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Osteochondroma after Total Body Irradiation: An Age-Related Complication
Abstract
The discovery of a mass lesion in a long-term cancer survivor causes significant anxiety. The causes of such a mass include benign osteochondroma, which has been reported following focal irradiation and total body irradiation (TBI).
To establish the incidence of osteochondromas following TBI, the medical records of all children treated at the Sydney Children's Hospital who received TBI as part of the conditioning prior to bone-marrow transplantation between 1978 and 1997 were reviewed.
Five of 58 children who received TBI as part of the conditioning therapy for bone-marrow transplantation and who have been followed for at least 30 months post-irradiation, developed osteochondromas. All five of the patients had been under 5 years of age when they received TBI (mean 2.4 years), giving an incidence of osteochondroma of 24% in those who received TBI in the first 5 years of life. No osteochondromas have been diagnosed among the 37 patients who were aged between 5 years and 15 years at the time of receiving TBI. The mean latent time to diagnosis of osteochondroma was 4.6 years (range 2.5-9 years). Two patients developed multiple osteochondromas. Two patients required resection of their osteochondromas because of symptoms. Neither showed malignant degeneration.
Younger patients are at increased risk of osteochondroma following TBI. Review of the available literature suggests a low malignant potential of radiation-induced osteochondromas. Knowledge about the behaviour of post-irradiation osteochondromas will help clinicians manage patients appropriately.
... 3 Early reports on OCs arising within RT fields included patients with what is now recognized as low-risk (i.e., readily curable) neuroblastoma (NB), namely, infants with localized NB. [7][8][9]11 Such patients no longer receive RT, 26,27 but irradiating the primary tumor bed is standard for high-risk NB. [28][29][30] OCs in this patient population have been linked to TBI administered at a young age, with a 20-45% incidence in long-term survivors. 17,[19][20][21][22] In contrast, without TBI, 0/30 19 and 1/57 31 long-term NB survivors in multi-institutional studies developed an OC, and no OCs were noted in a North American study of long-term outcomes of 954 patients treated in 1970-1986 for all stages of NB. 32 In recent singleinstitutional studies of late effects in high-risk NB patients, one OC (outside the RT field) was noted in 16 subjects in one report, 33 whereas no OCs were described among 63 and 52 patients, respectively, in two other reports. 34,35 A recent comprehensive review of late effects of childhood cancer therapy did not mention OC. 36 RT and TBI together have been widely used in children with high-risk NB, [20][21][22]30,37 setting these patients apart from those with other solid tumors (whose treatment can include local RT but not TBI) and from children with hematologic disorders (whose treatment can include TBI but not local RT). ...
... These treatments are now standard for high-risk NB but were not routinely used in NB patients covered in recent reports on late effects of oncologic therapy. [19][20][21]26,[31][32][33][34][35] OCs were common with TBI, 17,[19][20][21][22] which is no longer in the NB therapeutic repertoire, but were virtually absent without TBI (see Introduction above). 19,[31][32][33][34][35] Improvements in therapy translate into increasing numbers of NB patients who achieve long-term survival -with a consequent evolution regarding the panoply and incidence of late events. ...
... Yet spinal OCs are in fact rare, which has raised the possibility that vertebral bodies and pedicles may be inherently less predisposed to radiation-related or spontaneous OCs. 41,42 Spinal OCs were noted in two early reports on OCs and local RT, 9,10 but not in others, 6-8 and were not described in reports on toxicities of TBI 13,16,17,[21][22][23] or in other reports with details on sites of OCs. 11,31,33 A dose-response relation between radiation and OC has not been established. ...
BACKGROUND
Osteochondromas are benign bony protrusions that can be spontaneous or associated with radiotherapy (RT). Current treatment of high-risk neuroblastoma includes dose-intensive chemotherapy, local RT, an anti-GD2 monoclonal antibody (MoAb), and isotretinoin. Late effects are emerging.METHODS
The authors examined osteochondromas in 362 patients who were aged <10 years when diagnosed with neuroblastoma, had received a MoAb plus isotretinoin since 2000, and had survived >24 months from the time of the first dose of the MoAb. The incidence rate of osteochondroma was determined using the competing risks approach, in which the primary event was osteochondroma calculated from the date of neuroblastoma diagnosis and the competing event was death without osteochondroma.RESULTSA total of 21 osteochondroma cases were found among 14 patients who were aged 5.7 to 15.3 years (median, 10.4 years) and 3.1 to 11.2 years (median, 8.2 years) from the time of neuroblastoma diagnosis. The cumulative incidence rate was 0.6% at 5 years and 4.9% at 10 years from the neuroblastoma diagnosis. Nine osteochondromas were revealed incidentally during assessments of neuroblastoma disease status or bone age. Thirteen osteochondromas were detected outside RT portals and had characteristics of spontaneous forms. Complications were limited to pain necessitating surgical resection in 3 patients, but follow-up was short at 0.3 to 7.7 years (median, 3.5 years).CONCLUSIONS
Osteochondromas in long-term survivors of neuroblastoma should be expected because these benign growths can be related to RT and these patients undergo radiologic studies over years, are monitored for late toxicities through and beyond adolescence, and receive special attention (because of concerns about disease recurrence) if they develop a bony protuberance. A pathogenic role for chemotherapy, anti-GD2 MoAbs, or isotretinoin remains speculative. Cancer 2015. © 2015 American Cancer Society.
... Osteochondroma is the most common benign bone tumour, occurring as an abnormal osteocartilaginous outgrowth of the epiphyseal growth plate with a low rate ( 2%) of malignant transformation to secondary chondrosarcoma (Mavrogenis et al., 2008). These tumours are usually solitary and non-hereditary and are often triggered by injury, including high-dose irradiation (Taitz et al., 2004). In this study, 'osteochondroma' generally refers to sporadic, solitary osteochondromas. ...
... Defective osteogenic and chondrogenic differentiation has been implicated in osteochondroma and osteosarcoma, respectively. Differentiation is impaired by replicative senescence, although the exact biological process is unknown (Taitz et al., 2004;Wagner et al., 2011). For the growth and maintenance of the skeleton, differentiated progeny, including the osteoblastic, chondrogenic, and adipogenic cell lineages (producing bone, cartilage and fat, respectively), are produced by MSC (Wagner et al., 2011). ...
... Given that this benign bone tumour is usually found incidentally, after the tumour has occurred, the true decline is more gradual than the abrupt decline of the DSR. Notwithstanding, the relative shapes of the DSR and osteochondroma incidence curves fit with observations of a short, but variable, mean latent period of $5 years or less, which can range up to 27 years for radiation-induced tumours (Taitz et al., 2004). Both DSR and osteochondroma incidence rates exhibit no rise with old age. ...
Knudson's carcinogenic model, which simulates incidence rates for retinoblastoma, provides compelling evidence for a two-stage mutational process. However, for more complex cancers, existing multistage models are less convincing. To fill this gap, I hypothesize that neoplasms preferentially arise when stem cell exhaustion creates a short supply of progenitor cells at ages of high proliferative demand. To test this hypothesis, published datasets were employed to model the age distribution of osteochondroma, a benign lesion, and osteosarcoma, a malignant one. The supply of chondrogenic stem-like cells in femur growth plates of children and adolescents was evaluated and compared with the progenitor cell demand of longitudinal bone growth. Similarly, the supply of osteoprogenitor cells from birth to old age was compared with the demands of bone formation. Results show that progenitor cell demand-to-supply ratios are a good risk indicator, exhibiting similar trends to the unimodal and bimodal age distributions of osteochondroma and osteosarcoma, respectively. The hypothesis also helps explain Peto's paradox and the finding that taller individuals are more prone to cancers and have shorter lifespans. The hypothesis was tested, in the manner of Knudson, by its ability to convincingly explain and demonstrate, for the first time, a bone tumour's bimodal age-incidence curve.
... Ionizing radiation is associated with various skel-etal complications, including osteonecrosis, scoliosis, growth retardation, bowing, osteochondromas, and osteosarcoma. [8][9][10][11] Concurrent radiation-induced osteosarcoma and osteochondroma has been reported in the literature, but the incidence is rare. 12 Radiation-induced osteochondroma is a benign osseous excrescence with a cartilaginous cap that occurs in up to 24% of patients irradiated prior to age 5 years. ...
... 12 Radiation-induced osteochondroma is a benign osseous excrescence with a cartilaginous cap that occurs in up to 24% of patients irradiated prior to age 5 years. 8,9 Osteochondromas form by endochondral ossification, with the hyaline cartilage cap functioning as the epiphyseal plate. 1,9 Lesions typically remain stable after skeletal maturity; thus, pain or enlargement after epiphyseal closure may indicate malignant degeneration. ...
