多学科方法治疗意外非肿瘤性切除后高危的躯干局部软组织肉瘤

IF 503.1 1区 医学 Q1 ONCOLOGY CA: A Cancer Journal for Clinicians Pub Date : 2023-05-24 DOI:10.3322/caac.21787
Candace L. Haddox MD, Elizabeth H. Baldini MD, MPH, Jyothi P. Jagannathan MD, Jason L. Hornick MD, PhD, Chandrajit P. Raut MD, MS
{"title":"多学科方法治疗意外非肿瘤性切除后高危的躯干局部软组织肉瘤","authors":"Candace L. Haddox MD,&nbsp;Elizabeth H. Baldini MD, MPH,&nbsp;Jyothi P. Jagannathan MD,&nbsp;Jason L. Hornick MD, PhD,&nbsp;Chandrajit P. Raut MD, MS","doi":"10.3322/caac.21787","DOIUrl":null,"url":null,"abstract":"<p>A man aged 45 years with hypertension and hyperlipidemia presented to his primary care physician with a 3-month history of a golf ball-sized right upper back mass. Ultrasound was performed, revealing a well defined lesion with mixed echogenicity, thought to be consistent with a lipoma. Clinically, however, the mass rapidly enlarged and became painful. The patient was referred to dermatology and subsequently to a surgeon. He underwent surgery at his local institution 2 months after initial presentation.</p><p>The mass was excised in two fragments measuring 8 × 7 cm and 6 × 6 cm. Pathology revealed a high-grade pleomorphic liposarcoma (PLPS). Necrosis was observed, and the mitotic rate was 26 per 10 high-power fields. The tumor involved the margins of the piecemeal excision specimens. Computed tomography (CT) imaging of the chest, abdomen, and pelvis was notable for tiny, indeterminate pulmonary nodules and a 4.3 × 2.4 × 4.7 cm, well circumscribed area with central low density in the right posterolateral chest wall soft tissues, possibly reflecting a postoperative seroma (Figure 1A). The patient noted progressive enlargement of the operative site; therefore, repeat CT imaging of the chest was performed 3 weeks later and showed an enlarging soft tissue mass concerning for residual disease (Figure 1B). Magnetic resonance imaging (MRI) of the chest showed a 4.2 × 5.0 × 6.0 cm solid mass with enhancement and diffusion restriction contiguous with the latissimus dorsi muscle (Figure 1C,D). The patient was referred to our sarcoma specialty center and had a multidisciplinary evaluation with medical oncology, radiation oncology, and surgical oncology. Preoperative radiation therapy (RT) and surgery followed by adjuvant chemotherapy with doxorubicin and ifosfamide were recommended.</p><p>Ultrasonography (US) is often the first imaging examination performed to evaluate palpable, superficial soft tissue masses because of its wide availability, low cost, and ease of performance. US is most useful in distinguishing solid from cystic lesions without additional intravenous contrast, and it can identify specific benign lesions. However, the US findings of benign and malignant solid soft tissue tumors overlap, and accurate tissue diagnosis is not feasible in most instances.<span><sup>1, 2</sup></span> In this case, the US findings were reported as likely lipoma; therefore, the mass was resected because of rapid growth and pain. Findings concerning for malignancy are rapid growth, vascularity, and pain, which should prompt further workup with MRI or CT.<span><sup>2</sup></span> MRI is the imaging modality of choice for soft tissue tumors or tumor-like masses because of its superior contrast, allowing for tissue characterization and multiplanar capability without radiation exposure. In cases of suspected myxofibrosarcoma, MRI can be helpful diagnostically because these tumors are often infiltrative and extend along the fascial planes, referred to on MRI as the <i>tail sign</i>.<span><sup>3, 4</sup></span> CT is used primarily to guide the biopsy and can help in the identification of mineralization and osseous involvement, although it is not routinely used except in patients who have contraindications to MRI.</p><p>Postoperative seromas occur in up to 10% of patients and appear as a well marginated, fluid density structure with or without thin rim enhancement on contrast-enhanced CT or MRI. Local recurrence after excision of soft tissue sarcoma (STS) is seen in 5%–35% of cases, usually occurring within the first 2 years. Risk factors associated with recurrence are &gt;5 cm, intermediate-grade or high-grade tumors, and positive or close surgical margins. It is often difficult to distinguish recurrent tumor from postoperative seroma on CT, especially for tumors with myxoid elements, which can mimic low-density fluid on CT. Contrast-enhanced MRI is the modality of choice to distinguish between posttreatment changes and tumor recurrence.<span><sup>5, 6</sup></span> Recurrence is often seen as a discrete, T2, hyperintense, enhancing nodule or mass, with imaging characteristics often similar to the primary tumor.<span><sup>7</sup></span> In this case, the MRI features were consistent with recurrence.</p><p>Histologically, the tumor showed extensive myxoid stroma with curvilinear blood vessels and scattered pleomorphic cells, features characteristic of myxofibrosarcoma (Figure 2A). However, in addition, there were focal areas with pleomorphic lipoblasts, diagnostic of pleomorphic liposarcoma (Figure 2B). Pleomorphic liposarcoma may show a range of histologic appearances. Most examples are morphologically similar to undifferentiated pleomorphic sarcoma, other than the presence of lipoblasts (which range from few to extensive); some cases closely mimic myxofibrosarcoma, whereas others show strikingly epithelioid morphology, mimicking carcinomas (especially adrenal cortical carcinoma).<span><sup>8, 9</sup></span> The distinction between pleomorphic liposarcoma and myxofibrosarcoma has implications for both prognosis and surgical management.<span><sup>10</sup></span> The risk of distant metastasis for pleomorphic liposarcoma is around 50%, compared with 25%–30% for high-grade myxofibrosarcoma. Pleomorphic liposarcoma is generally well circumscribed, similar to most other adult sarcoma types; therefore, local control for extremity and trunk wall tumors is usually straightforward when managed in sarcoma centers with surgical and radiation oncology sarcoma expertise. In contrast, myxofibrosarcoma shows markedly infiltrative margins along fascial planes, often extending far beyond grossly and clinically apparent margins; without wide excision, the risk of recurrence is very high: myxofibrosarcoma is one of the few sarcoma types in the modern era that often necessitates amputation after multiple local recurrences.<span><sup>11</sup></span></p><p>Optimal treatment for localized, high-grade STS of the extremity and trunk is combined oncologic resection and RT. Three landmark randomized trials established this role for conservative surgery and RT. The first trial randomized patients with extremity STS to amputation (the standard of care at that time) versus conservative surgery and postoperative RT; all patients received adjuvant chemotherapy.<span><sup>12</sup></span> There was no statistically significant difference in overall survival (OS) between arms, and the patients who received surgery and RT experienced a local recurrence rate of only 15%. The next two trials assessed the need for RT and compared conservative surgery alone with conservative surgery and RT. The first trial randomized patients with low-grade and high-grade STS of the extremity to conservative surgery alone versus conservative surgery plus postoperative RT (63 grays [Gy]); all patients with high-grade disease also received postoperative chemotherapy.<span><sup>13</sup></span> Local recurrence rates were lower for patients who received RT. For patients with high-grade disease, the local recurrence rate in the RT arm was 0% compared with 20% for those who underwent surgery alone (<i>p</i> = .003). For patients with low-grade disease, the local recurrence rates were 4% and 33%, respectively (<i>p</i> = .016). There were no significant differences in OS between arms. The second trial randomized patients with STS of the extremity and trunk to conservative surgery alone versus conservative surgery and adjuvant RT (42–45 Gy) in the form of brachytherapy. The brachytherapy technique consisted of low-dose-rate iridum-192, which was after-loaded into catheters sewn into the tumor bed at the time of surgery.<span><sup>14</sup></span> Among patients with high-grade disease, the local recurrence rate in the RT arm was 9% compared with 30% for those who underwent surgery alone (<i>p</i> = .0025). No difference in local recurrence was observed in patients with low-grade STS, and, for this reason, brachytherapy is not typically recommended as a radiation modality for low-grade STS. Among all patients, there was no survival difference between arms.</p><p>Because the role for RT in addition to oncologic surgery had been established, the next question pertained to the optimal sequencing of RT and surgery. O’Sullivan et al. performed a seminal randomized trial in which they compared preoperative RT (50 Gy with or without a 16–20 Gy postoperative boost) with postoperative RT (66–70 Gy) for patients who had extremity STS.<span><sup>15</sup></span> Local control rates were not different between groups and were 93% and 92% for the preoperative and postoperative groups, respectively (<i>p</i> = .72). A 7-year update of the trial also showed no statistically significant difference in survival between treatment arms.<span><sup>16</sup></span> The side-effect profile was different, however. For patients who received preoperative RT, the rate of acute major wound complications after surgery was higher for patients who received preoperative RT compared with those who received postoperative RT (35% vs. 17%; <i>p</i> = 1). These complications are significant but reversible, and function was equivalent between treatment arms 1 year after surgery. For patients treated with the larger treatment field sizes typical for postoperative RT, grade ≥2 late toxicities were higher compared with patients treated with smaller field sizes. These toxicities include subcutaneous fibrosis, joint stiffness, and edema and are typically permanent.<span><sup>17</sup></span> Series have also demonstrated higher rates of bone fractures for patients who received postoperative RT compared with preoperative RT.<span><sup>18</sup></span> To summarize, the advantages of preoperative RT include irradiation of smaller volumes to lower doses compared with postoperative RT, albeit at the expense of a higher risk of wound complications, which are reversible. With postoperative RT (which uses higher doses to larger volumes), there is a higher rate of permanent long-term complications, such as edema, joint stiffness, fibrosis, and fracture. Both approaches are acceptable, but expert panels recommend preoperative RT for most situations.<span><sup>19</sup></span></p><p>Because STS is so rare, as was the case for the current patient, initial management is often inadvertent marginal surgery performed either for a presumed benign lesion or for a presumed malignant lesion without appreciating that wide margins are required for STS. As described above, the initial surgery for the patient in this case was piecemeal, and postoperative imaging showed gross residual disease. This commonplace situation is referred to as an <i>unplanned excision</i>. Expert guidelines in this scenario recommend preoperative RT followed by definitive oncologic re-resection.<span><sup>19</sup></span> Essentially, patients who undergo an <i>unplanned excision</i> are typically approached as though they have de novo disease. Accordingly, our recommendation for this patient with gross residual disease is standard preoperative RT (intensity-modulated RT to 50 Gy) followed by oncologic resection 4–6 weeks after the completion of RT.</p><p>With respect to defining the RT treatment fields, careful review of both the initial preoperative MRI (when available) and the postoperative/unplanned excision MRI with an experienced radiologist is crucial. Both studies should be fused with the radiation planning CT scan to define the sum of the initial de novo and postexcision gross tumor volumes. A wire should be placed on the incision at the time of simulation to help define the underlying tumor bed. Once the gross tumor volume has been established, typical clinical target volume expansions for a subcutaneous STS are 3–4 cm radially in every direction and 0.5–1.0 cm deep into underlying muscle/chest wall. Planning target volume expansions are institution-dependent and usually 0.5 cm if daily pretreatment volumetric imaging guidance is used.<span><sup>19</sup></span></p><p>There are also some planning nuances with respect to histology. Pathology review for this case showed high-grade pleomorphic liposarcoma <i>mimicking myxofibrosarcoma</i>. When planning local therapy, one's antenna should always go up if the histology shows myxofibrosarcoma because these tumors are particularly infiltrative and are associated with higher local recurrence rates if the extent of tumor is underappreciated.