Soft-tissue sarcomas are extremely rare, with an estimated 11 930newcases in theUnitedStates in2015, representing less than 1% of all new cancer cases.1 They are a heterogeneous group of diseases with more than 80 different histologic types and subtypes that have widely different clinical behaviors andoutcomes.2 Leiomyosarcomas involving the inferiorvenacava (IVC)are the rarest of the rare; even at tertiary referral centers, no more than approximately 1 case per year is seen.3 In this issue of JAMA Surgery, Roland et al4 describe one of the largest singleinstitution reviews of leiomyosarcomas arising from the IVC and other vessels, adding to our very limited understanding of these rare diseases. For all surgeonswho resect retroperitoneal neoplasms, an important take-home point is preoperative recognition and preparation.5 Consider the possibility of a leiomyosarcoma in the IVCwhen imagingshowsaright-sidedretroperitonealmass abutting the IVC (especially if no lumen is present at the site of contact) or an intraluminal IVC mass,6 and anticipate the complex surgical issuespotentially necessary for removal (eg, ligation, patch, or graft of IVC;managementof renal veins; hepatectomy; or cardiopulmonary bypass). A complete resection, performed safely, is the only chance for long-term survival.3 However, local and distant recurrences are common, so better adjuvant therapies are needed. Site is an important prognostic factor for soft-tissue sarcomas.2 The series of patients in Roland et al4 includes patientswith leiomyosarcomas arising fromthe IVC (n = 42) and patientswith leiomyosarcomas arising fromother vessels, includingsaphenous, femoral, renal,andupper-extremityveins.4 Certainly, the surgical complexity of resecting a leiomyosarcoma in the IVC is much greater than the surgical complexity of resecting one arising from an upper-extremity vein. Other factors, suchasunique tumorbiology,mayalso affect theoutcomes of patients with leiomyosarcomas arising from different vessels, so it may not be appropriate to lump all these heterogeneous sites together. Nevertheless, Roland et al4 should be applauded for their immunohistochemical studies seeking to identify the specificmolecular alterations thatmaybedriving tumorprogression and thatmay serve aspotential targets for therapy.4 Leiomyosarcomas arising from various vessels may share key signaling pathways that drive other forms of cancer. As new therapies targeting these signaling pathways are developed, there is the hope of improving the outcome of patients with cancer, including those patients with extremely rare types of cancer that share these molecular alterations.