... 8,9 Osteochondromas form by endochondral ossification, with the hyaline cartilage cap functioning as the epiphyseal plate. 1,9 Lesions typically remain stable after skeletal maturity; thus, pain or enlargement after epiphyseal closure may indicate malignant degeneration. 1,4 Ostochondromas are 10 times more common in radiationexposed patients, occurring in up to 28% of children irradiated prior to age 3 years. ...
The case: A 61-year-old man presented with a painful right knee. The patient reported instability and restricted motion, which had become progressively worse and painful. AP and lateral radiographs ( Figure ) of the knee are shown.
... Only a few reports are currently available on OC occurrence in cancer survivors [2][3][4]. Most of them are case reports or case series, or refer to selected populations exposed to radiotherapy in whom a high incidence of OC has been reported. ...
... In this analysis also the NB was not found to be a risk factor for OC. Most of the reports on OC after HSCT refer to selected populations (eg, those treated with TBI [2,4] or any type of radiation [6]). These authors reported that younger children (\5 years [2] or \8 years [7]) are at higher risk of radiation-induced OC. ...
... Most of the reports on OC after HSCT refer to selected populations (eg, those treated with TBI [2,4] or any type of radiation [6]). These authors reported that younger children (\5 years [2] or \8 years [7]) are at higher risk of radiation-induced OC. On the other hand, the only other study that included all transplanted children was the 1 by Bordigoni et al. [3], who found autologous transplant to be the only significant risk factor. ...
A retrospective study was conducted among Italian children treated with hematopoietic stem cell transplant (HSCT) to evaluate the incidence and risk factors in the development of osteochondroma (OC). OC occurred in 27 patients who received autologous or allogeneic HSCT. The estimated 5-, 10-, and 15-year cumulative risk of developing OC was 0.5%, 3.2%, and 6.1%, respectively. Analysis of cumulative risk stratified by the various risk factors revealed that male sex (P=.026), autologous HSCT (P=.001), age at HSCT (< or =3 years) (P < .0001), and total body irradiation (TBI) (P <.0001) significantly affected the risk of OC. Multivariate analysis, restricted only to tumor types with at least 1 case of OC, showed that earlier age at HSCT (P =.0004) and TBI (P < .0001) were the only factors that were significantly associated with OC.
... Radiation-induced osteochondromas occur at an incidence of 10% to 12% after radiotherapy and an incidence of 10% to 24% after TBI. [44][45][46][47] Younger children are at greatest risk because of their greater growth potential. Chemotherapy and radiotherapy can arrest growth and cause epiphyses to remain open longer than usual, permitting osteochondromas to develop. ...
... Chemotherapy and radiotherapy can arrest growth and cause epiphyses to remain open longer than usual, permitting osteochondromas to develop. Children receiving GH develop osteochondromas earlier and at a shorter time after transplantation than children not receiving GH. [45][46][47] These data suggest that in this population of children given TBI, use of GH may stimulate radiotherapy-disturbed epiphyses resulting in an increased incidence of osteochondromas. 45,47 GH recipients in the present study developed osteochondromas longer after transplantation but were younger at HCT than the non-GH-treated patients. ...
... Malignant degeneration of the osteochondromas has been rare. 46 All TBI recipients should be monitored carefully for the development of secondary malignancies, including those who develop osteochondromas. None of the children in the present report who have been receiving GH have experienced malignant degeneration related to osteochondroma, and GH therapy has not been discontinued because of the osteochondroma. ...
Growth impairment and growth hormone (GH) deficiency are complications after total body irradiation (TBI) and hematopoietic cell transplantation (HCT). To determine the impact of GH therapy on growth, the final heights of 90 GH-deficient children who underwent fractionated TBI and HCT for malignancy were evaluated. Changes in height standard deviation (SD) from the diagnosis of GH deficiency to the achievement of final height were compared among 42 who did and 48 who did not receive GH therapy. At HCT, GH-treated patients were younger (P = .001), more likely to have undergone central nervous system irradiation (P = .007), and shorter (P = .005) than patients who did not receive GH therapy. After HCT, GH deficiency was diagnosed at 1.5 years (range, 0.8-9.5 years) for GH-treated and 1.2 years (range, 0.9-8.8 years) for nontreated patients. GH therapy was associated with significantly improved final height in children younger than 10 years at HCT (P = .0001), but GH therapy did not impact the growth of older children. Girls (P = .0001) and children diagnosed with acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), or myelodysplastic syndromes (MDS) (compared with acute lymphoblastic leukemia [ALL] or non-Hodgkin lymphoma [NHL]; P = .02) also showed more rapid growth than their counterparts. These data demonstrate that GH therapy improves the final height of young children after fractionated TBI.
... Given our patient's history of a suprasellar pineal germinoma requiring chemotherapy and radiation, the spinal lesion was potentially radiation-induced. Pediatric oncology literature describes osteochondroma growth as a complication of both localized radiation therapy as well as total body irradiation [18]. The proposed pathogenesis is radiative damage to the epiphyseal plate resulting in immature cartilage fragment migration to the epiphysis and periosteal layers. ...
... These cartilage fragments expand during subsequent maturation and ossification. Radiation-induced osteochondromas have been reported in the ulna, tibia, and hands [18][19][20]. To our knowledge, this is the first detailed case report of a spinal osteochondroma in a pediatric patient with previous radiation treatment. ...
Background:
Osteochondromas are the most common benign bone tumor, accounting for 36% of benign bone tumors. Often found within the appendicular skeleton, osteochondromas of the spine are rare, comprising 4% to 7% of primary benign spinal tumors.
Case summary:
We report a case of a solitary lumbar osteochondroma in an 18-year-old male with a history of a suprasellar pineal germinoma treated with combined chemotherapy and radiation. He underwent mass excision and partial laminectomy with the ultrasonic bone scalpel (Misonix, Farmingdale, NY, United States) at the L5 Level without the use of adjuvants. The patient returned to work and full activities without back pain at 3 mo postoperatively.
Conclusion:
Osteochondromas are common tumors of the appendicular skeleton but rarely occur within the spine. This case discussion supplements current osteochondroma literature by describing an unusual presentation of this tumor.
... Osteochondroma is a benign bone tumor composed of bone and a cartilaginous cap, and it is the most common tumor secondary to radiation. The incidence of osteochondroma is approximately 10-12% after local radiation [116] and 5-24% after TBI [88,[117][118][119], with young age (3 years or younger) at the time of transplantation and conditioning with TBI as independent risk factors. Osteochondroma occurs due to disruption of the physis leading to abnormal endochondral ossification [102,120]. ...
... GH therapy may further increase growth of the exostosis and increase the likelihood of osteochondromas becoming symptomatic in patients during GH replacement (Fig. 5) [88,118,119]. Routine radiographic screening to detect osteochondromas is not recommended due to the unnecessary risk from radiation exposure and the lack of cost-effectiveness [88,117], particularly as thorough histories and physical examinations are sufficient for the detection and clinical diagnosis of osteochondromas [88]. Yet, common indications for imaging include rapid increase in size, suspected malignant transformation, worsening or new pain, decreased functionality of the affected limb, or cosmetic considerations [106,107,121]. ...
Skeletal abnormalities are common in children and adolescents diagnosed and treated for a malignancy. The spectrum ranges from mild pain to debilitating osteonecrosis and fractures. In this review, we summarize the impact of cancer therapy on the developing skeleton, provide an update on therapeutic strategies for prevention and treatment, and discuss the most recent advances in musculoskeletal research. Early recognition of skeletal abnormalities and strategies to optimize bone health are essential to prevent long-term skeletal sequelae and diminished quality of life in childhood cancer survivors.
... The occurrence of osteochondroma in patients treated with TBI has already been described by other authors (23,24), with a reported incidence between 20% and 24%, and a median interval after TBI of 4.6 and 7.3 years. Our data suggest that if follow-up is extended beyond 10 years, almost 28% of long-term survivors are diagnosed with this benign bone tumor. ...
... Our data suggest that if follow-up is extended beyond 10 years, almost 28% of long-term survivors are diagnosed with this benign bone tumor. Young age at TBI exposure and autologous transplant have been described as possible risk fac-tors associated with TBI for OS (23,24), and our data confirm that patients below 3 years of age at FTBI have an increased risk for benign tumor. This is probably the result of the more detrimental effect that radiation has on the growing skeleton. ...
To describe long-term late consequences in children who received total body irradiation (TBI) for hematopoietic stem cell transplantation 10 years earlier.
A cohort of 42 children treated with TBI between 1985 and 1993, still alive at least 10 years after fractionated TBI (FTBI), was evaluated. Twenty-five patients received FTBI at 330 cGy/day for 3 days (total dose 990 cGy), whereas 17 children were administered fractions of 200 cGy twice daily for 3 days (total dose 1200 cGy). Twenty-seven patients received autologous and 16 allogeneic hematopoietic stem cell transplantation. Median age at TBI was 6.3 years, and 18.4 years at most recent follow-up.
