Case study 106.1

A 38-year-old social worker noted a slowly growing lump on her right posterior upper arm. Physical exam reveals a 4 cm fatty mass suggestive of a lipoma.

1. What should the next step in her diagnostic work-up include?

To send her for a diagnostic biopsy
To set up an excisional biopsy
To set up an incision and drainage
Obtain an ultrasound or magnetic resonance imaging (MRI) of the right upper arm
Clinical follow-up in 6 months

Lipoma is a benign tumor composed of mature adipocytes that represent the most common adipocytic tumor. Imaging studies show a homogeneous soft tissue mass that is isodense to the subcutaneous tissue and demonstrates fat saturation. If these radiographic characteristics are confirmed, it can be followed and biopsy would be considered unnecessary. It could be excised for cosmetic reasons. Atypical lipomatous tumors or well-differentiated liposarcomas on the other hand, are low-grade, locally aggressive malignant adipocytic tumors that demonstrate prominent fibrous stranding in a fatty tumor on imaging. De-differentiated liposarcomas are tumors that show evidence of a transition, either in the primary or in a recurrence, from atypical lipomatous tumor or well-differentiated liposarcoma to a nonlipogenic pleomorphic spindle cell sarcoma, usually of high histological grade. Radiological imaging shows the coexistence of both fatty and non-fatty solid components in the tumor. If features of malignancy are noted on imaging, a biopsy or planned resection should be done to confirm the histology.

Case study 106.2

A 60-year-old male executive is diagnosed as having a 7.3 cm high-grade pleomorphic undifferentiated sarcoma of the left distal thigh after an ultrasound-guided biopsy.

1. Which of the following should be obtained as part of his sarcoma work-up?

MRI of the left thigh and computed tomography (CT) of the chest
Positron emission tomography (PET)–CT scan
MRI of the left thigh and bone scan
MRI of the thigh and MRI of the total spine

Adequate imaging is part of the essential work-up for a sarcoma and should provide details about the size of the tumor and proximity to nearby visceral structures and neurovascular landmarks. Chest imaging is vital especially in high-grade extremity sarcomas as the lung is one of the most common sites of metastasis. For patients with alveolar soft parts sarcoma, brain imaging should be considered in patients with metastatic disease. Lymph node metastases are rare in soft tissue sarcoma but can be seen in certain histologies such as small cell sarcomas, synovial sarcomas, clear cell sarcoma, angiosarcoma, and epithelioid sarcoma. Myxoid round cell liposarcomas have a propensity to metastasize to fat-containing areas and bone in addition to the lungs, and occasionally an MRI of the spine and CT of the chest, abdomen and pelvis is included in staging evaluation. PET–CT are not yet approved for routine management of soft tissue sarcomas.

Case study 106.3

A 56-year-old male construction worker had a 4.5 cm tumor removed from his right lateral leg, midway between the knee and ankle with the medial margin of the tumor adjoining the bone. The final pathology revealed a high-grade pleomorphic sarcoma, and all other margins were negative per the report. Postop MRI shows surgical changes, and CT chest shows no metastasis.

1. Which of the following statements is true?

He requires a below-knee amputation
Considering the tumor size is less than 5 cm, no further therapy is recommended
He should have a limb-sparing re-resection by a sarcoma surgeon
Adjuvant radiation therapy

Adjuvant radiation therapy (RT) should be considered in certain extremity tumors, especially following a resection with close margins (<1 cm) or a microscopically positive margin on bone, a major blood vessel, or nerve, where limb-sparing re-resection is not feasible. Randomized trials and retrospective analyses support the use of preoperative or postoperative external-beam RT in appropriately selected patients with soft tissue sarcoma of extremity. The efficacy of postoperative RT was demonstrated in a prospective randomized trial comparing limb-sparing surgery with postoperative RT and limb-sparing surgery alone. Postoperative RT reduced the 10-year local recurrence rate in patients with high-grade sarcoma (no local recurrences vs. 22%) as well as low-grade sarcoma (5% vs. 32%). The Canadian Sarcoma group conducted a phase III randomized trial looking at preoperative RT (50 Gy in 25 fractions) versus postoperative RT (66 Gy in 33 fractions) in patients with localized primary or recurrent extremity sarcoma and showed that local control and progression-free survival (PFS) rates were similar for both groups. However, preoperative RT was associated with a greater incidence of acute wound complications (35% vs. 17% for postoperative RT), and late treatment-related side effects such as fibrosis, edema, and joint stiffness were more common in patients receiving postoperative RT, most likely due to the higher RT dose and larger treatment volume. Preoperative RT is preferred due to these reasons, especially if margins are expected to be close.