<span><sup>11, 20, 21</sup></span> Knowing the diagnosis in this case was critical to formulating the appropriate management plan.</p><p>As discussed above, defining the sarcoma subtype often has implications for the comprehensive management plan, including surgery. Before any definitive surgical intervention for a presumed sarcoma, a core-needle biopsy should be performed by interventional radiology. A core-needle biopsy is preferred over fine-needle aspiration because it provides better tumor architectural information critical to identifying the type of sarcoma. Furthermore, the risk of needle-track seeding is very low at 0.0%–0.7%.<span><sup>22-26</sup></span></p><p>A core-needle biopsy is also preferred over an excisional biopsy for establishing a diagnosis. This allows for one definitive operation when the time comes for surgery, rather than one operation for excision followed by a second more definitive operation, if indicated. When evaluating a patient with a soft tissue mass, it is important to consider that the differential is extensive, and surgery may not be indicated at all. Examples include various subcutaneous manifestations of hematologic malignancies (such as lymphoma) that only require systemic therapy, benign neoplasms (such as desmoid fibromatosis, for which surgery is no longer considered first-line therapy), or even benign conditions (such as nodular fasciitis) that are self-limited and eventually resolve entirely without any intervention.</p><p>If sarcoma is suspected, confirmation of the diagnosis and histologic subtype by an experienced sarcoma pathologist is critical to ensure appropriate management. Different histologic subtypes under the broader sarcoma umbrella commonly require different management. For instance, in this case, distinguishing between myxofibrosarcoma and PLPS affects the extent of the surgical margin. Myxofibrosarcomas typically have microscopic extensions well beyond the palpable or radiographic margins and thus warrant wider margins of resection (approximately 3 cm) when feasible for this histology compared with others. Local recurrence is the predominant pattern of failure for myxofibrosarcoma; in fact, the 5-year local recurrence rates are higher (12% all grades, 31% intermediate-grade/high-grade) than they are for other histologies arising in the trunk or extremities.<span><sup>27, 28</sup></span> However, with a diagnosis of PLPS, the surgical goal was to achieve margins of 2 cm, which is less than the margins needed for myxofibrosarcomas.</p><p>Piecemeal resections or incisional biopsies should be avoided because these can increase the risk of recurrence. Ideally, resections should be macroscopically complete with negative microscopic margins (R0 resections) to minimize local recurrence rates (6% at 5 years; 8% at 10 years).<span><sup>29</sup></span> <i>Preplanned</i> positive margins against critical structures (macroscopically complete with positive microscopic margins, or R1 resection) do not necessarily have higher rates of local recurrence (10% at 5 years; 12% at 10 years).<span><sup>29</sup></span> Importantly, <i>unplanned excisions</i> or <i>whoops</i> operations (margin-positive resections when sarcoma was not suspected) are associated with high rates of local recurrence even after re-excision (18% at 5 years; 24% at 10 years).<span><sup>29</sup></span></p><p>After the initial multidisciplinary consultation, the patient was not able to obtain insurance authorization to return for treatment at our sarcoma specialty center. Despite appeals motivated by improved outcomes and OS for patients managed at sarcoma specialty centers,<span><sup>30</sup></span> the patient received neoadjuvant treatment in the community without expertise in sarcoma. This led to delays in initiating RT, and the patient's tumor progressed rapidly in the interim. Initiation of neoadjuvant systemic therapy with combined doxorubicin, ifosfamide, and mesna was considered; however, the center had insufficient staff and availability to administer ifosfamide. Ultimately, the patient completed RT locally.</p><p>Restaging imaging (MRI of the chest to evaluate the primary site and CT of the chest, abdomen, and pelvis) was obtained for surgical planning and to re-evaluate for metastatic disease. Eventually, the patient was able to undergo definitive surgery at our institution.</p><p>Based on the histology, the goal of the operation was to obtain a margin-negative resection. The tumor was primarily located in the subcutaneous soft tissue, but its deep margin was inseparable from the underlying latissimus dorsi muscle. To get an adequate margin superficially, a paddle of skin extending beyond the palpable mass circumferentially was resected, continuing with wide soft tissue radial margins around the tumor in the subcutaneous soft tissue down to the fascia. The deep margin largely consisted of the latissimus dorsi muscle; however, anteriorly, the specimen was more adherent to the serratus anterior muscle than anticipated based on imaging. Therefore, for the deep margin, a portion of the serratus along the anterior aspect of the mass and a portion of the latissimus along the posterior aspect of the mass were removed. This provided a uniform muscle layer as a deep margin. The thoracodorsal neurovascular structures to the uninvolved portion of the latissimus were preserved.</p><p>Final pathology demonstrated a 9.3-cm, high-grade PLPS. Margins were &gt;2 cm circumferentially around all aspects of the tumor. Only 5% of the tumor was viable, indicating treatment response.</p><p>The role of perioperative chemotherapy in localized STS arising in the extremity or trunk is controversial. Several studies over recent decades resulted in conflicting conclusions, leading to varied practice patterns across sarcoma specialty centers. For example, a large meta-analysis published in 1997 included 14 trials that randomized patients with localized, resectable STS to receive chemotherapy versus no chemotherapy and concluded that anthracycline-based chemotherapy is associated with an absolute reduction in the risk of local recurrence by 6% (95% CI, 1%–10%), a 10% reduction in the risk of distant metastasis at 10 years (95% CI, 5%–15%), and a trend toward improved OS (HR, 0·89; 95% CI, 0.76–1.03).<span><sup>31</sup></span> These conclusions have been interpreted cautiously, however, given the heterogeneity of the STS subtypes, sizes, grades, and sites of disease included, the limited use of RT (47% of cases), and the varied chemotherapy regimens and doses used. A subsequent meta-analysis combining data from the 1997 analysis with four additional trials also demonstrated a modest risk reduction in local and distant recurrence (HR, 0.67; 95% CI, 0.56–0.82) and an improvement in OS (HR, 0.77; 95% CI, 0.64–0.93), but similar concerns about the heterogeneity of the included studies have limited widespread adoption of perioperative chemotherapy.<span><sup>32</sup></span> To address the limitations of the prior meta-analyses, The European Organization for Research and Treatment of Cancer (EORTC) 62931 trial (ClinicalTrials.gov identifier NCT00002641) randomized 351 patients with intermediate-grade or high-grade, localized STS to receive adjuvant chemotherapy with doxorubicin 75 mg/m<sup>2</sup> plus 5 g/m<sup>2</sup> ifosfamide and mesna in a 21-day cycle for five cycles versus observation alone.<span><sup>33</sup></span> The study demonstrated that adjuvant chemotherapy did not improve relapse-free survival (HR, 0.91; 95% CI, 0.67–0.22) or OS (HR, 0.94; 95% CI, 0.68–1.31).</p><p>The varied results of these studies often leave the oncologist conflicted about what to recommend for an individual patient. To address this, several nomograms have emerged to predict outcomes in patients with STS and can be used as tools to inform clinical decisions.<span><sup>34-39</sup></span> One of the most widely accepted nomograms with robust external validation is the Sarculator.<span><sup>40</sup></span> The Sarculator was developed for extremity STS but was retrospectively applied to the EORTC 62931 trial, which included nonextremity tumors, and demonstrated that patients with a low predicted OS (pOS) (&lt;60%) benefitted from adjuvant chemotherapy, with a significant improvement in disease-free survival (HR, 0.49; 95% CI, 0.28–0.85) and OS (HR, 0.50; 95% CI, 0.30–0.90).<span><sup>41</sup></span> In addition, the Italian Sarcoma Group (ISG)-STS 1001 trial (ClincalTrials.gov identifier NCT01710176) randomized patients with localized, high-risk, extremity or trunk STS to receive neoadjuvant anthracycline and ifosfamide (AI) chemotherapy versus a histology-tailored regimen and demonstrated improved outcomes in the AI arm, suggesting that AI chemotherapy may also be better than no chemotherapy in this population.<span><sup>42</sup></span> The Sarculator nomogram was also applied to the ISG-STS 1001 results and indicated that patients with low pOS had better outcomes than predicted by the Sarculator, further supporting a role for AI-based perioperative chemotherapy in these patients.<span><sup>43</sup></span> Taken together, these emerging data suggest that recommendations for perioperative chemotherapy should be individualized to the patient, and discussions on risks and benefits may be informed by predictive nomograms.</p><p>For the patient described in our case, the pOS was 57% based on the Sarculator's prediction for an extremity tumor, so adjuvant doxorubicin plus ifosfamide chemotherapy was discussed with the patient. After discussion of the potential side effects, long-term complications, and benefits, the patient agreed with adding systemic therapy after local treatment.</p><p>The clinical trial landscape for STS is skewed toward treatment of advanced, inoperable, and metastatic disease; however, several notable combined modality studies are underway to optimize the management of localized disease. Several trials are exploring perioperative RT combined with checkpoint inhibitors, oncolytic viruses, tyrosine kinase inhibitors, MDM2 inhibitors, DNA damage repair inhibitors, and combination chemotherapy and targeted therapies. It is important to refer patients to a sarcoma center with expertise and active clinical trials so patients can have access to these novel approaches that may improve upon the standard of care.</p><p>The patient has now completed local therapy for his trunk sarcoma and has no evidence of disease. He is anticipating initiating adjuvant chemotherapy followed by surveillance according to National Comprehensive Cancer Network guidelines. For this high-risk tumor, we would typically recommend CT of the chest and MRI of the primary site every 3 months for the first 2 years after completing therapy, then every 6 months through year 5, then annually through year 10.</p><p>STSs are rare malignancies with over 70 subtypes that have distinct behaviors and biological underpinnings. Increasingly, treatment is becoming more nuanced and tailored to the specific subtype of sarcoma. Our case highlights that it is essential to accurately diagnose the subtype of STS and have a multidisciplinary consultation at a sarcoma center to provide a comprehensive plan for optimal treatment; this is endorsed globally by international guidelines and the National Comprehensive Cancer Network STS guidelines. For these reasons, we endorse early referral to a sarcoma center for multidisciplinary planning and local therapy. When feasible and indicated, systemic therapy can be delivered at a sarcoma center or at a local oncology practice after consultation with a sarcoma medical oncologist. Telehealth options and shared care models now allow for partnerships between community oncologists and sarcoma experts to manage patients on surveillance and seamlessly address concerns during long-term follow-up.</p><p>Elizabeth H. Baldini reports personal fees from UpToDate outside the submitted work. Jason L. Hornick reports personal fees from Aadi Bioscience, Adaptimmune LLC, and TRACON Pharmaceuticals outside the submitted work. Candace L. Haddox, Jyothi P. Jagannathan, and Chandrajit P. Raut disclosed no conflicts of interest.