Cataract was diagnosed in 78% of patients after a median of 5.7 years. Hypothyroidism was detected in 12%, whereas thyroid nodules were observed in 60% of our population after a median interval of 10.2 years. Patients treated with 990 cGy developed thyroid nodules more frequently than those treated with 1200 cGy (p = 0.0002). Thyroid carcinoma was diagnosed in 14% of the total population. Females who received FTBI after menarche more frequently developed temporary ovarian dysfunction than those treated before menarche, but cases of persistent ovarian dysfunction did not differ between the two groups. Indirect signs of germinal testicular dysfunction were detected in 87% of males. Restrictive pulmonary disease was observed in 74% of patients. Osteochondroma was found in 29% of patients after a median interval of 9.2 years. This latter complication appeared more frequently in patients irradiated before the age of 3 years (p < 0.001).
This study shows that late effects that are likely permanent, although not fatal, are frequent in survivors 10 years after TBI. However, some of the side effects observed shortly after TBI either disappeared or remained unchanged without signs of evolution. Monitoring is recommended to pursue secondary prevention strategies and counseling on family planning.
... In a series of 42 patients with Wilm's tumour treated with radiotherapy and a minimum follow-up of 5 years, there was a 4.8% incidence of osteochondromas and a 2.4% incidence of sarcomas [1]. In another series of 58 children who received radiotherapy as part of therapy for bone marrow transplantation, 5 developed osteochondromas and all of these 5 children were less than 5 years of age at the time of radiotherapy with no patient who underwent radiotherapy after 5 years of age developing osteochondromas [2]. There is an average latent period of about 5-8 years before these lesions develop [2,3] and they may be found to be enlarging until normal growth ceases and growth of tumour is maximal at times of patient's growth spurt [4]. ...
... In another series of 58 children who received radiotherapy as part of therapy for bone marrow transplantation, 5 developed osteochondromas and all of these 5 children were less than 5 years of age at the time of radiotherapy with no patient who underwent radiotherapy after 5 years of age developing osteochondromas [2]. There is an average latent period of about 5-8 years before these lesions develop [2,3] and they may be found to be enlarging until normal growth ceases and growth of tumour is maximal at times of patient's growth spurt [4]. Malignant degeneration in radiationinduced osteochondromas is uncommon and the criteria applied to spontaneous lesions such as increase in size of the lesion after epiphyses closure, increasing soft tissue mass and development of pain in the absence of an alternative explanation should be used for these as well [3,5]. ...
... These patients warrant anticipatory guidance regarding balanced nutrition and further monitoring regarding health consequences of abnormal BMI. Musculoskeletal changes are not unexpected in children treated with radiation, including an increased prevalence of osteochondromas [27,28]. Taitz et al. [27] noted the overall risk of osteochondromas to be 24% after TBI, especially when the child was under the age of 5-year at time of treatment. ...
... Musculoskeletal changes are not unexpected in children treated with radiation, including an increased prevalence of osteochondromas [27,28]. Taitz et al. [27] noted the overall risk of osteochondromas to be 24% after TBI, especially when the child was under the age of 5-year at time of treatment. When compared to previous studies, a larger percentage of patients in this study (46%) developed bony changes consistent with osteochondromas [18]. ...
Increasing numbers of children with advanced neuroblastoma are achieving cure. We describe the clinical late effects specific to survivors of stage IV neuroblastoma all similarly treated using tandem autologous peripheral blood stem cell rescue with TBI.
The medical records of 35 neuroblastoma patients treated at CHOP between 1997 and 2001 were examined. Eighteen of the 35 patients died of progressive disease, and 4 were lost to follow-up. Thirteen patients continue to follow-up in our Multidisciplinary Cancer Survivorship Clinic where they are evaluated and monitored by a consistent group of subspecialists that evaluate long-term sequelae. Data on treatment exposures including TBI and treatment related sequelae identified by clinician assessment and/or diagnostic testing were collected.
Results indicate late effects were present in all 13 subjects, 12 of whom suffered from multiple negative sequelae, including issues with growth hormone deficiency, dental problems, osteochondromas and hearing deficiencies, among others, most at higher rates than reported previously.
The findings in this small cohort indicate the need for future prospective studies of this intensive pediatric cancer treatment, and underscore the importance of medical intervention and long-term monitoring of these at-risk subjects to increase overall quality-of-life.
... Young children, treated with local or whole-body irradiation for various pediatric malignancies, may develop, in addition to osteochondromas, soft tissues myxomas and schwannomas. 19 Induction of bone or, more often, soft tissue sarcoma, such as undifferentiated pleiomorphic sarcoma (including formerly diagnosed as fibrosarcoma), angiosarcoma, and osteosarcoma, is one of the most dreaded complications (►Fig. 7). ...
Knowledge of imaging findings related to therapy administered to patients with sarcoma is pivotal in selecting appropriate care for these patients. Imaging studies are performed as surveillance in asymptomatic patients or because symptoms, including anxiety, develop. In addition to detection of recurrent disease and assessment of response to therapy, diagnosis of conditions related to therapy that may or may not need treatment has a marked positive impact on quality of life. The purpose of this review is to assist radiologists, nuclear physicians, and others clinicians involved in the diagnosis and treatment of these patients in recognizing imaging findings related to therapy and not to activity of the previously treated sarcoma. Imaging findings are time dependent and often specific in relation to therapy given.
... More significant cardiotoxicity has been reported in children who receive anthracyclines and radiation therapy, and there is an increased risk for osteochondromas in children exposed to TBI at age o 5 years. 32,33 Similarly, one study of adult and pediatric HSCT recipients found an increase in nevus counts compared to age matched controls only among those age o20 years at HSCT. 17 In addition, studies of mixed age HSCT recipients demonstrate age o 10 years at HSCT and exposure to TBI as risk factors for NMSC. 1,3 These data suggest that the childhood years may represent a time during which 20 44 Abbreviations: HSCT = hematopoietic stem cell transplantation; OR = Odds Ratio. ...
There is a known increased risk of skin cancer in the adult population after hematopoietic stem cell transplantation (HSCT). However, late dermatologic effects that children may experience after HSCT have not been well described. The primary objective of this study was to characterize nevi and skin cancers affecting children after allogeneic HSCT. A cross-sectional cohort study of 85 pediatric HSCT recipients and 85 controls matched for age, sex and skin phototype was performed at a single institution. All participants underwent a full skin examination. Median age at study visit was 13.8 years in HSCT patients with median time post-HSCT of 3.6 years. HSCT patients had significantly more nevi than control patients (median (range): 44 (0-150) vs 11 (0-94), P<0.0001). HSCT patients also had significantly more nevi >5?mm in diameter and atypical nevi than controls. Factors associated with increased nevus count included malignant indication for HSCT, pretransplant chemotherapy, TBI exposure and myeloablative conditioning. A total of 16.5% of HSCT patients developed cancerous, precancerous lesions and/or lentigines. Our study suggests that pediatric HSCT recipients have an increased risk of benign and atypical melanocytic proliferations and nonmelanoma skin cancer that can manifest even during childhood.Bone Marrow Transplantation advance online publication, 3 April 2017; doi:10.1038/bmt.2017.57.
... Osteochondromas are increasingly recognised as a complication of total body irradiation, with children who are irradiated under the age of 5 years at particular risk. 12 Although benign, they are a cause of anxiety. ...
... We saw less osteochondroma than the 24% to 36% reported for FTBI. 15,28,38 Our rate of cGVHD at 2 years (28%) was comparable with that seen in a large study by Zecca et al 39 at 3 years (27%). ...
Single fraction total body irradiation (SFTBI) as part of a myeloablative preparative regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for hematopoietic malignancies was shown to have similar survival compared with fractionated total body irradiation (FTBI)-containing regimens, with less acute toxicity. The objective of this study was to determine long-term toxicity >2 years following SFTBI-based HSCT. Twenty-one patients were evaluated at a median follow-up of 6.8 years. Thyroid dysfunction was found in 21% of patients, 1 of whom (5.2%) was symptomatic; 23% had gonadal failure; 50% of patients with growth potential had linear growth disturbance; 27% had mild to moderate pulmonary disease; and 25% had cataracts. Intelligence quotient was stable. cGVHD was present in 28%, and 4 patients (19%) were on immune suppression 2 years posttransplant. Overall survival subsequent to 2 years posttransplant was 76% in this cohort of patients. No secondary malignancies were observed. In conclusion, the toxicities of SFTBI occurred at similar or reduced frequency compared with FTBI. SFTBI should be considered for patients who may benefit from a radiation-containing HSCT preparative regimen.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivitives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/3.0.
... Exostoses occur in the general population, although the incidence may be underestimated, as many sporadic exostoses cause no symptoms and may go undetected [5]. The incidence in the general population is reported at 1%, with an increase to 10% in those where local irradiation has induced an osseous change [4]. ...
