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Clinicopathologic Features of Osteosarcoma in Patients With Rothmund-Thomson Syndrome

M. John Hicks, Jill R. Roth, Claudia A. Kozinetz, Lisa L. Wang

From the Baylor College of Medicine, Houston, TX

Address reprint requests to Lisa L. Wang, MD, Texas Children's Cancer Center, Baylor College of Medicine, 6621 Fannin MC 3-3320, Houston, TX 77030; e-mail: llwang{at}bcm.tmc.edu

	ABSTRACT

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Purpose Patients with Rothmund-Thomson syndrome (RTS) and RECQL4 gene mutations have an increased risk of developing osteosarcoma (OS). Because RTS is considered a genomic instability syndrome, patients may experience increased toxicity with chemotherapy. The purpose of this study was to summarize the clinical features and response to therapy of OS in patients with RTS. The results of this analysis will help to define treatment guidelines for this complex and rare condition.

Patients and Methods An international cohort of patients with RTS and OS was enrolled in an institutional review board–approved study at Baylor College of Medicine (Houston, TX). Medical records were reviewed, and the following information was extracted: clinical features, treatment, pathologic findings, and clinical outcome.

Results The median age at diagnosis of OS for the 12 patients was 10 years. The most common primary tumor sites were the long bones (femur, tibia); the most frequent histologic subtype was conventional OS. Histologic response to chemotherapy and outcome were similar to other published large series of sporadic OS. Eight patients are alive and disease free; four died as a result of cancer. Five patients required chemotherapy dose modifications, most commonly due to mucositis from doxorubicin.

Conclusion Our results indicate that patients with RTS and OS are younger, but that their clinical behavior is similar to patients with sporadic OS. Our report suggests that these patients should initially be treated with conventional doses of chemotherapy as prescribed by current protocols; however, cautious and careful clinical observation is warranted to monitor for enhanced doxorubicin sensitivity in patients with RTS.

	INTRODUCTION

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Osteosarcoma (OS) is the most common primary bone malignancy in childhood and adolescence.¹ In the general population, OS typically arises during the growth spurt in late adolescence, but there is also a later peak during the seventh and eighth decades of life, with some of these cases associated with Paget's disease or prior irradiation.² Current treatment recommendations include a multimodal approach with chemotherapy and surgery, because the tumor is relatively resistant to radiation therapy. OS is usually sporadic; however, genetic predisposition has been well documented in patients with Li-Fraumeni syndrome, hereditary retinoblastoma, and Rothmund-Thomson syndrome (RTS).³

RTS is an autosomal recessive disorder with a heterogeneous clinical profile. Patients may have a few or multiple clinical features including skin rash (poikiloderma), small stature, skeletal dysplasias, sparse or absent scalp hair, eyebrows and/or eyelashes, juvenile cataracts, and GI disturbance including chronic emesis and diarrhea. Cells from patients with RTS demonstrate genomic instability,⁴ and RTS patients are particularly prone to developing osteosarcoma as well as nonmelanoma skin cancers.⁵ RTS has been grouped with other genetic cancer predisposition disorders that fall into the class of DNA repair or chromosomal instability disorders, including ataxia-telangiectasia (A-T), Fanconi anemia and xeroderma pigmentosum.⁶ Patients with these other disorders have well-known increased sensitivity to DNA-damaging agents including ionizing radiation and ultraviolet radiation.^7,8 No systematic study has documented whether patients with RTS have enhanced sensitivity to chemotherapy or radiation. Increased sensitivity to chemotherapy has been reported in a few RTS patients^9-12; however, these are isolated case reports that may not be representative of the majority of RTS patients. The present study was undertaken to determine whether RTS patients diagnosed with OS require modifications in initial chemotherapy dosing given the possible risk of severe toxicities in the background of a genomic instability syndrome. To address this question, we reviewed the clinical features of OS in an unselected cohort of RTS patients. This report represents the largest series of patients with RTS and OS and offers guidelines for management in these patients.