</p>","PeriodicalId":137,"journal":{"name":"CA: A Cancer Journal for Clinicians","volume":null,"pages":null},"PeriodicalIF":503.1000,"publicationDate":"2023-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.3322/caac.21787","citationCount":"0","resultStr":"{\"title\":\"Multidisciplinary approach for a high-risk, localized soft tissue sarcoma of the trunk after unplanned nononcological resection\",\"authors\":\"Candace L. Haddox MD,&nbsp;Elizabeth H. Baldini MD, MPH,&nbsp;Jyothi P. Jagannathan MD,&nbsp;Jason L. Hornick MD, PhD,&nbsp;Chandrajit P. Raut MD, MS\",\"doi\":\"10.3322/caac.21787\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>A man aged 45 years with hypertension and hyperlipidemia presented to his primary care physician with a 3-month history of a golf ball-sized right upper back mass. Ultrasound was performed, revealing a well defined lesion with mixed echogenicity, thought to be consistent with a lipoma. Clinically, however, the mass rapidly enlarged and became painful. The patient was referred to dermatology and subsequently to a surgeon. He underwent surgery at his local institution 2 months after initial presentation.</p><p>The mass was excised in two fragments measuring 8 × 7 cm and 6 × 6 cm. Pathology revealed a high-grade pleomorphic liposarcoma (PLPS). Necrosis was observed, and the mitotic rate was 26 per 10 high-power fields. The tumor involved the margins of the piecemeal excision specimens. Computed tomography (CT) imaging of the chest, abdomen, and pelvis was notable for tiny, indeterminate pulmonary nodules and a 4.3 × 2.4 × 4.7 cm, well circumscribed area with central low density in the right posterolateral chest wall soft tissues, possibly reflecting a postoperative seroma (Figure 1A). The patient noted progressive enlargement of the operative site; therefore, repeat CT imaging of the chest was performed 3 weeks later and showed an enlarging soft tissue mass concerning for residual disease (Figure 1B). Magnetic resonance imaging (MRI) of the chest showed a 4.2 × 5.0 × 6.0 cm solid mass with enhancement and diffusion restriction contiguous with the latissimus dorsi muscle (Figure 1C,D). The patient was referred to our sarcoma specialty center and had a multidisciplinary evaluation with medical oncology, radiation oncology, and surgical oncology. Preoperative radiation therapy (RT) and surgery followed by adjuvant chemotherapy with doxorubicin and ifosfamide were recommended.</p><p>Ultrasonography (US) is often the first imaging examination performed to evaluate palpable, superficial soft tissue masses because of its wide availability, low cost, and ease of performance. US is most useful in distinguishing solid from cystic lesions without additional intravenous contrast, and it can identify specific benign lesions. However, the US findings of benign and malignant solid soft tissue tumors overlap, and accurate tissue diagnosis is not feasible in most instances.<span><sup>1, 2</sup></span> In this case, the US findings were reported as likely lipoma; therefore, the mass was resected because of rapid growth and pain. Findings concerning for malignancy are rapid growth, vascularity, and pain, which should prompt further workup with MRI or CT.<span><sup>2</sup></span> MRI is the imaging modality of choice for soft tissue tumors or tumor-like masses because of its superior contrast, allowing for tissue characterization and multiplanar capability without radiation exposure. In cases of suspected myxofibrosarcoma, MRI can be helpful diagnostically because these tumors are often infiltrative and extend along the fascial planes, referred to on MRI as the <i>tail sign</i>.<span><sup>3, 4</sup></span> CT is used primarily to guide the biopsy and can help in the identification of mineralization and osseous involvement, although it is not routinely used except in patients who have contraindications to MRI.</p><p>Postoperative seromas occur in up to 10% of patients and appear as a well marginated, fluid density structure with or without thin rim enhancement on contrast-enhanced CT or MRI. Local recurrence after excision of soft tissue sarcoma (STS) is seen in 5%–35% of cases, usually occurring within the first 2 years. Risk factors associated with recurrence are &gt;5 cm, intermediate-grade or high-grade tumors, and positive or close surgical margins. It is often difficult to distinguish recurrent tumor from postoperative seroma on CT, especially for tumors with myxoid elements, which can mimic low-density fluid on CT. Contrast-enhanced MRI is the modality of choice to distinguish between posttreatment changes and tumor recurrence.<span><sup>5, 6</sup></span> Recurrence is often seen as a discrete, T2, hyperintense, enhancing nodule or mass, with imaging characteristics often similar to the primary tumor.<span><sup>7</sup></span> In this case, the MRI features were consistent with recurrence.</p><p>Histologically, the tumor showed extensive myxoid stroma with curvilinear blood vessels and scattered pleomorphic cells, features characteristic of myxofibrosarcoma (Figure 2A). However, in addition, there were focal areas with pleomorphic lipoblasts, diagnostic of pleomorphic liposarcoma (Figure 2B). Pleomorphic liposarcoma may show a range of histologic appearances. Most examples are morphologically similar to undifferentiated pleomorphic sarcoma, other than the presence of lipoblasts (which range from few to extensive); some cases closely mimic myxofibrosarcoma, whereas others show strikingly epithelioid morphology, mimicking carcinomas (especially adrenal cortical carcinoma).<span><sup>8, 9</sup></span> The distinction between pleomorphic liposarcoma and myxofibrosarcoma has implications for both prognosis and surgical management.<span><sup>10</sup></span> The risk of distant metastasis for pleomorphic liposarcoma is around 50%, compared with 25%–30% for high-grade myxofibrosarcoma. Pleomorphic liposarcoma is generally well circumscribed, similar to most other adult sarcoma types; therefore, local control for extremity and trunk wall tumors is usually straightforward when managed in sarcoma centers with surgical and radiation oncology sarcoma expertise. In contrast, myxofibrosarcoma shows markedly infiltrative margins along fascial planes, often extending far beyond grossly and clinically apparent margins; without wide excision, the risk of recurrence is very high: myxofibrosarcoma is one of the few sarcoma types in the modern era that often necessitates amputation after multiple local recurrences.<span><sup>11</sup></span></p><p>Optimal treatment for localized, high-grade STS of the extremity and trunk is combined oncologic resection and RT. Three landmark randomized trials established this role for conservative surgery and RT. The first trial randomized patients with extremity STS to amputation (the standard of care at that time) versus conservative surgery and postoperative RT; all patients received adjuvant chemotherapy.<span><sup>12</sup></span> There was no statistically significant difference in overall survival (OS) between arms, and the patients who received surgery and RT experienced a local recurrence rate of only 15%. The next two trials assessed the need for RT and compared conservative surgery alone with conservative surgery and RT. The first trial randomized patients with low-grade and high-grade STS of the extremity to conservative surgery alone versus conservative surgery plus postoperative RT (63 grays [Gy]); all patients with high-grade disease also received postoperative chemotherapy.<span><sup>13</sup></span> Local recurrence rates were lower for patients who received RT. For patients with high-grade disease, the local recurrence rate in the RT arm was 0% compared with 20% for those who underwent surgery alone (<i>p</i> = .003). For patients with low-grade disease, the local recurrence rates were 4% and 33%, respectively (<i>p</i> = .016). There were no significant differences in OS between arms. The second trial randomized patients with STS of the extremity and trunk to conservative surgery alone versus conservative surgery and adjuvant RT (42–45 Gy) in the form of brachytherapy. The brachytherapy technique consisted of low-dose-rate iridum-192, which was after-loaded into catheters sewn into the tumor bed at the time of surgery.<span><sup>14</sup></span> Among patients with high-grade disease, the local recurrence rate in the RT arm was 9% compared with 30% for those who underwent surgery alone (<i>p</i> = .0025). No difference in local recurrence was observed in patients with low-grade STS, and, for this reason, brachytherapy is not typically recommended as a radiation modality for low-grade STS. Among all patients, there was no survival difference between arms.</p><p>Because the role for RT in addition to oncologic surgery had been established, the next question pertained to the optimal sequencing of RT and surgery. O’Sullivan et al. performed a seminal randomized trial in which they compared preoperative RT (50 Gy with or without a 16–20 Gy postoperative boost) with postoperative RT (66–70 Gy) for patients who had extremity STS.<span><sup>15</sup></span> Local control rates were not different between groups and were 93% and 92% for the preoperative and postoperative groups, respectively (<i>p</i> = .72). A 7-year update of the trial also showed no statistically significant difference in survival between treatment arms.<span><sup>16</sup></span> The side-effect profile was different, however. For patients who received preoperative RT, the rate of acute major wound complications after surgery was higher for patients who received preoperative RT compared with those who received postoperative RT (35% vs. 17%; <i>p</i> = 1). These complications are significant but reversible, and function was equivalent between treatment arms 1 year after surgery. For patients treated with the larger treatment field sizes typical for postoperative RT, grade ≥2 late toxicities were higher compared with patients treated with smaller field sizes. These toxicities include subcutaneous fibrosis, joint stiffness, and edema and are typically permanent.<span><sup>17</sup></span> Series have also demonstrated higher rates of bone fractures for patients who received postoperative RT compared with preoperative RT.<span><sup>18</sup></span> To summarize, the advantages of preoperative RT include irradiation of smaller volumes to lower doses compared with postoperative RT, albeit at the expense of a higher risk of wound complications, which are reversible. With postoperative RT (which uses higher doses to larger volumes), there is a higher rate of permanent long-term complications, such as edema, joint stiffness, fibrosis, and fracture. Both approaches are acceptable, but expert panels recommend preoperative RT for most situations.<span><sup>19</sup></span></p><p>Because STS is so rare, as was the case for the current patient, initial management is often inadvertent marginal surgery performed either for a presumed benign lesion or for a presumed malignant lesion without appreciating that wide margins are required for STS. As described above, the initial surgery for the patient in this case was piecemeal, and postoperative imaging showed gross residual disease. This commonplace situation is referred to as an <i>unplanned excision</i>. Expert guidelines in this scenario recommend preoperative RT followed by definitive oncologic re-resection.<span><sup>19</sup></span> Essentially, patients who undergo an <i>unplanned excision</i> are typically approached as though they have de novo disease. Accordingly, our recommendation for this patient with gross residual disease is standard preoperative RT (intensity-modulated RT to 50 Gy) followed by oncologic resection 4–6 weeks after the completion of RT.</p><p>With respect to defining the RT treatment fields, careful review of both the initial preoperative MRI (when available) and the postoperative/unplanned excision MRI with an experienced radiologist is crucial. Both studies should be fused with the radiation planning CT scan to define the sum of the initial de novo and postexcision gross tumor volumes. A wire should be placed on the incision at the time of simulation to help define the underlying tumor bed. Once the gross tumor volume has been established, typical clinical target volume expansions for a subcutaneous STS are 3–4 cm radially in every direction and 0.5–1.0 cm deep into underlying muscle/chest wall. Planning target volume expansions are institution-dependent and usually 0.5 cm if daily pretreatment volumetric imaging guidance is used.<span><sup>19</sup></span></p><p>There are also some planning nuances with respect to histology. Pathology review for this case showed high-grade pleomorphic liposarcoma <i>mimicking myxofibrosarcoma</i>. When planning local therapy, one's antenna should always go up if the histology shows myxofibrosarcoma because these tumors are particularly infiltrative and are associated with higher local recurrence rates if the extent of tumor is underappreciated.