56-year-old man with a large undifferentiated pleomorphic sarcoma of the thigh
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A 56-year-old man presented to the ED with 3 months of atraumatic left thigh pain.
He had significant difficulty with ambulation that was not relieved with over-the-counter pain medications. His medical history included type 2 diabetes mellitus. On clinical examination, he had swelling, fullness and tenderness to palpation globally along the quadriceps muscle, with a firm but compressible anterior thigh compartment. There were no motor or sensory deficits of the extremity. Radiographs of the left femur demonstrated a soft tissue density of the anterior thigh (Figure 1), and CT of the left femur revealed an intramuscular soft tissue mass of the anterior thigh measuring 22.5 cm x 10.4 cm x 7.7 cm (Figure 2). He underwent MRI with contrast, which better characterized this large, enhancing mass occupying almost all the vastus intermedius muscle with near complete circumferential envelopment of the femur.
The mass was predominantly isointense to muscle on T1-weighted scans with heterogeneous enhancement. There was a 2 cm area of anterior femoral cortical thinning, which suggested osseous extension of the tumor (Figure 3). Subsequent CT-guided soft tissue biopsy performed by interventional radiology was consistent with a high-grade sarcoma with pleomorphic cells present in addition to areas of necrosis. Mitotic activity and atypical mitotic figures were present. Other than patchy staining of Special AT-rich sequence-binding protein 2 compatible with osteoblastic differentiation and light positive smooth muscle antibodies, all other lineage-markers tested were negative. No identifiable fusion proteins were present in the tumor.
Source: Colleen Wixted, MD, MBA; Yixuan Tong, MD; and Karim Masrouha, MD
Based on this immunohistochemical and genomic sequencing, the patient was diagnosed with an undifferentiated pleomorphic sarcoma (UPS), previously known as malignant fibrous histiocytoma. There was no evidence of lymph node involvement. A CT scan of the chest for further staging did not show evidence of lung metastasis. The UPS was deemed a stage IIIB.
What are the best next steps in management of this patient?
See answer below.
Expedited surgical resection, reconstruction
After thorough multidisciplinary discussion of these findings, the decision was made to pursue expedited surgical resection and reconstruction rather than delay until after neo-adjuvant radiation. This was due to the tumor size and rapid growth, which could preclude the ability to perform a limb salvage surgery.
Operative procedure
An extensile lateral incision was made from just proximal to the greater trochanter to the lateral epicondyle of the femur. The iliotibial band was incised longitudinally and the fascia of the vastus lateralis was elevated anteriorly and posteriorly. The soft tissues from the femur to approximately 8 cm to 9 cm distal to the greater trochanter were elevated. Distally, soft tissue was elevated off the femur until the area was reached where the tumor was wrapped circumferentially. The rectus femoris was elevated anteriorly and transected distally. A distal wide margin was sent for frozen section, which confirmed a negative margin, the closest being 0.2 cm away from the tumor tissue at the anterior and medial margins.
Next, the distal femoral bone cut was made with an oscillating saw. The tumor then could be fully accessed distally and was circumferentially detached from the medial and posterior musculature, leaving a wide margin of muscle around the tumor. Branches from the femoral vessels to the tumor were carefully identified and tied off throughout dissection, taking care to ensure meticulous hemostasis. Next, the tumor was freed from the proximal soft tissues after careful dissection of two large arteries and veins branching from the main femoral vessels. These two large vessels appeared to be feeding into the tumor, perhaps in a form of neovascularization. The proximal margins were sent for frozen section and were also negative for tumor, again the closest 0.2 cm away from adjacent tumor tissue. Finally, the proximal femoral bone cut was made, again with an oscillating saw. The soft tissue mass and segmental femur were removed en bloc from the surgical field, measuring 18.5 cm in length (Figure 4).
The operative limb was re-draped, and fresh surgical instruments were brought onto the field for the reconstruction portion of the procedure. The proximal and distal ends of the femur were manually reamed. Trial modular intercalary prosthetic implants (LinkBio Corp.) were fitted both proximally and distally to their respective remaining femoral canals to reconstruct the length of femur resected. With trial implants in place — proximal stem size: 16 mm x 100 mm, distal stem size: 14 mm x 100 mm — the length of the femur was found to be slightly longer than the contralateral side. Because the desired limb length fell between sizes of the available proximal implant stem lengths, the longer option was utilized and shortened by 20 mm with a diamond cutting burr.
Next, the final implants were inserted and cemented into place (Figure 5). Once the cement hardened, the proximal and distal intercalary ends were linked with two screws. Rotational stabilization of the reconstruction was augmented further with a 20-hole lateral distal femoral locking plate, which bypassed the femur-implant junctions (Figure 6). During wound closure, superficial and deep drains were placed, and a negative pressure wound vacuum dressing was applied for two weeks. Immediate postoperative radiographs are shown in Figure 7. Surgical pathology of the resected specimen confirmed the diagnosis of UPS with negative surgical margins (Figure 8).
