BRIEF REPORT Recognition of Li Fraumeni Syndrome at Diagnosis of a Locally Advanced Extremity Rhabdomyosarcoma
T. Trahair, BSc(Med), MBBS, PhD, FRACP,1 L. Andrews, MBBS, MMed,2 and R.J. Cohn, MBBCh, FCP (SA), FRACP1*
A contemporaneous presentation of a second breast cancer in a mother and an extremity rhabdomyosarcoma (RMS) in her daughter led to the diagnosis of the Li Fraumeni syndrome (LFS). Although the association between LFS and RMS in young patients is well recognised [1] there are no guidelines as to how this knowledge should influence the optimal management of these patients. After reviewing the literature about the natural history of the LFS [2], the incidence of second malignancy (SMN) in RMS survivors [3-6] and the management of extremity RMS [7-9], we are concerned that
contemporary RMS treatment, combining non-mutilating surgery with chemoradiotherapy, may be associated with an excessive SMN risk in LFS patients with advanced RMS. We question whether treatment should be individualised and, where possible and acceptable to the family, measures such as amputation should be the considered to attain local control for LFS patients with RMS as this will avoid the need for local radiotherapy without compromising long-term function and quality of life [10]. Pediatr Blood Cancer 2007;48:345-348. @ 2006 Wiley-Liss, Inc.
Key words: Li Fraumeni syndrome; p53; rhabdomyosarcoma; soft tissue sarcoma
INTRODUCTION
Treatment formulations for children with malignancy aim to balance the risks and benefits of therapy by maximizing the potential for cure and minimizing unacceptable treatment- related toxicities. For most patients this is straightforward as high quality clinical studies have resulted in risk adapted therapies tailored to the disease stage and tumor biology. There remain a small number of patients, who, as a result of individual attributes, potentially face substantial treatment- related complications and because of their rarity there is incomplete literature to guide therapeutic decisions. We present such a case, a young female with an advanced extremity rhabdomyosarcoma (RMS) and Li Fraumeni syndrome (LFS).
CASE REPORT
MS, a 34-month-old girl, was referred for investigation after presenting with a 1 month history of limp associated with a calf mass. There was no history of pain or trauma. Apart from the mass, her physical examination was normal and no involved local or regional lymph nodes were found.
MRI images showed a 7.8 x 4.5 x 3 cm mass in the tibialis posterior with displacement of the neurovascular bundle. No other sites of disease were identified on staging examination, which included a CT scan of the chest, abdomen and pelvis, bone scan and bilateral bone marrow examination.
At attempted excision, the tumor was found to extend into the anterior compartment, encasing both anterior and posterior tibial arteries, precluding complete removal. Histo- pathological examination showed a high-grade sarcoma with strong staining for desmin and myogenin, consistent with RMS. The tumor was classified as a pleomorphic RMS arising on a background of embryonal RMS.
There was a significant family history. The child’s mother had had bilateral breast cancer. The first cancer, on the left, was found at the age of 30 and the second, on the right, at 34 years. The second breast cancer had been identified in the months prior to her daughter’s presentation. Concern about a hereditary cancer syndrome had been raised by the mother’s breast surgeon but had not been pursued due to her daughter’s illness. Four other relatives affected by cancer at a young age were identified (Fig. 1). The maternal grandfather had been diagnosed with a fibrosarcoma of the thigh following a traumatic deep vein thrombosis and died at the age of 43 years. A first cousin had been diagnosed with an adrenal cortical cell carcinoma at 8 years, a great uncle had oesophageal carcinoma diagnosed in his 40’s and a great grandfather had a liver tumor detected in his 20’s. A clinical diagnosis of LFS was made and confirmed by the identifica- tion of a TP53 truncating mutation (R213X), in both MS and her mother.
The option of amputation to attain local control was discussed with the family due to the incomplete resection, unfavorable location and diagnosis of LFS. After considera- tion of the risks and benefits of amputation compared to a
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1Centre for Children’s Cancer & Blood Disorders, Sydney Children’s Hospital, Randwick, New South Wales Australia; 2Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, New South Wales Australia
T. Trahair’s present address is Stem Cell Biology Laboratory, Peter MacCallum Cancer Centre, St. Andrew’s Place, East Melbourne, Victoria 3002, Australia.