<span><sup>11, 20, 21</sup></span> Knowing the diagnosis in this case was critical to formulating the appropriate management plan.</p><p>As discussed above, defining the sarcoma subtype often has implications for the comprehensive management plan, including surgery. Before any definitive surgical intervention for a presumed sarcoma, a core-needle biopsy should be performed by interventional radiology. A core-needle biopsy is preferred over fine-needle aspiration because it provides better tumor architectural information critical to identifying the type of sarcoma. Furthermore, the risk of needle-track seeding is very low at 0.0%–0.7%.<span><sup>22-26</sup></span></p><p>A core-needle biopsy is also preferred over an excisional biopsy for establishing a diagnosis. This allows for one definitive operation when the time comes for surgery, rather than one operation for excision followed by a second more definitive operation, if indicated. When evaluating a patient with a soft tissue mass, it is important to consider that the differential is extensive, and surgery may not be indicated at all. Examples include various subcutaneous manifestations of hematologic malignancies (such as lymphoma) that only require systemic therapy, benign neoplasms (such as desmoid fibromatosis, for which surgery is no longer considered first-line therapy), or even benign conditions (such as nodular fasciitis) that are self-limited and eventually resolve entirely without any intervention.</p><p>If sarcoma is suspected, confirmation of the diagnosis and histologic subtype by an experienced sarcoma pathologist is critical to ensure appropriate management. Different histologic subtypes under the broader sarcoma umbrella commonly require different management. For instance, in this case, distinguishing between myxofibrosarcoma and PLPS affects the extent of the surgical margin. Myxofibrosarcomas typically have microscopic extensions well beyond the palpable or radiographic margins and thus warrant wider margins of resection (approximately 3 cm) when feasible for this histology compared with others. Local recurrence is the predominant pattern of failure for myxofibrosarcoma; in fact, the 5-year local recurrence rates are higher (12% all grades, 31% intermediate-grade/high-grade) than they are for other histologies arising in the trunk or extremities.<span><sup>27, 28</sup></span> However, with a diagnosis of PLPS, the surgical goal was to achieve margins of 2 cm, which is less than the margins needed for myxofibrosarcomas.</p><p>Piecemeal resections or incisional biopsies should be avoided because these can increase the risk of recurrence. Ideally, resections should be macroscopically complete with negative microscopic margins (R0 resections) to minimize local recurrence rates (6% at 5 years; 8% at 10 years).<span><sup>29</sup></span> <i>Preplanned</i> positive margins against critical structures (macroscopically complete with positive microscopic margins, or R1 resection) do not necessarily have higher rates of local recurrence (10% at 5 years; 12% at 10 years).<span><sup>29</sup></span> Importantly, <i>unplanned excisions</i> or <i>whoops</i> operations (margin-positive resections when sarcoma was not suspected) are associated with high rates of local recurrence even after re-excision (18% at 5 years; 24% at 10 years).<span><sup>29</sup></span></p><p>After the initial multidisciplinary consultation, the patient was not able to obtain insurance authorization to return for treatment at our sarcoma specialty center. Despite appeals motivated by improved outcomes and OS for patients managed at sarcoma specialty centers,<span><sup>30</sup></span> the patient received neoadjuvant treatment in the community without expertise in sarcoma. This led to delays in initiating RT, and the patient's tumor progressed rapidly in the interim. Initiation of neoadjuvant systemic therapy with combined doxorubicin, ifosfamide, and mesna was considered; however, the center had insufficient staff and availability to administer ifosfamide. Ultimately, the patient completed RT locally.</p><p>Restaging imaging (MRI of the chest to evaluate the primary site and CT of the chest, abdomen, and pelvis) was obtained for surgical planning and to re-evaluate for metastatic disease. Eventually, the patient was able to undergo definitive surgery at our institution.</p><p>Based on the histology, the goal of the operation was to obtain a margin-negative resection. The tumor was primarily located in the subcutaneous soft tissue, but its deep margin was inseparable from the underlying latissimus dorsi muscle. To get an adequate margin superficially, a paddle of skin extending beyond the palpable mass circumferentially was resected, continuing with wide soft tissue radial margins around the tumor in the subcutaneous soft tissue down to the fascia. The deep margin largely consisted of the latissimus dorsi muscle; however, anteriorly, the specimen was more adherent to the serratus anterior muscle than anticipated based on imaging. Therefore, for the deep margin, a portion of the serratus along the anterior aspect of the mass and a portion of the latissimus along the posterior aspect of the mass were removed. This provided a uniform muscle layer as a deep margin. The thoracodorsal neurovascular structures to the uninvolved portion of the latissimus were preserved.</p><p>Final pathology demonstrated a 9.3-cm, high-grade PLPS. Margins were &gt;2 cm circumferentially around all aspects of the tumor. Only 5% of the tumor was viable, indicating treatment response.</p><p>The role of perioperative chemotherapy in localized STS arising in the extremity or trunk is controversial. Several studies over recent decades resulted in conflicting conclusions, leading to varied practice patterns across sarcoma specialty centers. For example, a large meta-analysis published in 1997 included 14 trials that randomized patients with localized, resectable STS to receive chemotherapy versus no chemotherapy and concluded that anthracycline-based chemotherapy is associated with an absolute reduction in the risk of local recurrence by 6% (95% CI, 1%–10%), a 10% reduction in the risk of distant metastasis at 10 years (95% CI, 5%–15%), and a trend toward improved OS (HR, 0·89; 95% CI, 0.76–1.03).<span><sup>31</sup></span> These conclusions have been interpreted cautiously, however, given the heterogeneity of the STS subtypes, sizes, grades, and sites of disease included, the limited use of RT (47% of cases), and the varied chemotherapy regimens and doses used. A subsequent meta-analysis combining data from the 1997 analysis with four additional trials also demonstrated a modest risk reduction in local and distant recurrence (HR, 0.67; 95% CI, 0.56–0.82) and an improvement in OS (HR, 0.77; 95% CI, 0.64–0.93), but similar concerns about the heterogeneity of the included studies have limited widespread adoption of perioperative chemotherapy.<span><sup>32</sup></span> To address the limitations of the prior meta-analyses, The European Organization for Research and Treatment of Cancer (EORTC) 62931 trial (ClinicalTrials.gov identifier NCT00002641) randomized 351 patients with intermediate-grade or high-grade, localized STS to receive adjuvant chemotherapy with doxorubicin 75 mg/m<sup>2</sup> plus 5 g/m<sup>2</sup> ifosfamide and mesna in a 21-day cycle for five cycles versus observation alone.<span><sup>33</sup></span> The study demonstrated that adjuvant chemotherapy did not improve relapse-free survival (HR, 0.91; 95% CI, 0.67–0.22) or OS (HR, 0.94; 95% CI, 0.68–1.31).</p><p>The varied results of these studies often leave the oncologist conflicted about what to recommend for an individual patient. To address this, several nomograms have emerged to predict outcomes in patients with STS and can be used as tools to inform clinical decisions.<span><sup>34-39</sup></span> One of the most widely accepted nomograms with robust external validation is the Sarculator.<span><sup>40</sup></span> The Sarculator was developed for extremity STS but was retrospectively applied to the EORTC 62931 trial, which included nonextremity tumors, and demonstrated that patients with a low predicted OS (pOS) (&lt;60%) benefitted from adjuvant chemotherapy, with a significant improvement in disease-free survival (HR, 0.49; 95% CI, 0.28–0.85) and OS (HR, 0.50; 95% CI, 0.30–0.90).<span><sup>41</sup></span> In addition, the Italian Sarcoma Group (ISG)-STS 1001 trial (ClincalTrials.gov identifier NCT01710176) randomized patients with localized, high-risk, extremity or trunk STS to receive neoadjuvant anthracycline and ifosfamide (AI) chemotherapy versus a histology-tailored regimen and demonstrated improved outcomes in the AI arm, suggesting that AI chemotherapy may also be better than no chemotherapy in this population.<span><sup>42</sup></span> The Sarculator nomogram was also applied to the ISG-STS 1001 results and indicated that patients with low pOS had better outcomes than predicted by the Sarculator, further supporting a role for AI-based perioperative chemotherapy in these patients.<span><sup>43</sup></span> Taken together, these emerging data suggest that recommendations for perioperative chemotherapy should be individualized to the patient, and discussions on risks and benefits may be informed by predictive nomograms.</p><p>For the patient described in our case, the pOS was 57% based on the Sarculator's prediction for an extremity tumor, so adjuvant doxorubicin plus ifosfamide chemotherapy was discussed with the patient. After discussion of the potential side effects, long-term complications, and benefits, the patient agreed with adding systemic therapy after local treatment.</p><p>The clinical trial landscape for STS is skewed toward treatment of advanced, inoperable, and metastatic disease; however, several notable combined modality studies are underway to optimize the management of localized disease. Several trials are exploring perioperative RT combined with checkpoint inhibitors, oncolytic viruses, tyrosine kinase inhibitors, MDM2 inhibitors, DNA damage repair inhibitors, and combination chemotherapy and targeted therapies. It is important to refer patients to a sarcoma center with expertise and active clinical trials so patients can have access to these novel approaches that may improve upon the standard of care.</p><p>The patient has now completed local therapy for his trunk sarcoma and has no evidence of disease. He is anticipating initiating adjuvant chemotherapy followed by surveillance according to National Comprehensive Cancer Network guidelines. For this high-risk tumor, we would typically recommend CT of the chest and MRI of the primary site every 3 months for the first 2 years after completing therapy, then every 6 months through year 5, then annually through year 10.</p><p>STSs are rare malignancies with over 70 subtypes that have distinct behaviors and biological underpinnings. Increasingly, treatment is becoming more nuanced and tailored to the specific subtype of sarcoma. Our case highlights that it is essential to accurately diagnose the subtype of STS and have a multidisciplinary consultation at a sarcoma center to provide a comprehensive plan for optimal treatment; this is endorsed globally by international guidelines and the National Comprehensive Cancer Network STS guidelines. For these reasons, we endorse early referral to a sarcoma center for multidisciplinary planning and local therapy. When feasible and indicated, systemic therapy can be delivered at a sarcoma center or at a local oncology practice after consultation with a sarcoma medical oncologist. Telehealth options and shared care models now allow for partnerships between community oncologists and sarcoma experts to manage patients on surveillance and seamlessly address concerns during long-term follow-up.</p><p>Elizabeth H. Baldini reports personal fees from UpToDate outside the submitted work. Jason L. Hornick reports personal fees from Aadi Bioscience, Adaptimmune LLC, and TRACON Pharmaceuticals outside the submitted work. Candace L. Haddox, Jyothi P. Jagannathan, and Chandrajit P. Raut disclosed no conflicts of interest.</p>\",\"PeriodicalId\":137,\"journal\":{\"name\":\"CA: A Cancer Journal for Clinicians\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":503.1000,\"publicationDate\":\"2023-05-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.3322/caac.21787\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"CA: A Cancer Journal for Clinicians\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.3322/caac.21787\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"CA: A Cancer Journal for Clinicians","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.3322/caac.21787","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

