appeared in the first 4 years after treatment injury and concluded that larger total dose and larger dose per fraction were the main factors defining the rate of complication whereas overall treatment time was not. Phillips et al.[23] studied human muscle response after irradiation, and observed muscle degeneration and vacuolization associated with a loss of capillaries 2-4 months after doses of 20 Gy.

Muscle changes in response to radiation can be impressive and acute changes on MRI can be seen by bright T2-weighted signal intensity in the treated field indicating inflammation and/or edema.[24] Chronic or late changes usually seen as discrete areas of fibrosis and muscle atrophy often with overlying volume deficits corresponding to the radiation treatment portals. Lefaix et al. demonstrated that muscle fibrosis is a common and late side effect of radiation on skeletal muscle.[25] Fibrosis is usually irreversible and results in chronic pain deformity and impaired mobility in severe cases. Delayed necrosis of striated muscle can also be seen after receiving therapeutic doses of radiation because of damage to capillaries and connective tissue. Several reports [26] also described patients of Hodgkin's lymphoma having myopathy within the radiated muscles.

Most common histopathological changes due to postradiation myopathy are presence of nemalin rods. Other changes include variation in muscle fiber size, disorganized architecture, nuclear variations, and infiltration by adipocytes.[27] Pathophysiology underlying these muscle changes is due to damage to vessel and blood capillaries and their consequent ischemia along with the inflammation. The endothelial cell are most sensitive to radiation and they exhibit swelling and necrosis acutely followed by intimal proliferation and increase in collagen content and its deposition, which along with ischemia and inflammation leads to the development of muscle fibrosis and which in turn causes a nonspecific repair reaction which causes alteration in muscle parenchyma.[28],[29] Although rare, progressive muscle damage can continue for up to 10 years following treatment.[29] Radiation also affects muscle satellite cells by impairing their activation, proliferation, and differentiation by preventing their mitosis by causing breaks in DNA strands, which leads to the inhibition of regeneration and muscle hypertrophy.[30]

Changes seen in our patient can be explained by the fact that relatively large daily fractionated doses were administered to the pelvic muscles. Also, with the decision to use two-field technique, the pelvic muscle might have received larger dose pre fraction and cumulative dose than if 3 or 4 field techniques have been used.

Skin reaction to radiation can be classified as early (before 6 months) or late (<6 months). Early reactions include transient erythema causing vasodilatation, increased vascular permeability and edema, epilation, and skin dryness is also seen due to damage to hair follicles and sebaceous glands, these changes are followed by dry desquamation, pruritus, scaling, hyperpigmentation, and moist desquamation usually seen after 2-3 weeks of radiotherapy. Late reactions include hyperpigmentation and/or hypopigmentation, epidermal and/or dermal atrophy, skin dryness, loss of sweat glands and duct, alopecia, telectangasia, nuclear atypia, nuclear atypia of basal keratinocytes and melanocytes, dyskeratosis, loss of rete ridges, disappearance of the epidermal basement membrane, fibrin formation along the dermoepidermal junction, and decreased numbers of upper dermal blood capillaries [31],[32],[33],[34] hyperplasia of epidermis/dermis, hyperkeratosis, fibrosis, luminal narrowing or obliteration of vessels, radiation-induced neoplasm. Radiation-induced angiokeratoma is a rare phenomenon to occur and a recognized complication,[34],[35],[36],[37] angiokeratomas are benign lesions thought to be telangiectasias with secondary epithelial proliferation. Histologically, angiokeratomas are characterized by ectatic capillaries at the dermoepidermal junction, with reactive hyperkeratosis, acanthosis and focal papillomatosis of the overlying epidermis.[38] Proposed mechanisms responsible for the development of angiokeratomas include primary degeneration of the vascular elastic tissue, increased venous pressure with consequent destruction of elastic fibers resulting in over distension, and chronic inflammation causing phlebectasia.[35] Radiation-induced damage to blood vessels along with decreased blood return due to larger field sized used in treatment could lead to increase in venous blood pressure, which in turn is known to cause angiokeratoma. A possible mechanism is vascular injury because of radiotherapy-induced free radical production. Blood vessels are relatively resistant to radiation, hence this toxicity is very rare to occur. Patients having angiokeratomas are mostly asymptomatic, but sometimes patient may present with complains of dyspareunia, bleeding or pus discharge from some of the lesions, and these increase in number and size slowly in radiated area. Therapy is sometimes required when there is continuous bleeding, progressive pain, or anxiety.[35] In symptomatic cases, therapy is indicated and treatment modalities include surgical excision, electrocauterization, cryotherapy, or laser treatment, the choice of which largely depends on size of the lesion.

Our patient also showed vulvar lesions gradually increasing in number and size with discharge, but no bleeding resulting in dyspareunia and psychological burden to patient and was offered treatment in form of surgery, but patient refused surgery, hence a decision to treat conservatively was taken.


  Conclusion Top


Presence of late toxicities involving bones, muscle, and skin lesion in the form of vulvar angiokeratoma in a single patient is very rare and we could not find any such case in literature.

The most likely cause for the development of these late effects in the present case was the schedule and technique used for the delivery of radiation in an overweight patient with antero-posterior separation of 26 cm leading to increased integral dose.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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