Allogeneic hematopoeitic progenitor cell transplant (HPCT) is a curative therapy for pediatric patients with both malignant and non-malignant diseases. Single or multiple benign exostoses or osteochondromas have been reported following total body irradiation (TBI) as well as focal irradiation. Patients exposed to TBI at a young age are at highest risk of developing exostoses. The objective of this IRB approved study was to look at potential factors besides radiation that may play a role in development of exostoses. All patients who underwent allogeneic and autologous HPCT at a single institution between March 1992 and December 2003 and who developed an exostosis identified by clinical findings or as an incidental finding on a radiologic study were included. A case-control design matched patients with controls who had the same stem cell source.
... These osseous abnormalities are attributed to total body irradiation and include enchondromas, stippled epiphyses, metaphyseal abnormalities, slipped capital femoral epiphyses, and osteochondromas (71). A higher incidence of osteochondromas and other skeletal abnormalities is reported in younger children (72,73). There have been reports of radiation-induced malignant exostoses and at least one report of simultaneous osteochondroma and osteosarcoma after HSCT (74). ...
The use of hematopoietic stem cell transplantation (HSCT) in the treatment of children afflicted with many potentially fatal malignant and nonmalignant diseases is well recognized. Although outcomes continue to improve and the utility of HSCT is increasing, HSCT remains a complicated process necessitating support from many medical disciplines, including radiology. Importantly, children who undergo HSCT are at risk for the development of specific complications that are linked to the timeline of transplantation, as well as to the relationship between the underlying diagnoses, severe immune deficiency, cytoreductive regimen, and graft-versus-host reactions. An understanding of the complex interplay of the immune status, therapeutic regimen, and disease allows increased diagnostic accuracy. Successful treatment of these high-risk children requires that radiologists who are involved with their care be familiar with broad concepts, as well as with specific problems that frequently occur following HSCT. In this article, the clinical aspects of pediatric HSCT are summarized, including common complications, and imaging features of these complications are described.
... Pubertal failure has been a significant problem among our cohort and has been noted in NB survivors 24 and recipients of fractioned TBI for transplant conditioning. 34 Previously, we and others have reported osteochondromas arising in patients following ASCT for high-risk NB. 35,36 Since our previous report of 20 Although the post-transplant relapse rate is reduced in patients with responsive disease compared to historical series, 1-3,5 the overall burden of therapy is high and the range of toxicities in long-term survivors excessive. We believe that TBI is a major contributor to their genesis. ...
We retrospectively analysed the outcomes of children transplanted for high-risk neuroblastoma (NB) at a single institution predominantly transplanted with total body irradiation and chemotherapy. The aims of this study were to determine the prognostic impact of clinical and biological features and to document long-term health outcomes. Forty patients were transplanted with a single unpurged autograft. Fourteen patients died from disease progression and two from late complications of treatment. Twenty-three patients are alive at a median of 4.6 years from diagnosis. Kaplan-Meier estimates of overall survival at 2, 5 and 10 years are 76+/-7.0, 60.2+/-8.4 and 54.7+/-9.3% following transplant. Response to induction therapy was significantly associated with survival (P<0.01). Long-term complications included growth (100%) and pubertal failure (83%), hearing impairment (73%), orthopaedic complications (63%), renal impairment (47%) and thyroid abnormalities (36%). Intrinsic and acquired resistance to chemotherapy remains the major obstacle to improving outcomes in high-risk NB. Although patients with chemo-sensitive disease are less likely to experience a relapse, substantial therapy-related toxicities result in poor long-term health outcomes for survivors.
Silverberg's Principles and Practice of Surgical Pathology and Cytopathology is one of the most durable reference texts in pathology. Thoroughly revised and updated, this state-of-the-art new edition encompasses the entire fields of surgical pathology and cytopathology in a single source. Its practice-oriented format uniquely integrates these disciplines to present all the relevant features of a particular lesion, side by side. Over 4000 color images depict clinical features, morphological attributes, histochemical and immunohistochemical findings, and molecular characteristics of all lesions included. This edition features new highly experienced and academically accomplished editors, while chapters are written by the leading experts in the field (several new to this edition, bringing a fresh approach). Dr Steven Silverberg's practical approach to problem solving has been carefully preserved. The print book is packaged with access to a secure, electronic copy of the book, providing quick and easy access to its wealth of text and images.
Osteochondromas are bone lesions composed of medullary and cartilaginous bone covered by a cap of hyaline cartilage. The presence of medullary and cortical bone with the continuity of the tumor is pathognomonic for osteochondroma and aid in establishing the diagnosis.
We report a case of a two-year-old girl who presented to our clinic following her mother noticing a palpable, growing, and painful mass on her left scapula. There was no limitation in the range of motion. A clear-cut mass was seen on the dorsal aspect and palpated measuring around 2.5x3 cm. Surgical excision of the mass followed by histologic examination confirmed osteochondroma. Upon follow-up, the patient had no pain and had a full range of left shoulder motion without discomfort or pain.
In conclusion, scapular exostoses are very rare and more so when they present dorsally. Symptomatic lesions can be managed effectively with surgical excision of exostosis.
Background
Neuroblastoma is the most common extracranial solid tumor in children. Those with high-risk disease are treated with multimodal therapy, including high-dose chemotherapy, stem cell transplant, radiation, and immunotherapy that have led to multiple long-term complications in survivors. In the late 1990s, consolidation therapy involved myeloablative conditioning including total body irradiation (TBI) with autologous stem cell rescue. Recognizing the significant long-term toxicities of exposure to TBI, more contemporary treatment protocols have removed this from conditioning regimens. This study examines an expanded cohort of 48 high-risk neuroblastoma patients to identify differences in the late effect profiles for those treated with TBI and those treated without TBI.
Procedure
Data on the study cohort were collected from clinic charts, provider documentation in the electronic medical record of visits to survivorship clinic, including all subspecialists, and ancillary reports of laboratory and diagnostic tests done as part of risk-based screening at each visit.
Results
All 48 survivors of BMT for high-risk neuroblastoma had numerous late effects of therapy, with 73% having between five and 10 late effects. TBI impacted some late effects significantly, including growth hormone deficiency (GHD), bone outcomes, and cataracts.
Conclusion
Although high-risk neuroblastoma survivors treated with TBI have significant late effects, those treated without TBI also continue to have significant morbidity related to high-dose chemotherapy and local radiation. A multidisciplinary care team assists in providing comprehensive care to those survivors who are at highest risk for significant late effects.
More than half a million hematopoietic cell transplant (HCT) survivors are estimated by 2030 due to improvements in human leukocyte antigen‐typing and supportive care. Children's Oncology Group, provides more granular long‐term follow‐up (LTFU) guidelines specifically for survivors of childhood, adolescent, and young adult cancers but not exclusive to HCT survivors. Peripheral neuropathy can be a chief complaint for some survivors and etiologies frequently include pre‐HCT neurotoxic chemotherapies like vincristine, platinum agents, or brentuximab, and posttransplant calcineurin inhibitor therapy can exacerbate. Certain heritable pediatric conditions have an increased risk for solid tumors independent of HCT that warrant subsequent neoplasms screening beyond the usual and might require relevant organ‐specific subspecialist consultation. Survivorship care plan usage appears to improve quality of life among HCT survivors. There is much more work to be done to optimize LTFU particularly for pediatric HCT survivors who are more prone to becoming lost to follow‐up.
Total body irradiation (TBI) is commonly used in conditioning regimens for allogeneic hematopoietic stem cell transplantation (HSCT) to treat benign and malignant disease. Though life-saving, these therapies place patients at risk for important side effects, including musculoskeletal complications such as short stature, osteonecrosis, slipped capital femoral epiphysis, and the development of benign and malignant bone tumors. With an increasing number of HSCT survivors, there is a growing need for awareness of the musculoskeletal complications of HSCT and TBI.
Chronische pijnpatiënten vormen een heterogene populatie. Het mag duidelijk zijn dat niet alle chronische pijnpatiënten per definitie een klinisch beeld hebben dat gedomineerd wordt door centrale sensitisatie. Bij medische diagnosen zoals whiplash, fibromyalgie, prikkelbaredarmsyndroom en het chronischevermoeidheidssyndroom, vertonen patiënten typisch dominante centrale sensitisatiepijn. Bij atraumatische chronische nekpijn is er echter weinig tot geen bewijs voor de aanwezigheid van centrale sensitisatie. Patiënten met artrose, tenniselleboog, schouderpijn en lage rugpijn zijn groepen pijnpatiënten waarvan de minderheid een klinisch beeld vertoont dat gedomineerd wordt door centrale sensitisatie. Daarom is goede differentiaaldiagnostiek noodzakelijk.