男性,45岁,高血压和高脂血症,以3个月的高尔夫球大小的右上背部肿块就诊于他的初级保健医生。行超声检查,发现一清晰的病变伴混合回声,认为与脂肪瘤一致。然而,临床上,肿块迅速扩大并变得疼痛。病人转到皮肤科,随后转到外科医生那里。在初次就诊2个月后,他在当地医院接受了手术。将肿物切成8 × 7 cm和6 × 6 cm两块。病理显示为高度多形性脂肪肉瘤(PLPS)。观察到坏死,有丝分裂率为26 / 10倍视场。肿瘤累及切片切除标本的边缘。胸部、腹部和骨盆的计算机断层扫描(CT)显示微小的、不确定的肺结节和4.3 × 2.4 × 4.7 cm的、界限清晰的、中央低密度的右后外侧胸壁软组织区域,可能反映了术后血清肿(图1A)。患者注意到手术部位进行性扩大;因此,3周后复查胸部CT,发现软组织肿块增大,可能存在残留病变(图1B)。胸部磁共振成像(MRI)显示4.2 × 5.0 × 6.0 cm实性肿块,强化且扩散受限,毗邻背阔肌(图1C,D)。患者被转介到我们的肉瘤专科中心,接受了包括内科肿瘤学、放射肿瘤学和外科肿瘤学在内的多学科评估。建议术前放疗和手术配合阿霉素和异环磷酰胺辅助化疗。超声检查(US)通常是评估可触及的浅表软组织肿块的首选影像学检查,因为它广泛可用,成本低,易于执行。超声在区分实性和囊性病变时最有用,无需额外的静脉造影剂,它可以识别特定的良性病变。然而,美国对软组织良恶性实体瘤的表现有重叠,多数情况下组织诊断不准确。1,2在这个病例中,美国报告的结果可能是脂肪瘤;因此,肿块因快速生长和疼痛而被切除。恶性肿瘤的表现为快速生长、血管扩张和疼痛,应进一步进行MRI或ct检查。2 MRI是软组织肿瘤或肿瘤样肿块的首选成像方式,因为它具有优越的对比度,允许组织表征和无辐射暴露的多平面成像能力。在疑似黏液纤维肉瘤的病例中,MRI可以帮助诊断,因为这些肿瘤通常是浸润性的,沿着筋膜平面延伸,在MRI上被称为尾部征象。3,4 CT主要用于指导活检,可以帮助识别矿化和骨受累,尽管除了有MRI禁忌症的患者外,它并不常规使用。术后血清肿发生率高达10%,在增强CT或MRI上表现为边缘良好的流体密度结构,有或没有薄边缘增强。软组织肉瘤(STS)切除后局部复发见于5%-35%的病例,通常发生在前2年内。与复发相关的危险因素为:5厘米、中度或高度肿瘤、手术切缘阳性或闭合。在CT上很难区分复发性肿瘤和术后血肿,特别是有黏液成分的肿瘤,在CT上表现为低密度液体。对比增强MRI是鉴别治疗后改变和肿瘤复发的首选方式。复发常表现为离散、T2、高信号、强化结节或肿块,影像学特征常与原发肿瘤相似本例MRI表现与复发相符。组织学上,肿瘤表现为广泛的黏液样间质,血管呈曲线状,分散的多形性细胞,具有黏液纤维肉瘤的特征(图2A)。然而,除此之外,还有多形性脂肪母细胞的病灶区域,诊断多形性脂肪肉瘤(图2B)。多形性脂肪肉瘤可表现出一系列的组织学表现。大多数病例在形态上与未分化的多形性肉瘤相似,除了存在脂肪母细胞(从少量到广泛);一些病例与黏液纤维肉瘤非常相似,而另一些则表现出明显的上皮样形态,类似于癌(尤其是肾上腺皮质癌)。8,9多形性脂肪肉瘤和黏液纤维肉瘤的区别对预后和手术处理都有影响。 多形性脂肪肉瘤发生远处转移的风险约为50%,而高级别黏液纤维肉瘤发生远处转移的风险为25%-30%。多形性脂肪肉瘤通常与大多数其他成人肉瘤类型相似,界限清楚;因此,在具有外科和放射肿瘤学肉瘤专业知识的肉瘤中心进行治疗时,肢体和干壁肿瘤的局部控制通常是直截了当的。相反,黏液纤维肉瘤沿筋膜平面表现出明显的浸润性边缘,通常远远超出肉眼和临床明显的边缘;如果不广泛切除,复发的风险非常高:黏液纤维肉瘤是现代为数不多的在多发局部复发后需要截肢的肉瘤类型之一。11肢体和躯干局部、高度STS的最佳治疗方法是肿瘤切除和RT联合治疗。三个具有里程碑意义的随机试验确定了保守手术和RT的作用。第一项试验将肢体STS患者随机分为截肢(当时的标准治疗)和保守手术和术后RT;所有患者均接受辅助化疗两组患者的总生存率(OS)无统计学差异,接受手术和放疗的患者局部复发率仅为15%。接下来的两项试验评估了单纯保守手术与单纯保守手术加放疗的必要性。第一项试验将下肢低度和高度STS患者随机分为单纯保守手术与单纯保守手术加术后放疗两组(63灰色[Gy]);所有高度病变患者术后均接受化疗接受放疗的患者的局部复发率较低。对于高度病变的患者,放疗组的局部复发率为0%,而单独接受手术的患者为20% (p = 0.003)。低级别病变患者的局部复发率分别为4%和33% (p = 0.016)。两组间OS无显著差异。第二项试验将四肢和躯干STS患者随机分为单独保守手术和保守手术加辅助RT (42-45 Gy)近距离放疗两组。近距离放射治疗技术包括低剂量率的虹膜-192,在手术时将其加载到缝合在肿瘤床上的导管中在高级别疾病患者中,RT组的局部复发率为9%,而单独接受手术的患者为30% (p = 0.0025)。低级别STS患者局部复发无差异,因此,不推荐近距离放疗作为低级别STS的放疗方式。在所有患者中,两组之间没有生存差异。因为除了肿瘤手术之外,放射治疗的作用已经确立,下一个问题是放射治疗和手术的最佳顺序。O 'Sullivan等人进行了一项开创性的随机试验,他们比较了肢体sts患者的术前放疗(50 Gy,术后有或没有16-20 Gy的增强)和术后放疗(66-70 Gy)。15组间局部控制率没有差异,术前组和术后组分别为93%和92% (p = .72)。该试验的7年更新也显示治疗组之间的生存率没有统计学上的显著差异然而,副作用是不同的。对于术前接受RT治疗的患者,术前接受RT治疗的患者术后急性大伤口并发症发生率高于术后接受RT治疗的患者(35% vs 17%;p = 1)。这些并发症很严重,但是可逆的,手术后1年治疗组之间的功能相同。对于术后放疗典型的较大治疗野的患者,与较小治疗野的患者相比,≥2级的晚期毒性更高。这些毒性包括皮下纤维化、关节僵硬和水肿,通常是永久性的系列研究也表明,与术前相比,术后接受放疗的患者骨折发生率更高。18总的来说,术前放疗的优势包括与术后放疗相比,放疗的体积更小,剂量更低,尽管这是以更高的伤口并发症风险为代价的,而伤口并发症是可逆的。术后放疗(使用更高的剂量和更大的体积),永久性长期并发症的发生率更高,如水肿、关节僵硬、纤维化和骨折。这两种方法都是可以接受的,但专家小组建议在大多数情况下进行术前放疗。 19由于STS非常罕见,就像当前患者的情况一样,最初的治疗通常是对假定的良性病变或假定的恶性病变进行无意的边缘手术,而没有意识到STS需要宽边缘。如上所述,本例患者的初始手术是零碎的,术后影像学显示大体残留病变。这种常见的情况被称为计划外切除。专家指南在这种情况下建议术前放疗,然后进行肿瘤再切除从本质上讲,接受计划外切除的患者通常会被视为患有新发疾病。因此,我们建议对于有严重残留病变的患者进行标准术前放疗(强度调节至50 Gy),然后在放疗完成后4-6周进行肿瘤切除。关于确定放疗治疗范围,与经验丰富的放射科医生一起仔细检查初始术前MRI(如果可用)和术后/非计划切除MRI是至关重要的。这两项研究应与放射计划CT扫描相结合,以确定初始新生和切除后总肿瘤体积的总和。在模拟手术时,应在切口处放置金属丝,以帮助确定潜在的肿瘤床。一旦确定了大体肿瘤体积,典型的皮下STS临床靶体积在每个方向呈放射状扩张3-4厘米,0.5-1.0厘米深至下肌/胸壁。规划目标体积扩张取决于机构,如果使用每日预处理体积成像引导,通常为0.5厘米。在组织学方面也有一些计划上的细微差别。病理检查显示高级别多形性脂肪肉瘤与黏液纤维肉瘤相似。当计划局部治疗时,如果组织学显示黏液纤维肉瘤,则天线应始终上升,因为这些肿瘤特别具有浸润性,如果肿瘤的范围未被充分认识,则与较高的局部复发率相关。11,20,21了解该病例的诊断对于制定适当的治疗计划至关重要。如上所述,确定肉瘤亚型通常对包括手术在内的综合治疗计划有影响。在对推定的肉瘤进行任何明确的手术干预之前,应通过介入放射学进行芯针活检。芯针活检优于细针穿刺,因为它能提供更好的肿瘤结构信息,对确定肉瘤类型至关重要。此外,针径播种的风险很低,为0.0% ~ 0.7%。22-26在确定诊断时,芯针活检也优于切除活检。这允许在手术时间到来时进行一次明确的手术,而不是一次手术切除后再进行第二次更明确的手术,如果需要的话。当评估患有软组织肿块的患者时,重要的是要考虑到差异是广泛的,并且可能根本不需要手术。例如,各种只需要全身治疗的血液系统恶性肿瘤(如淋巴瘤)的皮下表现,良性肿瘤(如硬纤维瘤病,手术不再被认为是一线治疗方法),甚至是自限性的良性疾病(如结节性筋膜炎),最终无需任何干预即可完全消退。如果怀疑是肉瘤,由经验丰富的肉瘤病理学家确认诊断和组织学亚型是确保适当治疗的关键。在更广泛的肉瘤范畴下,不同的组织学亚型通常需要不同的治疗方法。例如,在本例中,区分黏液纤维肉瘤和PLPS影响手术切缘的范围。黏液纤维肉瘤通常在显微镜下的延伸远远超出可触及或x线摄影的边缘,因此在这种组织学下,与其他组织学相比,需要更宽的切除边缘(约3cm)。局部复发是粘液纤维肉瘤失败的主要模式;事实上,5年局部复发率(所有级别12%,中/高级级别31%)高于躯干或四肢其他组织学的复发率。27,28然而,对于PLPS的诊断,手术目标是达到2厘米的切缘,这比粘液纤维肉瘤所需的切缘要小。应避免切片切除或切口活检,因为这些会增加复发的风险。理想情况下,切除应在宏观上完全,镜下切缘为阴性(R0切除),以尽量减少局部复发率(5年6%;10年期8%)。 29预先计划的针对关键结构的阳性切缘(宏观上完整,显微镜下切缘阳性,或R1切除)不一定有更高的局部复发率(5年10%;10年12%)重要的是,非计划切除或whoops手术(未怀疑肉瘤的边缘阳性切除)与再次切除后的高局部复发率相关(5年为18%;10年24%)。29在最初的多学科会诊后,患者无法获得保险授权返回我们的肉瘤专科中心治疗。尽管在肉瘤专科中心治疗的患者的预后和OS得到改善,但患者在没有肉瘤专业知识的社区接受了新辅助治疗。这导致了开始RT的延迟,并且患者的肿瘤在此期间进展迅速。考虑联合阿霉素、异环磷酰胺和mesna进行新辅助全身治疗;然而,该中心没有足够的人员和可用性来管理异环磷酰胺。最终,患者完成了局部放疗。重新分期成像(胸部MRI评估原发部位,胸部、腹部和骨盆CT)用于手术计划和重新评估转移性疾病。最终,患者在我们的机构接受了最终的手术。根据组织学,手术的目的是获得边缘阴性切除。肿瘤主要位于皮下软组织,但其深缘与下面的背阔肌是分不开的。为了在表面上获得足够的边缘,切除可触及肿块外的一层皮肤,继续在肿瘤周围的皮下软组织中保留宽的软组织径向边缘,直至筋膜。深缘主要由背阔肌组成;然而,在前面,标本比基于成像的预期更粘附于前锯肌。因此,对于深缘,沿着肿块前部的一部分锯肌和沿着肿块后部的一部分阔肌被切除。这提供了一个均匀的肌肉层作为深缘。阔肌未受累部分的胸背神经血管结构得以保留。最终病理显示9.3 cm,高度PLPS。边缘沿肿瘤各方面圆周长2cm。只有5%的肿瘤存活,表明治疗有反应。围手术期化疗在四肢或躯干局限性STS中的作用存在争议。近几十年来的几项研究得出了相互矛盾的结论,导致肉瘤专科中心的实践模式各不相同。例如,1997年发表的一项大型荟萃分析包括14项试验,将局部可切除的STS患者随机分配接受化疗与不接受化疗,并得出结论:蒽环类化疗可使局部复发风险绝对降低6% (95% CI, 1%-10%), 10年远处转移风险降低10% (95% CI, 5%-15%),并有改善OS的趋势(HR, 0.89;95% ci, 0.76-1.03)然而,考虑到STS亚型、大小、分级和疾病部位的异质性、RT的有限使用(47%的病例)以及不同的化疗方案和剂量,这些结论被谨慎地解释。随后的荟萃分析将1997年的分析数据与另外四项试验相结合,也表明局部和远处复发的风险适度降低(HR, 0.67;95% CI, 0.56-0.82), OS改善(HR, 0.77;95% CI, 0.64-0.93),但对纳入研究的异质性的类似担忧限制了围手术期化疗的广泛采用为了解决先前荟萃分析的局限性,欧洲癌症研究和治疗组织(EORTC) 62931试验(ClinicalTrials.gov identifier NCT00002641)随机选择351例中度或高度局限性STS患者,接受阿霉素75 mg/m2 + 5 g/m2异环酰胺和mesna辅助化疗,为期21天,共5个周期,与单独观察相比研究表明,辅助化疗不能改善无复发生存(HR, 0.91;95% CI, 0.67-0.22)或OS (HR, 0.94;95% ci, 0.68-1.31)。这些研究的不同结果常常使肿瘤学家对个别患者的建议产生矛盾。为了解决这个问题,已经出现了几种图来预测STS患者的预后,并可作为告知临床决策的工具。34-39其中一个最广泛接受的具有可靠的外部验证的nomogram是sarator。 Sarculator是为四肢STS开发的,但回顾性应用于EORTC 62931试验,该试验包括非四肢肿瘤,结果表明,低预测OS (pOS) (&lt;60%)的患者受益于辅助化疗,无病生存期显著提高(HR, 0.49;95% CI, 0.28-0.85)和OS (HR, 0.50;95% ci, 0.30-0.90)此外,意大利肉瘤组(ISG)-STS 1001试验(ClincalTrials.gov标识号NCT01710176)将局限性、高风险、肢体或躯干STS患者随机分组,接受新辅助蒽环类和异环磷酰胺(AI)化疗,而不是组织学定制方案,结果显示AI组的预后改善,表明AI化疗在该人群中也可能比不化疗更好ISG-STS 1001结果也应用了Sarculator nomogram,结果显示低pOS患者的预后比Sarculator预测的要好,这进一步支持了基于人工智能的围手术期化疗在这些患者中的作用综上所述,这些新出现的数据表明围手术期化疗的建议应该针对患者进行个体化,并且可以通过预测nomographic来讨论风险和收益。对于我们病例中描述的患者,基于Sarculator对四肢肿瘤的预测,pOS为57%,因此与患者讨论了辅助阿霉素加异环磷酰胺化疗。在讨论了潜在的副作用、长期并发症和益处后,患者同意在局部治疗后增加全身治疗。STS的临床试验前景倾向于治疗晚期、不能手术和转移性疾病;然而,一些值得注意的联合模式研究正在进行中,以优化局部疾病的管理。一些试验正在探索围手术期RT联合检查点抑制剂、溶瘤病毒、酪氨酸激酶抑制剂、MDM2抑制剂、DNA损伤修复抑制剂,以及联合化疗和靶向治疗。将患者转到具有专业知识和积极临床试验的肉瘤中心是很重要的,这样患者就可以获得这些可能提高护理标准的新方法。该患者已完成躯干肉瘤的局部治疗,无疾病迹象。他预计开始辅助化疗,然后根据国家综合癌症网络指南进行监测。对于这种高危肿瘤,我们通常建议在完成治疗后的前两年每3个月进行一次胸部CT和原发部位的MRI检查,然后在第5年每6个月进行一次,然后在第10年每年进行一次。STSs是一种罕见的恶性肿瘤,有70多种亚型,具有不同的行为和生物学基础。越来越多地,治疗变得更加细致和量身定制的特定亚型肉瘤。我们的病例强调了准确诊断STS亚型和在肉瘤中心进行多学科会诊以提供最佳治疗的综合计划是至关重要的;这得到了国际指南和国家综合癌症网络STS指南的全球认可。基于这些原因,我们支持早期转诊到肉瘤中心进行多学科规划和局部治疗。在可行和有指示的情况下,系统性治疗可以在肉瘤中心进行,或者在与肉瘤医学肿瘤学家会诊后在当地的肿瘤诊所进行。远程医疗选择和共享护理模式现在允许社区肿瘤学家和肉瘤专家之间建立伙伴关系,以管理监测中的患者,并在长期随访期间无缝地解决问题。Elizabeth H. Baldini报告了UpToDate提交作品之外的个人费用。Jason L. Hornick报告了Aadi Bioscience, Adaptimmune LLC和TRACON Pharmaceuticals在提交的工作之外的个人费用。Candace L. Haddox、Jyothi P. Jagannathan和Chandrajit P. Raut没有披露任何利益冲突。
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Multidisciplinary approach for a high-risk, localized soft tissue sarcoma of the trunk after unplanned nononcological resection