	PATIENTS AND METHODS

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Patients with RTS identified as part of an international, multidisciplinary clinical and molecular study of RTS were enrolled onto a research protocol approved by the institutional review board for human subjects research of Baylor College of Medicine (Houston, TX). All RTS patients or their parents provided informed written consent for enrollment, family history information, and signed release of medical records from treating institutions. Twelve of the enrolled RTS patients who also carried a pathologic diagnosis of OS are the subjects of the present study; two of these patients were treated for OS at our institution. Four patients have been previously reported, but not specifically regarding treatment of OS.^13-15 Medical records including radiology, surgical and pathology reports were collected from treating institutions. Specific information extracted from the medical charts included the patient's age at diagnosis of OS, histologic subtype of OS, location of the primary tumor, type of definitive surgery, chemotherapeutic agents used, percentage tumor necrosis after neoadjuvant chemotherapy, toxicities and modifications to chemotherapy, and secondary malignant neoplasms (SMNs). Pathology slides of OS tumors were also requested from treating institutions. These included both initial biopsy specimens as well as specimens from definitive surgery. Available slides were reviewed by a pediatric pathologist at our institution to confirm the pathologic diagnosis, histologic subtype of OS, and pathologic grading of tumor necrosis. Mean age at diagnosis of this sample and of a previously reported sample were compared using a standard statistical method with standard deviation and sample size.¹⁶ Survival estimates were performed using the nonparametric method of Kaplan and Meier.¹⁷ To assess whether a patient had increased toxicity to chemotherapy, we determined whether delivery of planned chemotherapy was altered from the original protocol (reduction in the dose of an agent or extended periods between treatments). Our results were analyzed to determine whether there was a major difference between OS in RTS and sporadic OS with regard to clinicopathologic features and patient responses.

	RESULTS

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Twelve patients diagnosed with both RTS and OS were evaluated. Diagnosis of RTS was made on the basis of previously published clinical criteria⁵ and confirmed by RECQL4 molecular testing by polymerase chain reaction and DNA sequencing of genomic DNA.¹⁸ Seven of these patients were diagnosed with RTS before developing OS; five were diagnosed with RTS after an initial diagnosis of OS. Table 1 summarizes the patient and OS characteristics, chemotherapy treatment, and responses.

Treatment
All patients received chemotherapy with standard agents used for the treatment of OS, including cisplatin, doxorubicin, methotrexate, and ifosfamide (Table 1). None of the patients received radiation therapy. For initial therapy of the primary tumor, two patients (Patients 5 and 6) were empirically started with reduced doses of chemotherapy, presumably due to their diagnosis of RTS. Six patients received a combination of cisplatin (120 to 150 mg/m²/course), doxorubicin (60 to 90 mg/m²/course) and high-dose methotrexate (12 to 15 g/m²/course), and three patients received the same regimen with addition of ifosfamide (1.8 g/m²/course). One patient received a combination of cisplatin, doxorubicin, high-dose methotrexate, bleomycin, cyclophosphamide, and dactinomycin. One patient is currently still receiving chemotherapy. Patients with recurrent or progressive disease were treated with different combinations of salvage therapy.

Histologic Response to Chemotherapy
Pathology slides at the time of definitive surgery (after preoperative chemotherapy) were available for confirmation in seven tumor samples. Histologic response was not assessable in four OS samples: Patient 5, definitive surgery was refused by the family; Patient 7, the entire patella had been removed at diagnosis; Patients 3 and 8, information was not available. The Huvos grading system was used to grade the response of the tumor to chemotherapy.^20-22 Of the 11 assessable tumors in this study, five had more than 90% tumor necrosis (all grade 3), one was reported as "significant" necrosis, and five had less than 90% tumor necrosis (four grade 1 and one grade 2).