In dit hoofdstuk reiken we de clinicus praktijkrichtlijnen aan voor de differentiaaldiagnostiek tussen de drie grote pijntypen: dominant nociceptieve, neuropathische en centrale sensitisatiepijn. De klinische werkmethode voor de differentiaaldiagnostiek tussen dominant nociceptieve, neuropathische en centrale sensitisatiepijn bestaat uit twee stappen:1.
de diagnostiek of uitsluiting van de aanwezigheid van dominant neuropathische pijn;
2.
de differentiaaldiagnostiek tussen dominant nociceptieve en centrale sensitisatiepijn.
Stap 2 omvat het screenen van drie criteria aan de hand van een beslisboom.
In het laatste deel van het hoofdstuk worden deze criteria toegepast op en gespecificeerd voor (1) de lage rugpijnpopulatie en (2) pijn bij/na kanker.
The quality of life (QOL) of pediatric patients that undergo stem cell transplantation (SCT) and the late effects they experience have become more important issues because of improvements in the survival of such patients. The late effects seen in such cases were attributed to 2 major causes: conditioning treatment and chronic graft-versus-host disease (GVHD). More than 40% of the surviving SCT-treated patients were underweight and of short stature, which was twice as high as the equivalent value for the no SCT group. Late effects were observed in 78% of the patients in the SCT group and 45% of those in the no SCT group. Lung toxicity was found to be a common cause of morbidity and mortality after SCT. Many of the children that underwent SCT developed endocrinological dysfunction, including growth hormone and thyroid hormone deficiencies, and gonadal damage and infertility occurred frequently after myeloablative SCT. Persistent secondary immunodeficiency was observed in all of the children with SCT; therefore, post-transplantation re-immunization is indispensable in such patients. The cumulative probability of secondary solid tumors increases after SCT, and the incidence of such tumors is associated with chronic GVHD and radiotherapy. The number of studies examining the QOL of pediatric survivors of SCT is growing. The results of the present study confirm that children that receive SCT should undergo long-term follow-up.
Hematopoietic stem cell transplant (HSCT) is increasingly used for the treatment of both malignancies and nonmalignant diseases. This has been made possible by several factors, including expansion of the unrelated donor pool, advances in mobilization and collection of autologous cells, and reduced intensity conditioning regimens. Although transplant-related mortality and relapse remain obstacles, an increasing number of children are surviving following HSCT. Both the HSCT antecedent therapy and the posttransplant complications have multisystem effects, and understanding and anticipating these are important in caring for the children affected. This chapter will provide a brief overview, as many of these complications are discussed in more depth in other chapters of this book.
Das Kapitel umfasst eine ausführliche Darstellung der Tumoren des Skelettsystems, wobei nahezu alle in der aktuellen WHO-Klassifikation erfassten Entitäten in Bezug auf Pathogenese, Epidemiologie und Manifestationsalter, Lokalisation und Symptomatik, Morphologie, Verlauf und Differentialdiagnose abgehandelt werden. Besonderes Augenmerk wird darauf gelegt, die Zusammenhänge zwischen den bildgebenden Befunden (Röntgenbild, Schnittbildgebung) und den pathologisch-anatomischen Befunden zu verdeutlichen. Auch die differentialdiagnostischen Erörterungen gehen neben den morphologischen Befunden auf die Zusammenhänge zu Bildgebung, Lokalisation und Manifestationsalter ein.
Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for various malignant and nonmalignant diseases. Improvement of HSCT in children has resulted in many long-term survivors with substantial long-term morbidities. Endocrine complications are most frequently observed as late effects in HSCT recipients. Growth failure, pubertal disorders, thyroid dysfunctions, obesity, metabolic syndrome and bone loss are usually encountered after HSCT in children, while infertility is an important problem in adulthood. Patient age at HSCT, characteristics of primary diseases, intervention duration, preparative conditioning regimens, dose of irradiation and specificity of chemotherapeutic agents affect the prevalence of endocrine late effects. Awareness of endocrine late effects of HSCT and close follow-up of patients would help to increase the quality of health of patients.
A relationship has been reported between total body irradiation (TBI) and later development of osteochondromas in children who receive radiation therapy as conditioning before hematopoietic stem cell transplantation (HSCT). The goal of this study was to better characterize osteochondromas occurring in these children.
We identified all children (0 to 18 y) who received an allogeneic HSCT and TBI from 2000 to 2012 from a blood and marrow transplant (BMT) database. Thereafter, we identified those who developed osteochondromas through a chart review. In addition, we searched for diagnosis and operative codes from 1996 to 2012 in our pediatric orthopaedic clinical records, isolating osteochondroma patients with a history of radiation exposure.
Four patients who underwent allogeneic HSCT and were later diagnosed with osteochondromas were identified from the BMT database (N=233 children); all 4 were among a group of 72 patients who received TBI. Three patients were identified from orthopaedic records. The cohort included 5 boys and 2 girls with acute lymphoblastic leukemia (N=5) or neuroblastoma (N=2), diagnosed at a median age of 2.0 years. Therapy for all patients included chemotherapy, radiation therapy (TBI, N=5; abdominal, N=2), and HSCT. A diagnosis of osteochondroma was made at a median age of 11.7 years (range, 5 to 16 y), on average 8.6 years after radiation therapy. Diagnosis was incidental in 2 patients and secondary to symptoms (pain or genu valgum) in 5. Locations of osteochondromas were the proximal tibia (N=3), distal tibia, distal femur, distal ulna, and the distal phalanx (N=1 each). Three patients underwent surgical resection.
Children may be more likely to develop osteochondromas after early exposure to radiation therapy, which may cause pain and require surgical resection. To the best of our knowledge, this is the first reported case of a radiation-induced osteochondroma causing lower extremity malalignment. Patients typically present to the pediatric orthopaedist's attention when symptomatic, but there may be an expanded role for counseling for potential for long-term skeletal effects in this group.
Level IV, case series.
Zusammenfassung Das solitäre Osteochondrom der Skapula kommt sehr selten vor, weshalb es bei dieser atypischen Lokalisation mit diffuser Schmerzhaftigkeit der Schulter häufig erst nach Jahren diagnostiziert wird. Wir berichten über einen 35-jährigen Patienten mit einem solitären Osteochondrom an der Skapula, der seit 4 Jahren diffuse Beschwerden in der Schulter-Hals-Region hatte. Im Rahmen einer Lungen-Übersichtsaufnahme vor 2 Jahren wurde eine Raumforderung im Bereich des linken Thorax diagnostiziert. CT- und MRT-Untersuchungen erbrachten den Verdacht auf ein solitäres Osteochondrom der Skapula. Aufgrund zunehmender Beschwerden wurde die Exzision durchgeführt.
Malignant degeneration arising in radiation-induced osteochondromas is extremely rare. We report a case of a 34-year-old man with a chondrosarcoma arising from an osteochondroma of the left posterior eighth rib that developed following total body irradiation received as part of the conditioning regimen prior to bone marrow transplantation at age 8. To our knowledge, this is only the fourth reported case of a chondrosarcoma arising within a radiation-induced osteochondroma and the first case occurring following childhood total body irradiation.
Background
Children undergoing total body irradiation (TBI) often develop delayed skeletal complications. Bone-age studies in these children often reveal subtle paraphyseal changes including physeal widening, metaphyseal irregularity and paraphyseal exostoses.
Objective
To investigate whether paraphyseal changes on a bone-age study following TBI indicate a predisposition toward developing other radiation-associated skeletal complications.
Materials and methods
We retrospectively reviewed medical records and bone-age studies of 77 children receiving TBI at our institution between 1995 and 2008 who had at least 2 years of clinical follow-up and one bone-age study after TBI. We graded bone-age studies according to the severity of paraphyseal changes. All documented skeletal complications following TBI were tabulated. Kendall’s tau-b was used to examine associations between degree of paraphyseal change and development of a skeletal complication.
Results
Kendall’s tau analyses showed that physeal widening and metaphyseal irregularity/sclerosis (tau = 0.87, P < 0.001) and paraphyseal exostoses (tau = 0.68, P < 0.001) seen on bone-age studies were significantly positively associated with the development of delayed skeletal complications following TBI. Thirty percent of children with no or mild paraphyseal changes developed a delayed skeletal complication, compared with 58% of children with moderate paraphyseal changes and 90% of children with severe paraphyseal changes.
Conclusion
Paraphyseal changes identified on a bone-age study correlate positively with the development of delayed skeletal complications elsewhere in the skeleton following TBI.
Benign cartilage tumours of bone are the most common benign primary bone tumours and include osteochondroma, (en)chondroma, periosteal chondroma, chondroblastoma and chondromyxoid fibroma. These neoplasms often demonstrate typical imaging features, which in conjunction with lesion location and clinical history, often allow an accurate diagnosis. The aim of this article is to review the clinical and imaging features of benign cartilage neoplasms of bone, as well as the complications of these lesions.