A man aged 45 years with hypertension and hyperlipidemia presented to his primary care physician with a 3-month history of a golf ball-sized right upper back mass. Ultrasound was performed, revealing a well defined lesion with mixed echogenicity, thought to be consistent with a lipoma. Clinically, however, the mass rapidly enlarged and became painful. The patient was referred to dermatology and subsequently to a surgeon. He underwent surgery at his local institution 2 months after initial presentation.

The mass was excised in two fragments measuring 8 × 7 cm and 6 × 6 cm. Pathology revealed a high-grade pleomorphic liposarcoma (PLPS). Necrosis was observed, and the mitotic rate was 26 per 10 high-power fields. The tumor involved the margins of the piecemeal excision specimens. Computed tomography (CT) imaging of the chest, abdomen, and pelvis was notable for tiny, indeterminate pulmonary nodules and a 4.3 × 2.4 × 4.7 cm, well circumscribed area with central low density in the right posterolateral chest wall soft tissues, possibly reflecting a postoperative seroma (Figure 1A). The patient noted progressive enlargement of the operative site; therefore, repeat CT imaging of the chest was performed 3 weeks later and showed an enlarging soft tissue mass concerning for residual disease (Figure 1B). Magnetic resonance imaging (MRI) of the chest showed a 4.2 × 5.0 × 6.0 cm solid mass with enhancement and diffusion restriction contiguous with the latissimus dorsi muscle (Figure 1C,D). The patient was referred to our sarcoma specialty center and had a multidisciplinary evaluation with medical oncology, radiation oncology, and surgical oncology. Preoperative radiation therapy (RT) and surgery followed by adjuvant chemotherapy with doxorubicin and ifosfamide were recommended.

