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Unilateral Leg Swelling in a Young Woman

Educational Objective
Based on this clinical scenario and the accompanying image, understand how to arrive at a correct diagnosis.
1 Credit CME

A 33-year-old woman with a history of hereditary bilateral retinoblastoma as an infant presented to a primary care clinic with 1 week of right lower extremity swelling. At age 8 months, she was treated with right enucleation and left eye radiotherapy (50.4 Gy). At age 4 years, she developed a recurrence of the retinoblastoma in the nasal cavity and was treated with 4 cycles of vincristine, doxorubicin, and cyclophosphamide followed by 1 cycle of cisplatin, etoposide, and intrathecal cytarabine.

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A. Leiomyosarcoma

The patient underwent a transvenous biopsy with an inferior vena cava filter, and pathology results were consistent with a leiomyosarcoma (LMS), grade 3. Computed tomography results of the chest, abdomen, and pelvis were negative for metastatic disease. She subsequently underwent a radical resection of the pelvic mass, which revealed a 4-cm mass deriving from and encapsulating the right external iliac vein with R1 margins, which was replaced with an interposition graft.

Retinoblastoma is the most common pediatric ocular tumor. The hereditary variant, which is caused by germline variations to the tumor suppressor gene RB1, comprises 40% of all retinoblastoma and is generally associated with bilateral disease.1 Long-term survival of these patients is typically excellent; however, there remains a 33.1% risk of developing a secondary cancer.2,3 This has important implications for monitoring survivors of hereditary retinoblastoma. The median time to development of a subsequent cancer is 18.9 years, and bone and soft-tissue sarcomas comprise most (40%-60%) subsequent cancers, followed by melanoma, accounting for approximately 10%.3 Among soft-tissue sarcomas (STS), LMS is most common, comprising at least 40% of all STS diagnosed in patients with retinoblastoma with a median age at presentation of approximately 32 years.3 Other commonly diagnosed subsequent STS include fibrosarcoma, undifferentiated pleomorphic sarcoma, and rhabdomyosarcoma.3 Prior treatment with radiation or chemotherapy may increase the risk of a subsequent cancer.4 Radiotherapy is a risk factor for developing a subsequent cancer within the treatment field, and alkylating agents, in particular, seem to increase systemic risk of subsequent cancer. Patients who were treated with radiotherapy and an alkylating agent before age 1 year, as with this patient, may have up to 3.8 times greater risk of developing LMS.4

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Article Information

Corresponding Author: Jason Lambden, MSPH, MD, Department of Internal Medicine, McGaw Medical Center of Northwestern University, 251 E Huron St, Chicago, IL 60611 (jason.lambden@northwestern.edu).

Published Online: September 2, 2021. doi:10.1001/jamaoncol.2021.3811

Conflict of Interest Disclosures: None reported.

Additional Contributions: We thank the patient for granting permission to publish this information and Seth Pollack, MD, Northwestern Medicine, for his contributions, for which he was not compensated.

References
1.
Dimaras  H , Kimani  K , Dimba  EA ,  et al.  Retinoblastoma.   Lancet. 2012;379(9824):1436-1446. doi:10.1016/S0140-6736(11)61137-9PubMedGoogle ScholarCrossref
2.
Kleinerman  RA , Schonfeld  SJ , Tucker  MA .  Sarcomas in hereditary retinoblastoma.   Clin Sarcoma Res. 2012;2(1):15. doi:10.1186/2045-3329-2-15PubMedGoogle ScholarCrossref
3.
Schonfeld  SJ , Kleinerman  RA , Abramson  DH , Seddon  JM , Tucker  MA , Morton  LM .  Long-term risk of subsequent cancer incidence among hereditary and nonhereditary retinoblastoma survivors.   Br J Cancer. 2021;124(7):1312-1319. doi:10.1038/s41416-020-01248-yPubMedGoogle ScholarCrossref
4.
Wong  JR , Morton  LM , Tucker  MA ,  et al.  Risk of subsequent malignant neoplasms in long-term hereditary retinoblastoma survivors after chemotherapy and radiotherapy.   J Clin Oncol. 2014;32(29):3284-3290. doi:10.1200/JCO.2013.54.7844PubMedGoogle ScholarCrossref
5.
Tripodi  E , Zanfagnin  V , Fava  C , Zola  P , Ferrero  A .  Leiomyosarcoma of the right iliac veins presenting as a pelvic mass: a case report.   Obstet Gynecol Cases Rev. 2015;2:40-4. doi:10.23937/2377-9004/1410040Google ScholarCrossref
6.
George  S , Serrano  C , Hensley  ML , Ray-Coquard  I .  Soft tissue and uterine leiomyosarcoma.   J Clin Oncol. 2018;36(2):144-150. doi:10.1200/JCO.2017.75.9845PubMedGoogle ScholarCrossref
7.
Bonvalot  S , Gronchi  A , Le Péchoux  C ,  et al.  Preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS): a multicentre, open-label, randomised, phase 3 trial.   Lancet Oncol. 2020;21(10):1366-1377. doi:10.1016/S1470-2045(20)30446-0PubMedGoogle ScholarCrossref
8.
Ducie  JA , Leitao  MM  Jr .  The role of adjuvant therapy in uterine leiomyosarcoma.   Expert Rev Anticancer Ther. 2016;16(1):45-55. doi:10.1586/14737140.2016.1115724PubMedGoogle ScholarCrossref
9.
Pasquali  S , Gronchi  A .  Neoadjuvant chemotherapy in soft tissue sarcomas: latest evidence and clinical implications.   Ther Adv Med Oncol. 2017;9(6):415-429. doi:10.1177/1758834017705588PubMedGoogle ScholarCrossref
10.
Kamihara  J , Bourdeaut  F , Foulkes  WD ,  et al.  Retinoblastoma and neuroblastoma predisposition and surveillance.   Clin Cancer Res. 2017;23(13):e98-e106. doi:10.1158/1078-0432.CCR-17-0652PubMedGoogle ScholarCrossref
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