Beenmergtransplantatie heeft zich in de afgelopen decennia ontwikkeld van een experimentele techniek tot een gangbare behandeling
voor tal van ernstige, vaak levensbedreigende ziektes. Met het toenemen van het aantal overlevenden na hemopoëtische-stamceltransplantatie
(hsct) op de kinderleeftijd komen ook de late effecten van deze behandeling aan het licht. De meeste ex-patiënten die als kindhsct ondergingen, hebben één of meer late effecten. De brede scala van late effecten nahsct wordt in dit hoofdstuk besproken. Een deel van deze late effecten is, ten minste aanvankelijk, subklinisch. Voor de huisarts
is het van belang alert te zijn op het hoge risico van hormonale uitval, met name na totale lichaamsbestraling (tbi). Daarnaast is subfertiliteit/infertiliteit een probleem waarmee de meeste overlevenden geconfronteerd worden. Ook is voor
de huisarts van belang te weten dat er in deze patiëntengroep een sterk verhoogd risico is op secundaire maligniteiten, dat
bovendien toeneemt met de termijn na transplantatie. Opvallend is dat ondanks de hoge prevalentie en ernst van late effecten
nahsct de kwaliteit van leven door de meeste overlevenden als goed ervaren wordt.beenmergtransplantatie, late effecten na
langetermijneffecten
kinderkanker, overlevenden van
follow-up, langdurige
hormonale uitval
lichaamsbestraling, totale
beenmergtransplantatie
Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancies that arise within bone marrow precursors
of the myeloid, monocyte, erythroid, and megakaryocytic lineages (Pizzo and Poplack 2005). It comprises between 15% and 20%
of all leukemias occurring during childhood. The incidence of new cases varies during childhood by year of age; the highest
incidence is in early childhood, with about 12 cases per million in children up to age 2, declining steadily thereafter to
its lowest incidence of about 4 per million at age 9, then climbing again during adolescence (Fig. 10.1). AML affects male
and female children and black and white children in the US about equally (Ries and Smith 1999). Survival after AML (5-year
relative survival) has increased steadily in the US over the period 1975–2005, from a rate of 18.8% in 1975–1977 to 60.2%
in the period 1999–2005 for children diagnosed from 0 to 14 years of age (Fig. 10.2). It is likely that the growth and refinement
of allogeneic hematopoietic stem cell transplant (HSCT) from related and unrelated donors since the 1970s has contributed
to this improvement. However, survival after AML still lags considerably behind acute lymphoblastic leukemia (ALL), for which
survival had reached 89.0% in the interval 1999–2005 (Ries and Smith 1999). Again in contrast to ALL, survival after AML was
slightly better for females than for males with AML, but there were no detectable differences between blacks and whites (Ries
and Smith 1999). Within Europe from 1988 to 1997, regional differences in survival after AML in children were pronounced from
North to East, where survival was significantly poorer.
The occurrence of osteochondroma after total body irradiation (TBI) followed by stem cell transplantation (SCT) in our institutions was described, and its clinical significance discussed. Of 305 cases treated with SCT using TBI conditioning from 1980 to 2001, 4 cases of osteochondroma were identified on clinical examination. Mean age at the time of TBI was 4.4 years (range, 1.6 to 8.0). One patient developed multiple osteochondromas. All 4 cases showed metaphyseal abnormalities, including sclerotic metaphyseal lesion, fraying, and longitudinal striation, in the area where osteochondromas occurred. Only 1 patient required resection of the tumor due to pain. Two cases had other skeletal abnormalities including slipped capital femoral epiphysis and valgus-knee deformity, which required surgical intervention to prevent or correct these deformities. Osteochondroma is one of the complications developing after TBI, possibly concurrently with the metaphyseal abnormalities as seen on radiographs. However, clinical problems arising from osteochondroma are minimal, and surgical intervention is necessary in limited cases.
To the Editor: A 9-year-old boy received the diagnosis of acute biphenotypic leukemia. Once remission was induced, treatment proceeded to bone marrow transplantation with donation from the child's HLA-identical sister. The patient received total-body irradiation consisting of four fractions of 300 cGy for a total dose of 1200 cGy. The patient did well initially, but at the age of 14 years, the leukemia relapsed. At the staging workup, he was found to have bilateral osteochondromas, benign tumors composed of bone projecting from endochondral bones, in the iliac wings. On the right side, one lesion had posterior projection, and on the . . .
Benign cartilaginous tumors of bones, intrinsic to their name, are tumors forming cartilaginous matrix with a clinically benign behavior. In this group, we recognize osteochondromas, (en)chondromas, chondroblastomas, and chondromyxoid fibromas. This group includes common tumors, that is, osteochondroma and (en)chondroma as well as rare tumors such as chondroblastoma and chondromyxoid fibroma. Several benign and malignant tumors may mimic benign cartilaginous tumors of bones. We reviewed the main morphologic features and the differential diagnosis is discussed. The genetics of these tumors is intriguing ranging from single gene event (ie, EXT mutation in multiple osteochondromas) to heterogeneous rearrangements with no recurrent involved chromosomal regions such as in chondroblastoma. The main genetic findings are hereby reviewed.
Solitary osteochondroma of the scapula is rare. Because of the atypical location with unspecific shoulder pain, the diagnosis is often made late. We present a 35 year old patient with a solitary ostochondroma of the scapula with unspecific pain of the shoulder-neck region over about 4 years. In a thorax x-ray 2 years ago, a tumor like lesion was found. CT and MRI scan led to suspicion of a solitary osteochondroma of the scapula. Because of progressive thoracic pressure pain, a wide excision was made. The problems of diagnosis and therapy are presented and the literature is discussed.
This study was conducted to determine the outcome of patients who develop a second neoplasm after radiotherapy (RT) for a childhood solid tumor. From 1956 to 1998, 429 children with a malignant solid tumor were treated at a single radiation oncology facility. The medical records and radiotherapy charts were reviewed to determine if the patient developed a secondary neoplasm after treatment for malignancy. Twenty-three (5.4%) patients developed a secondary neoplasm. There were 12 males and 11 females with a median age at RT of 6.6 years (range, 2 months to 20 years). There were 14 malignant neoplasms in 13 (3.0%) and 14 benign neoplasms in 11 patients (2.6%). The types of initial solid tumors treated with RT were Ewing sarcoma in 6, Wilms tumor in 6, medulloblastoma in 5, neuroblastoma in 3, and other in 3. Median RT dose was 45 Gy (range, 12.3 to 60 Gy) using 4 MV in 9, 1.25 MV in 8, 250 KV in 4, and 6 MV photons in 1 patient. One child was treated using 15-MeV electrons. Fourteen had chemotherapy. Median follow-up was 23.2 years (range, 5.3 to 44.4 years). For the 14 malignant neoplasms, the median time interval from initial tumor to second malignancy was 10.1 years. The 14 second malignant neoplasms (SMN) were osteosarcoma in 3, breast carcinoma in 2, melanoma in 2, malignant fibrous histiocytoma in 1, dermatofibrosarcoma in 1, leiomyosarcoma in 1, mucoepidermoid carcinoma in 1, colon cancer in 1, chronic myelogenous leukemia in 1, and basal cell carcinoma in 1. Ten of the 14 SMN (71%) were at the edge or inside the RT field. The 5- and 10-year overall survival rate after diagnosis of an SMN was 69.2%; it was 70% for children with a SMN at the edge or inside the RT field and 66.7% for those outside of the RT field. The 14 benign neoplasms appeared at a median time of 16.9 years and included cervical intraepithelial neoplasia in 3, osteochondroma in 3, thyroid adenoma in 1, duodenal adenoma in 1, lipoma in 1, cherry angioma in 1, uterine leiomyoma in 1, ovarian cystadenofibroma in 1, and giant cell tumor in 1. Only 5 (36%) of the 14 benign tumors occurred in the RT field, with osteochondroma being the most common. Of 189 deaths occurring in 429 patients, only 3 (1.6%) were secondary to radiation-induced malignancy. Not all SMN in children receiving RT occur in the irradiated field. More than two-thirds of children with a radiation-induced malignancy are alive 10 years after the diagnosis of a SMN.
The deleterious effects of X-rays on bone have been recognised for almost a century and continue to be seen today because of improved survival in patients treated for malignancy with radiotherapy with or without other treatments. In this pictorial review we present the imaging features of radiation damage to bone highlighting the differences seen in the immature skeleton and post-skeletal fusion. In the former, damage is greatest to the physis resulting in growth disturbances. In the mature skeleton there is a spectrum of changes from mild osteopenia, through disordered attempts at healing with varying degrees of sclerosis, radionecrosis which may lead to acute fractures following minimal trauma and insufficiency fractures both with refractory healing to the dreaded complication of sarcomatous transformation. The imaging appearances are illustrated and the features that help distinguish malignant change from other complications stressed.