Ultrasonography (US) is often the first imaging examination performed to evaluate palpable, superficial soft tissue masses because of its wide availability, low cost, and ease of performance. US is most useful in distinguishing solid from cystic lesions without additional intravenous contrast, and it can identify specific benign lesions. However, the US findings of benign and malignant solid soft tissue tumors overlap, and accurate tissue diagnosis is not feasible in most instances.1, 2 In this case, the US findings were reported as likely lipoma; therefore, the mass was resected because of rapid growth and pain. Findings concerning for malignancy are rapid growth, vascularity, and pain, which should prompt further workup with MRI or CT.2 MRI is the imaging modality of choice for soft tissue tumors or tumor-like masses because of its superior contrast, allowing for tissue characterization and multiplanar capability without radiation exposure. In cases of suspected myxofibrosarcoma, MRI can be helpful diagnostically because these tumors are often infiltrative and extend along the fascial planes, referred to on MRI as the tail sign.3, 4 CT is used primarily to guide the biopsy and can help in the identification of mineralization and osseous involvement, although it is not routinely used except in patients who have contraindications to MRI.

Postoperative seromas occur in up to 10% of patients and appear as a well marginated, fluid density structure with or without thin rim enhancement on contrast-enhanced CT or MRI. Local recurrence after excision of soft tissue sarcoma (STS) is seen in 5%–35% of cases, usually occurring within the first 2 years. Risk factors associated with recurrence are >5 cm, intermediate-grade or high-grade tumors, and positive or close surgical margins. It is often difficult to distinguish recurrent tumor from postoperative seroma on CT, especially for tumors with myxoid elements, which can mimic low-density fluid on CT. Contrast-enhanced MRI is the modality of choice to distinguish between posttreatment changes and tumor recurrence.5, 6 Recurrence is often seen as a discrete, T2, hyperintense, enhancing nodule or mass, with imaging characteristics often similar to the primary tumor.7 In this case, the MRI features were consistent with recurrence.

Histologically, the tumor showed extensive myxoid stroma with curvilinear blood vessels and scattered pleomorphic cells, features characteristic of myxofibrosarcoma (Figure 2A). However, in addition, there were focal areas with pleomorphic lipoblasts, diagnostic of pleomorphic liposarcoma (Figure 2B). Pleomorphic liposarcoma may show a range of histologic appearances. Most examples are morphologically similar to undifferentiated pleomorphic sarcoma, other than the presence of lipoblasts (which range from few to extensive); some cases closely mimic myxofibrosarcoma, whereas others show strikingly epithelioid morphology, mimicking carcinomas (especially adrenal cortical carcinoma).8, 9 The distinction between pleomorphic liposarcoma and myxofibrosarcoma has implications for both prognosis and surgical management.10 The risk of distant metastasis for pleomorphic liposarcoma is around 50%, compared with 25%–30% for high-grade myxofibrosarcoma. Pleomorphic liposarcoma is generally well circumscribed, similar to most other adult sarcoma types; therefore, local control for extremity and trunk wall tumors is usually straightforward when managed in sarcoma centers with surgical and radiation oncology sarcoma expertise. In contrast, myxofibrosarcoma shows markedly infiltrative margins along fascial planes, often extending far beyond grossly and clinically apparent margins; without wide excision, the risk of recurrence is very high: myxofibrosarcoma is one of the few sarcoma types in the modern era that often necessitates amputation after multiple local recurrences.11

Optimal treatment for localized, high-grade STS of the extremity and trunk is combined oncologic resection and RT. Three landmark randomized trials established this role for conservative surgery and RT. The first trial randomized patients with extremity STS to amputation (the standard of care at that time) versus conservative surgery and postoperative RT; all patients received adjuvant chemotherapy.12 There was no statistically significant difference in overall survival (OS) between arms, and the patients who received surgery and RT experienced a local recurrence rate of only 15%. The next two trials assessed the need for RT and compared conservative surgery alone with conservative surgery and RT. The first trial randomized patients with low-grade and high-grade STS of the extremity to conservative surgery alone versus conservative surgery plus postoperative RT (63 grays [Gy]); all patients with high-grade disease also received postoperative chemotherapy.13 Local recurrence rates were lower for patients who received RT. For patients with high-grade disease, the local recurrence rate in the RT arm was 0% compared with 20% for those who underwent surgery alone (p = .003). For patients with low-grade disease, the local recurrence rates were 4% and 33%, respectively (p = .016). There were no significant differences in OS between arms. The second trial randomized patients with STS of the extremity and trunk to conservative surgery alone versus conservative surgery and adjuvant RT (42–45 Gy) in the form of brachytherapy. The brachytherapy technique consisted of low-dose-rate iridum-192, which was after-loaded into catheters sewn into the tumor bed at the time of surgery.14 Among patients with high-grade disease, the local recurrence rate in the RT arm was 9% compared with 30% for those who underwent surgery alone (p = .0025). No difference in local recurrence was observed in patients with low-grade STS, and, for this reason, brachytherapy is not typically recommended as a radiation modality for low-grade STS. Among all patients, there was no survival difference between arms.

Because the role for RT in addition to oncologic surgery had been established, the next question pertained to the optimal sequencing of RT and surgery. O’Sullivan et al. performed a seminal randomized trial in which they compared preoperative RT (50 Gy with or without a 16–20 Gy postoperative boost) with postoperative RT (66–70 Gy) for patients who had extremity STS.15 Local control rates were not different between groups and were 93% and 92% for the preoperative and postoperative groups, respectively (p = .72). A 7-year update of the trial also showed no statistically significant difference in survival between treatment arms.16 The side-effect profile was different, however. For patients who received preoperative RT, the rate of acute major wound complications after surgery was higher for patients who received preoperative RT compared with those who received postoperative RT (35% vs. 17%; p = 1). These complications are significant but reversible, and function was equivalent between treatment arms 1 year after surgery. For patients treated with the larger treatment field sizes typical for postoperative RT, grade ≥2 late toxicities were higher compared with patients treated with smaller field sizes. These toxicities include subcutaneous fibrosis, joint stiffness, and edema and are typically permanent.17 Series have also demonstrated higher rates of bone fractures for patients who received postoperative RT compared with preoperative RT.18 To summarize, the advantages of preoperative RT include irradiation of smaller volumes to lower doses compared with postoperative RT, albeit at the expense of a higher risk of wound complications, which are reversible. With postoperative RT (which uses higher doses to larger volumes), there is a higher rate of permanent long-term complications, such as edema, joint stiffness, fibrosis, and fracture. Both approaches are acceptable, but expert panels recommend preoperative RT for most situations.19

Because STS is so rare, as was the case for the current patient, initial management is often inadvertent marginal surgery performed either for a presumed benign lesion or for a presumed malignant lesion without appreciating that wide margins are required for STS. As described above, the initial surgery for the patient in this case was piecemeal, and postoperative imaging showed gross residual disease. This commonplace situation is referred to as an unplanned excision. Expert guidelines in this scenario recommend preoperative RT followed by definitive oncologic re-resection.19 Essentially, patients who undergo an unplanned excision are typically approached as though they have de novo disease. Accordingly, our recommendation for this patient with gross residual disease is standard preoperative RT (intensity-modulated RT to 50 Gy) followed by oncologic resection 4–6 weeks after the completion of RT.

With respect to defining the RT treatment fields, careful review of both the initial preoperative MRI (when available) and the postoperative/unplanned excision MRI with an experienced radiologist is crucial. Both studies should be fused with the radiation planning CT scan to define the sum of the initial de novo and postexcision gross tumor volumes. A wire should be placed on the incision at the time of simulation to help define the underlying tumor bed. Once the gross tumor volume has been established, typical clinical target volume expansions for a subcutaneous STS are 3–4 cm radially in every direction and 0.5–1.0 cm deep into underlying muscle/chest wall. Planning target volume expansions are institution-dependent and usually 0.5 cm if daily pretreatment volumetric imaging guidance is used.19

There are also some planning nuances with respect to histology. Pathology review for this case showed high-grade pleomorphic liposarcoma mimicking myxofibrosarcoma. When planning local therapy, one's antenna should always go up if the histology shows myxofibrosarcoma because these tumors are particularly infiltrative and are associated with higher local recurrence rates if the extent of tumor is underappreciated.11, 20, 21 Knowing the diagnosis in this case was critical to formulating the appropriate management plan.