Postoperative course
The patient was made weight-bearing as tolerated on the operative extremity in a knee immobilizer brace. He subsequently received 6 weeks of adjuvant radiation therapy (6,300 cGy). At 4 months postoperatively, he developed evidence of new lung metastases, confirmed with subsequent lung biopsy, and was started on doxorubicin-based chemotherapy (Figure 9). This was unsurprising given the size of his tumor at diagnosis and high likelihood of micro-metastases.
At 6-month follow-up, the patient remains ambulatory with a walker as an assistive device and has a residual 40° extensor lag at the knee. Postoperative radiographs at 6-month follow-up demonstrate intact hardware without evidence of failure or local recurrence (Figure 10).
Discussion
Soft tissue sarcomas are rare tumors, accounting for less than 1% of malignancies. These sarcomas include various histologic subtypes, UPS among the most common, which is defined by its histologic pleomorphism and unidentifiable cellular lineage. They are typically diagnosed in older adults in their sixth and seventh decade. Given these are often painless masses, most commonly in the thigh, diagnosis may be delayed until the tumor is large enough to compress surrounding structures and cause symptoms, at which point the tumor may have metastasized. Distant metastases in high-grade UPS are most identified in the lungs, which is why chest CT is a critical part of initial work-up prior to treatment of locoregional disease.
Size at initial presentation is one of the most important prognosticators, as larger tumors carry an increased risk of metastatic disease. Localized disease tends to have a more favorable prognosis. Thus, early recognition of these tumors is paramount. This increased risk may be related to larger tumors having a higher propensity to invade adjacent neurovascular structures. Further, larger tumors have undergone a greater number of cellular divisions. This increased mitotic activity lends itself to mutations that can enhance the tumor’s capacity for metastasis or promote a more aggressive tumor biology. In addition to tumor size, previous studies have shown negative margins at the time of initial resection to be a key, positive prognostic factor. A 2008 study of 123 patients with median follow-up of 4.3 years reported the 5-year survival for patients with negative margins was 3.5 times higher than those with positive margins (79% vs. 23%). In a second study in 2019 of 266 patients with median 7.8 years of follow-up, the authors reported a 60.9% 5-year survival rate for those with negative margins compared with 45.6% for those with positive margins.
Radical surgery is the cornerstone of UPS treatment. The decision to pursue adjuvant radiation following surgical resection is primarily intended to reduce the risk of local recurrence, with some studies reporting a 0% risk at 10 years. However, it may not have a significant effect on overall survival given distant metastases have a larger impact on mortality. Thus, radiation therapy may be deferred in situations where it confers a high morbidity for the patient. In addition, low-grade tumors at a smaller risk of recurrence do not necessitate radiation treatment. A nomogram developed by Oren Cahlon, MD, and colleagues based on age, size of tumor, margin status, grade of tumor and histology can be utilized to estimate risk of local recurrence following surgical resection of these tumors and help guide adjuvant radiation treatment.
Adjuvant chemotherapy with doxorubicin-based regimens have also been shown to provide an additional survival benefit in more advanced disease. However, the role of systemic chemotherapy remains controversial as there lacks a robust body of evidence supporting consistent benefit. This may be partly explained by the expression of genes laptm4a and laptm4b that confer chemotherapy resistance. As such, indications remain inexplicit and there is no consensus on implementation guidelines. In general, systemic chemotherapy is reserved for patients with tumors larger than 10 cm and higher risk for metastatic disease.
Another viable option for the treatment of UPS may be immunotherapy. A study that included 40 patients with UPS, bone sarcoma or liposarcoma received pembrolizumab (Keytruda, Merck & Co.) that was then expanded in 2019 to include an additional 40 patients with UPS. The response rate was found to be 23% in the UPS cohort. Additional trials will help establish the role of immunotherapy in the treatment of UPS and identify genetic markers of these tumors that make this therapy more efficacious.
Key points
- Early detection of soft tissue sarcoma is challenging but critical in optimizing prognosis in patients with UPS.
- Diagnostic evaluation of UPS includes radiographic and advanced imaging, tissue biopsy and staging to rule out lung metastasis.
- Treatment includes radical surgical resection, with adjuvant radiation mitigating the risk of local recurrence and chemotherapy reserved for larger tumors at high risk of progressing to metastatic disease.
- Patients should undergo postoperative surveillance chest CTs to monitor for pulmonary metastases, which can occur years after surgical resection.
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- For more information:
- Karim Masrouha, MD; Yixuan Tong, MD; and Colleen Wixted, MD, MBA, can be reached at the department of orthopedic surgery at the NYU Langone Orthopedic Hospital. Masrouha’s email: karim.masrouha@nyulangone.org. Tong’s email: yixuan.tong@nyulangone.org. Wixted’s email: colleen.wixted@nyulangone.org.
- Edited by Nicole Rynecki, MD, and Harold I. Salmons, MD. Rynecki is a chief resident in orthopedic surgery at NYU Langone. She will be pursuing a sports medicine fellowship at Hospital for Special Surgery following residency completion. Salmons is a chief orthopedic surgery resident at the Mayo Clinic. He will be pursuing an adult reconstruction fellowship at Hospital for Special Surgery following residency completion. For more information on submitting Orthopedics Today Grand Rounds cases, please email orthopedics@healio.com.
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