For over five decades, osteochondromas (exostoses) and associated growth retardation have been known to be caused by radiation damage to the growing skeleton. Patients can be divided into three exposure groups. Group I received external beam radiation therapy primarily for the treatment of childhood cancers (typical dose 3,500 cGy), and 6-20% developed osteochondromas and growth retardation within the radiation portal. Group II consists of recently described patients who received total body irradiation in preparation for bone marrow transplant (typical dose: 800-1,200 cGy), and about 20% developed osteochondromas and growth retardation. Group III consists of 206 German children who in the 1940s and early 1950s received intravenous radioactive Peteosthor (Ra-224) to treat bone tuberculosis (estimated typical dose: 1,000-2,000 cGy), and 14% developed osteochondromas and growth retardation, among other benign and malignant sequelae. Combining these three exposure groups, osteochondromas and growth retardation develop in at least 6-20% of children who receive therapeutic radiation to their growing skeletons.
In January 1997 we introduced a protocol for the treatment with GH of children with impaired growth after unfractionated total body irradiation (TBI). This study is an evaluation of that protocol.
Between January 1997 and July 2005, 66 patients (48 male) treated for haematological malignancies had at least two years of disease-free survival after TBI-based conditioning for stem cell transplantation (SCT). Stimulated and/or spontaneous GH secretion was decreased in 8 of the 29 patients tested because of impaired growth. Treatment with GH (daily dose 1.3 mg/m2 body surface area) was offered to all 29 patients and initiated in 23 of them (17 male). The main outcome measure was the effect of GH therapy on height standard deviation scores (SDS) after onset of GH therapy, estimated by random-effect modelling with corrections for sex, age at time of SCT and puberty (data analysed on intention-to-treat basis).
At time of analysis, median duration of therapy was 3.2 years; median follow-up after start of GH therapy was 4.2 years. The estimated effect of GH therapy, modelled as nonlinear (logit) curve, was +1.1 SD after 5 years. Response to GH therapy did not correlate to GH secretion status.
GH therapy has a positive effect on height SDS after TBI, irrespective of GH secretion status.
Childhood cancer survivors are a growing population with special medical needs. It is projected that 66% of these survivors will have at least 1 adverse health effect and 33% will have a severe, chronic, or lethal health disorder. The Institute of Medicine (2003) has recognized the skeletal system to be at risk for long-term complications from treatment for childhood cancer. Bone marrow transplant is frequently used to treat childhood malignancies and is known to cause skeletal complications. Complex mechanisms contribute to skeletal outcomes after bone marrow transplant, all of which can affect optimal physical functioning. Nurses have taken an important role in providing clinical care and conducting research for this population. A thorough understanding of the mechanisms involved in skeletal complications can help the nurse provide state-of-the-art care and design studies to promote optimal results for bone marrow transplant survivors. This article reviews the literature on skeletal complications associated with allogeneic bone marrow transplant and identifies incidence, etiology, symptoms, monitoring, and treatment of specific complications.
From the records of Memorial Hospital of the past 50 years, 47 cases with an established diagnosis of radiation-induced sarcoma were identified and divided into two groups: the first included 20 cases of soft-tissue sarcoma arising from irradiated tissues, and the second comprised 27 cases of bone sarcoma arising from normal bones in the irradiated field. Medians for the latent periods from irradiation to diagnosis of bone and soft-tissue sarcoma were 11 and 12, years, respectively. In bone sarcomas, the latent period was longer after larger radiation doses and children appeared to be more susceptible to cancer induction than adults. Criteria for establishing the diagnosis of radiation-induced sarcoma and the magnitude of the risk of bone sarcoma are discussed.
Results of a study of the effects of external irradiation on growing bone conducted at Stanford University School of Medicine are presented together with a review of the literature. Standing and sitting heights of 29 children receiving more than 3,500 rads of megavoltage radiation to the spine and 15 children receiving less than 2,500 rads were compared with those of 15,000 normal children. Retardation of spinal growth was seen in children irradiated during the periods of most active bone growth, i.e., under 6 years of age and during puberty. Correlative radiographic findings similar to those seen with orthovoltage therapy were seen in the high-dose group but not in the low-dose group.
Skeletal aberrations may develop in patients who survive childhood tumors treated with radiotherapy. In our series of fifty-one children with Wilms' tumor and forty-six with neuroblastoma, nineteen and thirteen, respectively, survived after surgical and radiation therapy. Of these, twenty-eight patients were available for critical follow-up study three to twenty-four years after treatment. In addition, three other patients treated for retinoblastoma, a hemangiolymphangioma of the lower extremity, and a hemangioma of the wrist, respectively, are included in this study because of interesting skeletal changes following irradiation.
The skeletal sequelae observed were changes in the vertebral bodies, scoliosis, hypoplasia of the ilium and rib cage, osteocartilaginous exostoses, epiphyseal destruction with limb-length discrepancy and deformity, and postirradiation sarcoma. These complications of radiotherapy were related to the age of the patient, the nature of the primary disease, and the amount and quality of the radiation administered.
Because of such changes, it is our belief that all children treated with radiation should be followed carefully during their skeletal growth.
Finally, it must be re-emphasized that these injurious effects should not obscure the significant role that radiotherapy played in the survival of these patients.
In this paper the author examines the biological and physical mechanisms involved in growth impairment due to radiotherapy, and assesses the degree of disability to be expected following radiotherapy in childhood.
The experimental literature is reviewed with special regard to the effect of radiation on young bone. Sensitivity is found to be more marked the younger the subject and the more actively growing the tissue irradiated. Developmental impairment of an irradiated bone is symmetrical after uniform irradiation in the absence of mechanical strain: asymmetrical irradiation and uneven stress give rise to uneven growth. There is some evidence that bone growth is more seriously impaired by lower than by higher voltage irradiation.
The records of the Liverpool Regional Radiotherapy Service have been analysed: 35 patients irradiated in childhood have been examined. Developmental impairment of muscle and fat is as conspicuous as that of bone: it is argued that maldevelopment of these tissues is probably due to a fundamental effect of radiation on the growing cell rather than to radiation fibrosis. The effect of X-rays on breast and tooth development is noted. Clinical observation supports the experimental evidence that the effect of radiation on bone is greater for younger subjects and for lower voltage radiations.
Although many of the Liverpool patients show obvious growth impairment, none shows any marked degree of functional incapacity, although it is thought that uneven bone growth with resulting abnormal joint planes may predispose some patients to osteoarthritis. Obviously when treating children with radium and X-rays every effort should be made to protect such important and sensitive structures as the breast and epiphyses. But, when radiotherapy is life-saving, some degree of deformity may be the price of survival.
We reviewed the cases of twenty-four patients with solitary or multiple exostoses to correlate their radiographic, scintigraphic, and histological evaluations. We studied twenty-five excised lesions, two of them exostotic chondrosarcomas, from twenty-two patients. There were two patterns of bone-scan activity and there was a direct correlation between enchondral bone formation and radionuclide uptake in all patients, both skeletally immature and mature. So-called quiescent lesions--those with inactive scans--were those that lacked histological evidence of enchondral bone formation. Those with increased uptake--active exostoses--all demonstrated active formation of enchondral bone. Evidence of active exostotic growth could be demonstrated on bone scans well beyond the time of skeletal maturity. The bone scan did not qualitatively differentiate the benign active exostoses from the two lesions with malignant degeneration. Increased uptake related to enchondral bone formation was a feature of both. An inactive scan, however, seemed to exclude the possibility of malignant degeneration in the exostosis.
Radiation-induced osteochondromas, either single or multiple, occur more commonly than is generally recognized. The incidence following irradiation for childhood malignancy is approximately 12%. Any open epiphysis is vulnerable. Age at irradiation, time of appearance following therapy, dose and type of radiation, and clinical course in 14 cases are discussed. Due to growth of the lesion and/or pain, 3 tumors were excised. None revealed malignant degeneration.
Secondary chondrosarcomas are rare. An analysis of 75 cases of chondrosarcomas secondary to osteochondroma (42 lesions were from the Mayo Clinic files and 33 were from consultation files) revealed that 40 of the patients had single exostosis and 35 had multiple lesions. More males than females were affected, and most of the patients were age 20 to 40 years. The tumors involved various bones. Malignant change was manifested radiologically by fuzzy margins of the cartilage cap and by the presence of lucent zones within the lesion. Grossly, the surface of the thickened cartilage cap is irregular. Microscopically, most of the tumors were well-differentiated (Grade 1). Treatment was surgical. Simple excision of the tumor resulted in a large recurrence rate. Resection and amputation were generally curative. Only 12 of the patients have died of their tumor. Most patients died of local recurrence. Only two of the 75 patients had definite evidence of metastatic disease.
The study was undertaken to determine the incidence of second malignant neoplasms (SMNs) in patients treated for Wilms' tumor and demonstrate how the incidence varied with the initial treatment protocol.