As discussed above, defining the sarcoma subtype often has implications for the comprehensive management plan, including surgery. Before any definitive surgical intervention for a presumed sarcoma, a core-needle biopsy should be performed by interventional radiology. A core-needle biopsy is preferred over fine-needle aspiration because it provides better tumor architectural information critical to identifying the type of sarcoma. Furthermore, the risk of needle-track seeding is very low at 0.0%–0.7%.22-26

A core-needle biopsy is also preferred over an excisional biopsy for establishing a diagnosis. This allows for one definitive operation when the time comes for surgery, rather than one operation for excision followed by a second more definitive operation, if indicated. When evaluating a patient with a soft tissue mass, it is important to consider that the differential is extensive, and surgery may not be indicated at all. Examples include various subcutaneous manifestations of hematologic malignancies (such as lymphoma) that only require systemic therapy, benign neoplasms (such as desmoid fibromatosis, for which surgery is no longer considered first-line therapy), or even benign conditions (such as nodular fasciitis) that are self-limited and eventually resolve entirely without any intervention.

If sarcoma is suspected, confirmation of the diagnosis and histologic subtype by an experienced sarcoma pathologist is critical to ensure appropriate management. Different histologic subtypes under the broader sarcoma umbrella commonly require different management. For instance, in this case, distinguishing between myxofibrosarcoma and PLPS affects the extent of the surgical margin. Myxofibrosarcomas typically have microscopic extensions well beyond the palpable or radiographic margins and thus warrant wider margins of resection (approximately 3 cm) when feasible for this histology compared with others. Local recurrence is the predominant pattern of failure for myxofibrosarcoma; in fact, the 5-year local recurrence rates are higher (12% all grades, 31% intermediate-grade/high-grade) than they are for other histologies arising in the trunk or extremities.27, 28 However, with a diagnosis of PLPS, the surgical goal was to achieve margins of 2 cm, which is less than the margins needed for myxofibrosarcomas.

Piecemeal resections or incisional biopsies should be avoided because these can increase the risk of recurrence. Ideally, resections should be macroscopically complete with negative microscopic margins (R0 resections) to minimize local recurrence rates (6% at 5 years; 8% at 10 years).29 Preplanned positive margins against critical structures (macroscopically complete with positive microscopic margins, or R1 resection) do not necessarily have higher rates of local recurrence (10% at 5 years; 12% at 10 years).29 Importantly, unplanned excisions or whoops operations (margin-positive resections when sarcoma was not suspected) are associated with high rates of local recurrence even after re-excision (18% at 5 years; 24% at 10 years).29

After the initial multidisciplinary consultation, the patient was not able to obtain insurance authorization to return for treatment at our sarcoma specialty center. Despite appeals motivated by improved outcomes and OS for patients managed at sarcoma specialty centers,30 the patient received neoadjuvant treatment in the community without expertise in sarcoma. This led to delays in initiating RT, and the patient's tumor progressed rapidly in the interim. Initiation of neoadjuvant systemic therapy with combined doxorubicin, ifosfamide, and mesna was considered; however, the center had insufficient staff and availability to administer ifosfamide. Ultimately, the patient completed RT locally.

Restaging imaging (MRI of the chest to evaluate the primary site and CT of the chest, abdomen, and pelvis) was obtained for surgical planning and to re-evaluate for metastatic disease. Eventually, the patient was able to undergo definitive surgery at our institution.

Based on the histology, the goal of the operation was to obtain a margin-negative resection. The tumor was primarily located in the subcutaneous soft tissue, but its deep margin was inseparable from the underlying latissimus dorsi muscle. To get an adequate margin superficially, a paddle of skin extending beyond the palpable mass circumferentially was resected, continuing with wide soft tissue radial margins around the tumor in the subcutaneous soft tissue down to the fascia. The deep margin largely consisted of the latissimus dorsi muscle; however, anteriorly, the specimen was more adherent to the serratus anterior muscle than anticipated based on imaging. Therefore, for the deep margin, a portion of the serratus along the anterior aspect of the mass and a portion of the latissimus along the posterior aspect of the mass were removed. This provided a uniform muscle layer as a deep margin. The thoracodorsal neurovascular structures to the uninvolved portion of the latissimus were preserved.

Final pathology demonstrated a 9.3-cm, high-grade PLPS. Margins were >2 cm circumferentially around all aspects of the tumor. Only 5% of the tumor was viable, indicating treatment response.

The role of perioperative chemotherapy in localized STS arising in the extremity or trunk is controversial. Several studies over recent decades resulted in conflicting conclusions, leading to varied practice patterns across sarcoma specialty centers. For example, a large meta-analysis published in 1997 included 14 trials that randomized patients with localized, resectable STS to receive chemotherapy versus no chemotherapy and concluded that anthracycline-based chemotherapy is associated with an absolute reduction in the risk of local recurrence by 6% (95% CI, 1%–10%), a 10% reduction in the risk of distant metastasis at 10 years (95% CI, 5%–15%), and a trend toward improved OS (HR, 0·89; 95% CI, 0.76–1.03).31 These conclusions have been interpreted cautiously, however, given the heterogeneity of the STS subtypes, sizes, grades, and sites of disease included, the limited use of RT (47% of cases), and the varied chemotherapy regimens and doses used. A subsequent meta-analysis combining data from the 1997 analysis with four additional trials also demonstrated a modest risk reduction in local and distant recurrence (HR, 0.67; 95% CI, 0.56–0.82) and an improvement in OS (HR, 0.77; 95% CI, 0.64–0.93), but similar concerns about the heterogeneity of the included studies have limited widespread adoption of perioperative chemotherapy.32 To address the limitations of the prior meta-analyses, The European Organization for Research and Treatment of Cancer (EORTC) 62931 trial (ClinicalTrials.gov identifier NCT00002641) randomized 351 patients with intermediate-grade or high-grade, localized STS to receive adjuvant chemotherapy with doxorubicin 75 mg/m2 plus 5 g/m2 ifosfamide and mesna in a 21-day cycle for five cycles versus observation alone.33 The study demonstrated that adjuvant chemotherapy did not improve relapse-free survival (HR, 0.91; 95% CI, 0.67–0.22) or OS (HR, 0.94; 95% CI, 0.68–1.31).

The varied results of these studies often leave the oncologist conflicted about what to recommend for an individual patient. To address this, several nomograms have emerged to predict outcomes in patients with STS and can be used as tools to inform clinical decisions.34-39 One of the most widely accepted nomograms with robust external validation is the Sarculator.40 The Sarculator was developed for extremity STS but was retrospectively applied to the EORTC 62931 trial, which included nonextremity tumors, and demonstrated that patients with a low predicted OS (pOS) (<60%) benefitted from adjuvant chemotherapy, with a significant improvement in disease-free survival (HR, 0.49; 95% CI, 0.28–0.85) and OS (HR, 0.50; 95% CI, 0.30–0.90).41 In addition, the Italian Sarcoma Group (ISG)-STS 1001 trial (ClincalTrials.gov identifier NCT01710176) randomized patients with localized, high-risk, extremity or trunk STS to receive neoadjuvant anthracycline and ifosfamide (AI) chemotherapy versus a histology-tailored regimen and demonstrated improved outcomes in the AI arm, suggesting that AI chemotherapy may also be better than no chemotherapy in this population.42 The Sarculator nomogram was also applied to the ISG-STS 1001 results and indicated that patients with low pOS had better outcomes than predicted by the Sarculator, further supporting a role for AI-based perioperative chemotherapy in these patients.43 Taken together, these emerging data suggest that recommendations for perioperative chemotherapy should be individualized to the patient, and discussions on risks and benefits may be informed by predictive nomograms.

For the patient described in our case, the pOS was 57% based on the Sarculator's prediction for an extremity tumor, so adjuvant doxorubicin plus ifosfamide chemotherapy was discussed with the patient. After discussion of the potential side effects, long-term complications, and benefits, the patient agreed with adding systemic therapy after local treatment.

The clinical trial landscape for STS is skewed toward treatment of advanced, inoperable, and metastatic disease; however, several notable combined modality studies are underway to optimize the management of localized disease. Several trials are exploring perioperative RT combined with checkpoint inhibitors, oncolytic viruses, tyrosine kinase inhibitors, MDM2 inhibitors, DNA damage repair inhibitors, and combination chemotherapy and targeted therapies. It is important to refer patients to a sarcoma center with expertise and active clinical trials so patients can have access to these novel approaches that may improve upon the standard of care.

The patient has now completed local therapy for his trunk sarcoma and has no evidence of disease. He is anticipating initiating adjuvant chemotherapy followed by surveillance according to National Comprehensive Cancer Network guidelines. For this high-risk tumor, we would typically recommend CT of the chest and MRI of the primary site every 3 months for the first 2 years after completing therapy, then every 6 months through year 5, then annually through year 10.

STSs are rare malignancies with over 70 subtypes that have distinct behaviors and biological underpinnings. Increasingly, treatment is becoming more nuanced and tailored to the specific subtype of sarcoma. Our case highlights that it is essential to accurately diagnose the subtype of STS and have a multidisciplinary consultation at a sarcoma center to provide a comprehensive plan for optimal treatment; this is endorsed globally by international guidelines and the National Comprehensive Cancer Network STS guidelines. For these reasons, we endorse early referral to a sarcoma center for multidisciplinary planning and local therapy. When feasible and indicated, systemic therapy can be delivered at a sarcoma center or at a local oncology practice after consultation with a sarcoma medical oncologist. Telehealth options and shared care models now allow for partnerships between community oncologists and sarcoma experts to manage patients on surveillance and seamlessly address concerns during long-term follow-up.

Elizabeth H. Baldini reports personal fees from UpToDate outside the submitted work. Jason L. Hornick reports personal fees from Aadi Bioscience, Adaptimmune LLC, and TRACON Pharmaceuticals outside the submitted work. Candace L. Haddox, Jyothi P. Jagannathan, and Chandrajit P. Raut disclosed no conflicts of interest.

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来源期刊
CiteScore
873.20
自引率
0.10%
发文量
51
审稿时长
1 months
期刊介绍: CA: A Cancer Journal for Clinicians" has been published by the American Cancer Society since 1950, making it one of the oldest peer-reviewed journals in oncology. It maintains the highest impact factor among all ISI-ranked journals. The journal effectively reaches a broad and diverse audience of health professionals, offering a unique platform to disseminate information on cancer prevention, early detection, various treatment modalities, palliative care, advocacy matters, quality-of-life topics, and more. As the premier journal of the American Cancer Society, it publishes mission-driven content that significantly influences patient care.
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