Toxicity Related to Chemotherapy
Five patients received standard chemotherapy regimens for treatment of OS and did not require any dosing modifications for the major toxicities, including renal impairment, neurotoxicity, ototoxicity, or cardiotoxicity. For two patients, no information was available regarding toxicities or dosing modifications. Five patients had modifications to standard dosing as shown in Table 1. Patient 5 was started at a methotrexate dose of 4 g/m², and this was incrementally increased to 16 g/m² on the basis of lack of toxicity. However, she had rapidly progressive disease and died 5 months after initiation of therapy. Patient 6 was started at a doxorubicin dose of 50% of standard dosing; this was increased to 75% and subsequently decreased to 60% of standard dosing due to severe mucositis. He received a total cumulative doxorubicin dose of 371 mg/m². This patient also had his fourth dose of methotrexate omitted due to mucositis, but received the last two courses without problems. Patient 4 was started at standard dosing of doxorubicin, but required a 25% dose reduction after the first course due to severe mucositis. He required no further dose reductions and received a cumulative doxorubicin dose of 345 mg/m². Patient 11 also experienced severe mucositis with doxorubicin, and this drug was omitted after two doses. Patient 12 tolerated his first two courses of doxorubicin, but after the third course developed severe mucositis; therefore the dose was decreased by 20% for the fourth course. He is currently still receiving chemotherapy. These results suggest that some (four patients, 33%), but not all RTS patients experience enhanced toxicity in the form of mucositis with doxorubicin. Two of the patients also had mucositis or minor delays in treatment due to methotrexate, but they did not require dose reductions. None of the patients in our study experienced severe toxicities requiring dose modifications to any of the other standard chemotherapy agents used to treat OS.

SMNs
Among those patients diagnosed with a subsequent tumor other than OS, one (Patient 2) developed an SMN and then a third malignant neoplasm. His original tumor was an OS of the distal femur diagnosed at age 13 years. At 21 years of age, he developed Hodgkin's lymphoma of the nasopharynx for which he received chemotherapy. Two years later, he developed squamous cell carcinoma of the esophagus and rapidly succumbed to this cancer.

Clinical Outcome
Eight patients (67%) are alive with no evidence of disease with a median follow-up time of 5 years (range, 8 months to 16 years). One patient is still undergoing treatment at the time of reporting. Four patients (33%) have died, three of them (25%) from recurrent or progressive OS, and one (8%) from a third malignant neoplasm as described above. The probability of event-free survival in our cohort was 83% at 5 years (95% CI, 48% to 96%) and 63% at 10 years (95% CI, 17% to 88%).

	DISCUSSION

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This is, to our knowledge, the largest clinical study of OS in patients with RTS. Our results indicate that the clinical features and outcomes of patients with RTS and OS are similar to those observed in patients with sporadic OS. For example, patients with RTS as well as those with sporadic OS most often had tumors that involved the femur and tibia,²³ and in most cases the osteoblastic subtype of conventional OS predominated.^16,24 Histologic response to chemotherapy in RTS patients was similar to that in the general population, with approximately 45% of tumors demonstrating more than 90% necrosis.²⁵ Outcomes of RTS patients with OS were also comparable to those of patients in the general population with nonmetastatic OS, who have an overall 5-year event-free survival of 60% to 70%.^1,16,25 However, our series suggests that patients with RTS and OS are affected at an earlier age (mean, 10 years; standard deviation [SD], 4.8 years) compared with the general population (mean, 16 years; SD, 7 years; P = .002).¹⁶ Therefore, the presence of OS in a young patient should raise the suspicion of a genetic syndrome such as RTS, especially because the clinical features of this syndrome can be subtle, as evidenced by the fact that five of the patients in this study were diagnosed with RTS after the diagnosis of OS was made. None of the RTS patients had metastases at diagnosis, whereas in the general population approximately 20% of patients will present with metastatic disease.¹ However, given the small number of patients in our cohort, it is difficult to determine whether this is a significant finding. Two RTS patients developed a metachronous skeletal OS. In a study by Jaffe et al, ¹⁹ of 270 patients treated for primary OS, 11 developed metachronous OS; four of these patients had an underlying genetic predisposition (retinoblastoma or Li-Fraumeni syndrome). Thus, seven nonsyndromic patients (2.6%) developed metachronous OS. In another study, by Aung et al, ²⁶ of 426 patients treated for nonmetastatic OS, 23 (5.4%) developed metachronous OS. Although the number of patients in our study is small, the apparent increased risk of metachronous OS (17%) likely reflects the significant genetic predisposition to OS seen in RTS patients with RECQL4 mutations even in the absence of chemotherapy.