Case study 106.4

A young engineer in his mid-30s presents with an 11.6 cm soft tissue mass above his right elbow, which he first noted several months ago and which has since noticeably increased in size. Biopsy is consistent with a monophasic synovial sarcoma with 30 mitoses per 10 high-power field (HPF). Immunohistochemical studies show nuclear reactivity for TLE1, weak reactivity for SMA, and patchy weak to equivocal reactivity for desmin. Fluorescence in situ hybridization (FISH) on interphase nuclei in paraffin-embedded sections reveals a clonal population of cells with rearrangement of the SYT/SS18 locus (18q11).

1. Out of the following, what is the best recommendation for his treatment?

Neoadjuvant chemotherapy, followed by radiation and then surgery in a multidisciplinary care setting
An above-elbow amputation
Limb-sparing surgery followed by adjuvant chemotherapy
Limb-sparing surgery followed by radiation therapy

Limb-sparing surgery ± radiation is recommended for most patients with soft tissue sarcoma of extremities to achieve local tumor control with minimal morbidity. Preoperative RT and/or neoadjuvant chemotherapy are used in certain situations to augment surgery to achieve a margin-negative resection. The benefit of adjuvant chemotherapy continues to be debated due to the challenge of performing an adequately powered randomized controlled study in a rare tumor that has tremendous heterogeneity in chemo-responsiveness of the various sarcoma subtypes. To address the problem of inadequately powered adjuvant sarcoma studies showing nonsignificant benefit in survival outcomes, the Sarcoma Meta-analysis Collaboration (SMAC) performed a meta-analysis of 14 studies, initially published in 1997. Eight of these studies used varying combinations of doxorubicin, and six studies used single-agent doxorubicin. The 10-year disease-free survival was improved (45 to 55%; P = 0.0001), but 10-year overall survival (OS) did not reach significance (50 to 54%; P = 0.12). Patients with extremity tumors appeared to have the clearest survival benefit with chemotherapy based on a subgroup analysis. An update of the SMAC analysis was published in 2008 and included four additional randomized trials. The pooled data from a total of 1953 patients demonstrated a statistically significant improvement in local and distant recurrence with adjuvant chemotherapy. There was a statistically significant survival benefit for doxorubicin combined with ifosfamide (OR 0.56; 95% confidence interval (CI): 0.36–0.85; P = 0.01)) but not for doxorubicin alone (OR of 0.84; 95% CI: 0.68–1.03; P = 0.09)). This study did not include the largest adjuvant study by the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC) study evaluating five cycles of adjuvant doxorubicin (75 mg/m²) and ifosfamide (5 gm/m²) versus observation in resected grade 2 and 3 extremity tumors. Survival in the observation arm was better than expected, leading to an interim analysis of futility. The dose of ifosfamide used in the trial was lower than what is routinely used in combination therapy for advanced disease. A separate update of the SMAC meta-analysis including this EORTC study, with a total of 2170 patients, showed a benefit of adjuvant chemotherapy for disease-free survival and OS after 5 years, but only a nonsignificant trend toward improved survival after 10 years (OR 0.87; P = 0.12).

Based on retrospective analyses however, the benefit of adjuvant chemotherapy appears to be much higher in patients with high-grade ≥5 cm tumors with certain chemosensitive histologies (i.e., myxoid or round cell liposarcomas and synovial sarcomas). Neo-adjuvant chemotherapy in this setting has the advantage of response assessment to allow for a more personalized risk–benefit approach while downsizing the tumor to improve chances of margin-negative surgery. Multidisciplinary care in a center with expertise in sarcoma is preferred as it leads to improved outcomes.

Case study 106.5

A 42-year-old businessman in otherwise good health noted an enlarging mass on the medial aspect of his left thigh. Ultrasound revealed a 5.3 cm superficial mass. He underwent a resection by his local surgeon, and pathology revealed a myxoid liposarcoma with tumor extending to the resection margin. Chest X-ray shows no abnormality. MRI of the arm shows some soft tissue enhancement next to the surgical bed.

1. Which of the following would be the best option?

Watchful waiting with a 3-month follow-up in clinic
Adjuvant radiation therapy alone
Re-resection to obtain negative margins, and then consider postop RT
Adjuvant chemotherapy with a doxorubicin-based combination

Microscopically positive surgical margins are associated with a higher rate of local recurrence and lower rate of disease-free survival, especially in patients with extremity sarcomas. Both the surgeon and the pathologist should document surgical margins in evaluating a resected specimen. Surgical re-resection to obtain negative margins should strongly be considered if resection margins are positive on final pathology (unless on bone, nerve, or major blood vessels). Referral for postoperative radiation therapy should be made for high-risk patients or if the margin status is close or unclear.