*Correspondence to: Dr. R.J. Cohn, Centre for Children’s Cancer and Blood Disorders, Sydney Children’s Hospital, High Street, Randwick, NSW 2031, Australia.
E-mail: Richard.Cohn@sesiahs.health.nsw.gov.au
Received 10 April 2005; Accepted 11 January 2006
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Liver cancer 20’s
Oesophageal cancer 40’s
Fibrosarcoma 43 y
Adrenal cortical cell carcinoma 8 y
DCIS 30 y, 34 y LGA 36 y Spindle cell sarcoma 36 y
Rhabdomyosarcoma 2 y
further attempted excision and local radiotherapy, the family preferred to avoid amputation. At a second operation a wide excision was not possible but the tumor was removed piecemeal to obtain a macroscopic resection.
MS was classified as intermediate risk according to the intergroup RMS staging classification based on her stage 3 and clinical group III disease. She was treated with a contemporary intermediate risk RMS protocol, consisting of adjuvant chemotherapy (vincristine, actinomycin D, and cyclophosphamide) combined with 52 Gy external beam radiotherapy to the gross tumor volume. She completed her therapy within 48 weeks of diagnosis.
Fifteen months later, her mother was found to have a low- grade astrocytoma, which was resected. Nine months following that, a high-grade spindle cell sarcoma arising from the retroperitoneum was detected, following com- plaints of persistent back pain. The mother subsequently died of tumor progression despite therapy. MS remains well with no evidence of tumor recurrence 36 months from diagnosis and 25 months from completion of therapy.
DISCUSSION
This family highlights the complexities of managing an advanced RMS within the context of LFS, which is diagnosed in 5-9% of RMS patients, but mainly restricted to those diagnosed under 3 years of age [1]. This autosomal dominant cancer predisposition syndrome was identified by excess malignancies, particularly breast cancer, in close relatives of RMS patients [11]. Criteria for a clinical diagnosis and the spectrum of malignancies in LFS are outlined in Table I [2,12]. Mutations in the TP53 gene are found in 50-70% of LFS families [2,13,14] with mutations in the CHK2 gene identified in a limited number of others [15]. The p53 pathway regulates the cellular response to DNA damage, which protects genomic integrity. Loss of p53 function is
TABLE I. Clinical features of LFS [2,12]
Criteria to establish a clinical diagnosis of LFS
A proband with a sarcoma diagnosed before 45 years of age and A first-degree relative with any cancer under 45 years of age and
A first- or second-degree relative with any cancer under 45 years of age or a sarcoma at any age
Cancer spectrum associated with LFSª Breast cancer
Soft tissue sarcoma
Osteosarcoma
Leukemia
Brain tumors Adrenocortical carcinoma
ªThese tumor types account for 70% of cancers arising in LFS patients.
associated with genetic instability and the acquisition of mutations, which promote neoplastic transformation [16].
Neoplasms arising at a young age and multiple malig- nancies are hallmarks of LFS [2,12,17]. The constellation of tumors and ages at presentation in the family of our patient suggested the diagnosis, even before her presentation (Fig. 1). For LFS patients with multiple malignancies, it is not possible to determine the relative contributions of the underlying cancer predisposition and prior therapies towards subsequent malignancies. Animal models and case reports demonstrate that cancer therapies influence the phenotype and reduce the latency of tumor formation [18,19]. Age and tumor diagnosis influence the risk of second malignancy (SMN) in LFS, with the highest risk in those with a first tumor at a young age or those diagnosed with RMS [2].
Follow-up of RMS survivors suggests that SMN are not equally distributed and are clustered in survivors with close relatives with excess malignancies or with family histories suggestive of LFS or neurofibromatosis [3-5]. RMS therapy influences SMN risk with the highest incidence amongst survivors treated with chemoradiotherapy, particularly cyclophosphamide and radiotherapy (Table II) [4-6]. The risk of SMN following contemporary RMS treatment may be greater since these reports are based on earlier, less dose intensive regimens [4-6].