One patient in our series (8%) developed a second and then a third malignant neoplasm 8 and 10 years, respectively, after treatment for primary OS. In a study of long-term survivors of OS treated at Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY), there were 14 cases of SMN in 509 patients with primary OS (2.8%).²⁷ The time interval from initial diagnosis of OS to development of SMN ranged from 0.1 to 13.1 years (median, 5.2 years). The most common SMNs were of the CNS, followed by hematologic malignancies, sarcomas, and mucoepidermoid carcinoma. It appears that the incidence of SMN other than OS is not substantially different in our RTS patients treated for OS compared with the general population; however, the number of assessable patients in our cohort is small, and the follow-up time is variable. Therefore, it is difficult to draw any conclusions at this point about risk of SMN or tumor spectrum in the context of RTS.

In the general population, patients treated for sporadic OS will not infrequently experience adverse effects that may necessitate dose modifications. These include hematologic toxicities (cytopenias) in up to 50% of patients, as well as nonhematologic toxicities such as renal impairment (10%), neurotoxicity (5%), ototoxicity (40%) or cardiac toxicity (0.4%).¹⁶ Of 34 reported cases of OS in RTS patients, seven patients (20%) experienced increased toxicities necessitating dose reduction, most often to doxorubicin.^9,11,28 The majority of reports, however, did not provide information regarding chemotherapy or toxicities. In our group of 12 unselected RTS patients with OS, four patients (33%) required modifications in their chemotherapy dosing, and these all occurred with doxorubicin. In one patient, a single dose of methotrexate was omitted due to mucositis, but subsequent doses were given at full dose without difficulties. Importantly, these RTS patients did not experience the sorts of toxicities that have been described in patients with A-T or other DNA repair disorders who receive genotoxic therapy, where the toxicities are so severe as to preclude administration of any agents. Patients with A-T have constitutional mutations in the ATM gene, which is involved in response to DNA damage and multiple pathways for DNA repair.²⁹ Cells from patients with A-T have increased sensitivity to ionizing radiation as determined by colony formation assay.³⁰ Similarly, patients with A-T are exquisitely sensitive to ionizing radiation and are unable to tolerate therapeutic doses of radiation to treat their cancers.³¹

The molecular basis for RTS was first described in 1998 by Kitao et al,³² who identified mutations in the RECQL4 gene in a subset of RTS cases. This was confirmed in a larger cohort of RTS probands in whom RECQL4 truncating mutations were identified in two thirds of patients with a clinical diagnosis of RTS.¹⁸ Genotype-phenotype analysis showed that presence of deleterious mutations in RECQL4 was highly correlated with development of OS, indicating a potential role for RECQL4 in the pathogenesis of OS in RTS patients. Two other RECQ helicase disorders, Bloom syndrome and Werner syndrome, are also associated with significant increased cancer risk. Patients with Bloom syndrome carry mutations in the BLM (RECQL2) gene and are at increased risk for multiple cancers seen in the general population, but at an earlier age and at increased frequency.³³ Patients with Werner syndrome have mutations in the WRN (RECQL3) gene and are at increased risk for soft tissue sarcomas, thyroid cancer, and melanomas, as well as other cancers including OS.³⁴ Therefore, the RECQ proteins are considered to be "caretakers of the genome" that may have many functions, including a role in tumor repression.³⁵ The specific role of RECQL4 in DNA repair has not been clearly demonstrated, nor has a characteristic cellular hypersensitivity phenotype to genotoxic agents been identified in cells from RTS patients who carry RECQL4 mutations.^10,36 Thus, it is not surprising that patients with RTS do not all display an exquisite sensitivity to chemotherapeutic agents in the same manner that A-T patients respond to ionizing radiation. There have been a few articles describing patients with RTS who have successfully undergone bone marrow transplantation. Rizzari et al³⁷ described a patient with RTS and myelodysplastic syndrome who underwent an allogeneic bone marrow transplantation and tolerated standard conditioning with busulfan and cyclophosphamide without difficulties. Another patient with combined immunodeficiency and a molecular diagnosis of RTS underwent successful umbilical cord blood stem-cell transplantation and tolerated conditioning with cyclophosphamide and fludarabine well.³⁸ These cases provide additional evidence that not all patients with RTS are susceptible to increased sensitivity to chemotherapy or radiation.