Between October 1969 and December 1991, 5,278 assessable patients were enrolled onto the National Wilms' Tumor Study (NWTS) and by the end of 1993 had contributed 39,461 person-years to a follow-up study. Expected numbers of second cancers were calculated by applying national incidence rates to person-years classified by age, sex, and calendar year.
Forty-three SMNs were observed, whereas only 5.1 were expected (standardized incidence ratio [SIR], 8.4; 95% confidence interval [CI], 6.1 to 11.4). Fifteen years after the Wilms' tumor diagnosis, the cumulative incidence of a SMN was 1.6% and increasing steadily. Abdominal irradiation received as part of the initial therapy increased the risk of a SMN (SIR, 1.43/10 Gy; 95% CI, 1.13 to 1.81). Doxorubicin potentiated the radiation effect. Among 234 patients who received doxorubicin and greater than 35 Gy of abdominal radiation, eight SMNs were observed, whereas only 0.22 were expected (SIR, 36; 95% CI, 16 to 72). Treatment for relapse further increased the SMN risk by a factor of 4 to 5.
These results demonstrate the importance of current efforts to limit the use of intensive chemotherapy and radiation therapy, which are now applied only to patients with the most aggressive disease. Continuing close surveillance of the great majority of Wilms' tumor patients who become long-term survivors is essential for early diagnosis of SMNs and other late sequelae of therapy.
To identify bone abnormalities related to total-body irradiation (TBI) in long-term survivors of bone marrow transplantation (BMT) for childhood leukemia.
The authors obtained skeletal surveys of 10 survivors of childhood leukemia, ages 5-27 years, who had undergone BMT 7-9 years previously. Pretransplantation "conditioning" regimens were composed of chemotherapy and TBI in doses of 12 or 14.4 Gy.
Of the six survivors who received TBI before age 8 years, five had osteochondromas and three had metaphyseal growth abnormalities. One also had slipped femoral capital epiphysis. Findings in the four remaining patients, who received TBI at ages 12-19 years, were less severe and less clearly related to TBI (mild scoliosis in two cases, avascular necrosis of the femoral condyles in one, and a femoral enchondroma in one).
Skeletal abnormalities, previously recognized as sequelae of local external-beam irradiation in children, may occur in long-term survivors of BMT who have received TBI. Younger patients appear to be at the greatest risk.
A case of a radiation-induced osteochondroma occurring in the posterior elements of the L3 vertebra in a 29-year-old woman is reported. At age 16 months, the patient was treated for an abdominal neuroblastoma. There were also radiation changes affecting the spine, ribs, and ilium. The lesion was excised "en bloc" and a spinal fusion performed. This is the third reported case of such a lesion occurring in the lumbar spine consequent to radiation therapy. The extremely long, latent period between radiation treatment and diagnosis of secondary tumor should be noted.
Radiation-induced bone changes and second malignancies, as well as benign tumors, following bone marrow transplantation are being reported with increasing frequency. An osteosarcoma of the fourth right rib and an osteochondroma of the left scapula developed in a long-term survivor of abdominal neuroblastoma treated with chemotherapy, local radiation, and bone marrow transplantation. All these treatment modalities are known to induce neoplasia.
A case of low-grade chondrosarcoma of the pelvis arising from a previous post-radiation osteochondroma is reported.
Nine patients developed osteochondromata, a mean of 6 years after total body irradiation (TBI) given before bone marrow transplantation for childhood leukaemia. This represents 23% of patients receiving TBI during the period from 1981 to 1989 surviving > or =5 years after bone marrow transplantation. The patients were followed up for a mean of 12.5 years from diagnosis of leukaemia and a mean of 2.5 years from diagnosis of osteochondromata. No osteochondroma, including three lesions removed surgically, showed evidence of malignant change. Six patients received growth hormone for irradiation-induced growth hormone deficiency, but this did not appear to influence the natural history of the osteochondromata. Radiation-induced osteochondromata (RIO) are often multiple and are indistinguishable from the more common idiopathic type. The incidence of RIO after TBI was higher than that reported after local irradiation.
A 38-year old man developed compressive myelopathy due to radiation-induced osteochondroma at T7. The patient had been given radiotherapy at the age of 7 years for a lymphosarcoma situated at the lower part of the neck. Radiation is an exceptional cause of spinal compression which can be avoided by regular surveillance of patients given radiotherapy in the spinal area as children.
More than 70% of children diagnosed with cancer can now be expected to be long-term survivors. However, the consequences of 'cure' might be considerable for the survivors of cancer: 60-70% of young adults who have survived childhood cancer will develop at least one medical disability as a result of their cancer or, more commonly, as a result of their therapy. Of these, the most devastating is a second cancer.
In administering roentgen therapy to retroperitoneal or paravertebral neoplasms in children, the radiologist is faced with these two questions: “What possible effects on the growth of the spine may result from the therapy?,” and “How can the tumor be irradiated in adequate dosage with minimal damage to the spine?” These were the questions which led to the present study. It consists of a follow-up of 45 patients who received roentgen therapy over the spine. Thirty-four living patients were observed over a period averaging six and a half years. Postmortem examination on 11 patients provided additional material used in the study. The experimental work concerning the effect of roentgen irradiation on the growth of bone in animals has been presented by Gates and Warren (1), Hinkel (2–4), Barr (5), Reidy (6), Gall (7), and coworkers. They have shown that when an epiphysis was exposed to 600 r or more of x-radiation, some retardation of growth usually occurred. Hinkel found that less than 500 r did not produce d...
During the past three years, development of osteochondromata was
observed within the area of irradiation in eight children treated by surgical and
irradiation therapy. Although the occurrence of malignant change in bone
following irradiation is well known, development of benign tumors of bone, such
as reported here, is not well documented. Seven of the reported cases occurred
following radiation treatment for neuroblastoma and nephroblastoma. A summary of
the cases is presented with respect to radiation dose andd field area, latent
period, and survival time. The records show 153 cases of neuroblastoma.andd
nephroblastoma, 67 of which are living. Sixty-two living patients received
irradiation with or without operation andd seven (10%) of these living irradiated
patients show osteochondromata. None of the few surviving children treated by
operatation developed osteochondromata. The patients were there years of age or
less when treated, a period when bone is growing rapidly and may be more
sensitive to irradiation From the cases reviewed and the literature it is evident
that the age at which the patient is irradiated is important for tumorigenesis.
The total absorbed tumor dose was estimated to vary from 1050 to 2850 rad, given
over 13 to 29 days and a field of 10 x 20 cm. It is suggested that use of
megavoltage sources may decrease the incidence of these tumors by decreasing the
differential in absorption by bone and soft tissue. The latent period ranged
from 17 months to 9 years 3 months. An exostosis is the result of disturbance of
enchondral ossification and it is suggested that irradiation in these children
initiated this disturbance. Reasons for removal of osteochondromata are cited.
In only one case was the osteochondroma removed, because of the possibility of
its being a bony metastatic lesion. Patients with such tumors should be
carefully followed because of the possibility of malignant change in the lesion.
(BBB)
A series of 1,644 persons of a total of 2,230 who were irradiated over
the head, neck, and chest in infancy and childhood was compared with 3,777
siblings with respect to subsequent medical history. Eleven carcinomas of the
thyroid were found in the patient group; none were found in the sibling controls.
This incidence of carcinoma of the thyroid in the irradiated group is about one-
hundred times that expected from current tables of morbidity and is comparable to
that reported in other similar surveys. The incidence of infections and other
non-neoplastic illness was greater among the patients than among their siblings.
But a statistically significant difference in the mortality ratio in the two
groups was also found, i.e., the death rate in the siblings was greater than that
in the patients. Although there is a significant increase in the incidence of
cancer of the thyroid following irradiation, radiation does not appear to be the
sole factor responsible for the increased incidence but rather a contributing
factor. This survey differs from previously reported surveys in the extent to
which the total family health history was evaluated. The information obtained is
extremely useful in placing in proper perspective possible carcinogenic factors
other than radiation. (auth)
Osteochondroma following irradiation in children
- Cole Arc Darte
- Jm
Cole ARC, Darte JM. Osteochondroma following irradiation in children. Pediatr 1963;32:285–288.
Imitation of chondrodysplasia by localised roentgen ray injury–an experimental study of bone growth
- Langenskiold A
Langenskiold A, Edgren W. Imitation of chondrodysplasia by localised roentgen ray injury–an experimental study of bone growth. Acta Chir Scand 1950;99:353–373.
American Cancer Society: Workshop on children with cancer. Long-term survival. Clinical care, research, and education
- Meadows At B Black
- Nesbit
- Me
Meadows AT, Black B, Nesbit ME, et al. American Cancer Society: Workshop on children with cancer. Long-term survival. Clinical care, research, and education. Cancer 1993;71:3213–3215.