We aimed to control the primary, cure the RMS and minimize the risks of therapy, particularly the SMN risk. Optimizing local control was particularly important due to the risk of local recurrence from a large, locally invasive, extremity RMS. Although risk factors for treatment failure include tumor stage and group, local invasion and nodal metastasis, the most important predictor for extremity RMS remains extent of resection [9]. Surgical management has favored pre-treatment reexcision whilst avoiding mutilating procedures, an approach justified by improved survival with intensive chemoradiotherapy and excellent functional out- comes [20]. We offered amputation since it would provide effective local control, avoid radiotherapy and is justifiable based on the equivalent functional and quality-of-life outcomes of amputees compared to children treated with
TABLE II. Increased Risk of SMN Following the Combination of Chemotherapy and Radiotherapy for RMS
A. Increased risk of SMN following treatment on IRS I and II (Data from Heyn and co-workers [4], reprinted with permission from the American Society of Clinical Oncology)
| Treatment | No. of Patients | No. of SMN | Incidence density per 10,000 patient years | Estimated 10 year cumulative incidence of SMN |
|---|---|---|---|---|
| VA | 68 | 0 | 0 | 0 |
| VA + RTX | 136 | 1 | 9.9 | 1.4±1.4 |
| VAC | 169 | 1 | 8.7 | 0.8±0.8 |
| VAC+ RTX | 1397 | 20 | 27.4 | 2.0±0.7 |
B. Increased risk of SMN in patients treated for childhood soft tissue sarcoma and reported to SEER (Data from Cohen and co-workers [6], reprinted with permission from the American Society of Clinical Oncology)
| Treatment | No. patients | No. SMN | Observed/expected | 95% CI |
|---|---|---|---|---|
| Surgery only | 480 | 3 | 1.4 | 0.3-4.2 |
| Chemotherapy only | 102 | 3 | 7.6 | 1.5-22.1 |
| Radiotherapy only | 318 | 2 | 3.5 | 0.4-12.8 |
| Radiation and chemotherapy | 555 | 18 | 15.2 | 9.0-24.0 |
IRS, Intergroup rhabdomyosarcoma study; RTX, radiotherapy; SEER, Surveillance, Epidemiology and End Results cancer registry; SMN, second malignant neoplasm; VA, vincristine and actinomycin D; VAC, vincristine, actinomycin D and cyclophosphamide.
limb-sparing approaches [10]. The family preferred to avoid amputation and we accepted that contemporary RMS therapy with adjuvant chemotherapy and radiotherapy was the best means to achieve local control and cure.
However, we remain apprehensive about the benefits of such therapy in this patient group, since improvements in survival from intensified RMS therapy have not been enjoyed by all patients [8]. If our patient survives, we believe that she has a high risk of SMN based on her age at presentation [2], the natural history of LFS [2], the use of chemoradiotherapy [4-6] and the aggressive maternal phenotype. We are follow- ing her to detect local recurrence in the short term and a secondary tumor in the longer term. We intend to avoid further radiation exposure by using MRI imaging in pre- ference to CT scanning or nuclear medicine investigations.
The LFS diagnosis raises the problem of preventive screening for mutation carriers who have a high lifetime risk of malignancy, estimated at 73% for male and 100% for female carriers [14]. The protean manifestations of LFS make screening difficult and are illustrated by the mother who developed further malignancies despite the LFS diagnosis. Practically, breast and brain tumors are most common in adult carriers [12,17], who should be offered annual clinical review and full physical examination with regular breast screening for females. A high index of suspicion should be maintained for LFS carriers who complain of persisting but unexplained symptoms.
A diagnosis of LFS should be considered in every child, under 3 years, diagnosed with RMS [1]. A comprehensive family cancer history, with emphasis on sarcomas, breast and brain tumors, which are highly correlated with LFS [12,17], should be obtained to establish a clinical diagnosis. Combined modality RMS therapy is associated with the highest risk of SMN [4-6], and some LFS patients with RMS may face an unacceptable SMN risk without a commensurate
improvement in survival. Since there is no correlation between the RMS site, histological type or clinical grouping and the presence of a TP53 mutation [1], we advocate that treatment formulations for LFS patients with RMS be based on standard risk stratification, but recommend that treatment alternatives be considered, particularly for patients with locally advanced or unfavorable histology tumors. For extremity RMS, amputation is the simplest means to achieve local control, avoid radiotherapy and maintain long term function and should be presented as an alternative to standard limb-sparing surgery and chemoradiotherapy. While not acceptable to all, we believe that this offers a reasonable balance between minimizing the SMN risk without jeopar- dizing the chance of cure.
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