Patients with constitutional RECQL4 mutations have a definite increased risk for developing OS. Loss of RECQL4 function or derangements in RECQL4 pathway(s) may play a role in generating the cancer phenotype in the RTS population. At present, there is not enough information to determine whether there are any genotype-phenotype correlations between the type of RECQL4 mutation or other potential genetic factors and the response to chemotherapy in RTS patients. Doxorubicin is an anthracycline agent that may exhibit antitumor activity through a variety of mechanisms, including intercalation into DNA and induction of topoisomerase II–mediated DNA strand breaks, generation of free radicals, and oxidative damage.³⁹ Enhanced sensitivity to doxorubicin observed in RTS patients with RECQL4 mutations may suggest a functional role for the RECQL4 protein in DNA repair pathways.

Our results indicate that patients with RTS who develop OS have a similar clinical presentation and response to therapy as do patients with sporadic OS, and therefore every attempt should be made to deliver all chemotherapy courses on time to optimize the survival outcome in these patients. Although some RTS patients may experience enhanced sensitivity to doxorubicin, others may tolerate chemotherapy without any difficulty, and there is no way to predict a priori how each individual patient will respond. Our recommendations are that RTS patients with OS should be treated with standard chemotherapy with the understanding that they may not tolerate full doses of doxorubicin, and that modifications should be made only as indicated by the individual clinical course. In addition, they should be monitored for second occurrence of OS as well as SMN given their known genetic predisposition to cancer.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Conception and design: Lisa L. Wang

Financial support: Lisa L. Wang

Administrative support: Lisa L. Wang

Provision of study materials or patients: M. John Hicks, Lisa L. Wang

Collection and assembly of data: M. John Hicks, Jill R. Roth, Lisa L. Wang

Data analysis and interpretation: M. John Hicks, Jill R. Roth, Claudia A. Kozinetz, Lisa L. Wang

Manuscript writing: M. John Hicks, Jill R. Roth, Lisa L. Wang

Final approval of manuscript: M. John Hicks, Jill R. Roth, Claudia A. Kozinetz, Lisa L. Wang

	ACKNOWLEDGMENTS

 
We thank the patients and families reported herein for their participation in this research, and the physicians, nurses, and genetic counselors who provided information and patients for this study. We thank Ta-Tara Rideau for data management support, and the following contributors to our research study: Moise Levy, Richard Lewis, Rochelle Bagatell, Dorit Lev, Julie McGaughran, and Edel O'Toole. We gratefully acknowledge critical reading of the manuscript and helpful discussions by Sharon Plon, MD, PhD; Alberto Pappo, MD; David Poplack, MD; Murali Chintagumpala, MD; and Mark Horowitz, MD.

	NOTES

 
Supported by NIH-NICHD K08HD42136, the Doris Duke Charitable Foundation Clinical Scientist Development Award, NIH-RR000188-42 (BCM-General Clinical Research Center), and NIH-HD024064 (BCM-Mental Retardation Developmental Disabilities Research Center, Tissue Culture Core).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted August 12, 2006; accepted November 15, 2006.

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