Journal of Surgical Oncology 2015;111:504–512

Biopsy Techniques for Soft Tissue and Bowel Sarcomas REBECCA TUTTLE, MD1

1

AND

JOHN M. KANE III,

2 MD *

Surgical Oncology Fellow, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York 2 Chief-Melanoma/Sarcoma Service, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York

There is overlap in the clinical presentation of benign soft tissue tumors and soft tissue sarcomas. A preoperative sarcoma diagnosis would allow for consideration for neoadjuvant therapy, including preoperative radiation, as well as optimal surgical treatment planning, and patient counseling. Image guided core needle biopsy is a low morbidity, cost-effective, highly accurate approach for obtaining a definitive pathologic diagnosis. Any biopsy approach should minimize the potential for tumor seeding of otherwise uninvolved anatomic structures.

J. Surg. Oncol. 2015;111:504–512. ß 2015 Wiley Periodicals, Inc.

KEY WORDS: sarcoma; core needle biopsy; fine-needle aspiration

TO BIOPSY OR NOT TO BIOPSY The differential diagnosis for a soft tissue mass is fairly extensive. Accounting for only 1% of adult malignancies, a soft tissue sarcoma (STS) is rare but always needs to be considered. In contrast, benign clinical processes (hematoma, abscess, ganglion cyst, hernia) are fairly common. The estimated incidence for a benign lipoma is 1:1000. Other benign soft tissue masses include intramuscular myxoma, neurofibroma/schwannoma, fibrous histiocytoma, nodular fasciitis, and hemangioma. Both nodal and extranodal lymphoma can mimic a soft tissue tumor. In the intra-abdominal or retroperitoneal location, the differential is even larger: metastatic testicular cancer, neuroendocrine tumors (pheochromocytoma, ganglioneuroma, paraganglioma), desmoid/aggressive fibromatosis, nodal metastatic carcinoid, and primary tumors of the kidney or adrenal gland. The potentially curative treatment for a STS is wide resection with negative margins. In certain clinical situations, radiation therapy would also play a role. In contrast, many benign tumors could be adequately treated with simple excision or even a course of clinical observation. The optimal management of a non-STS malignancy would be based upon the specific diagnosis; surgical resection is frequently not indicated. Therefore, the dilemma when faced with a suspicious soft tissue mass is “when is obtaining a preoperative biopsy clinically appropriate?” The vast majority of small, superficial soft tissue masses will be benign. In a population-based study of lipomata and STS by Rydholm and Berg, 80% of lipomata were less than 5 cm and only 3% were subfascial (with a mean size of 6 cm) [1]. A solitary subcutaneous lipoma was also rare on the hand, thigh, lower leg, or foot. Further analysis of independent features associated with a lipoma versus a STS showed that a STS diagnosis was more likely for tumors larger than 5 cm, the thigh location, or tumors deep to the muscular fascia. In general, soft tissue masses greater than 5 cm or deep to fascia would warrant additional preoperative evaluation, including consideration for biopsy. Other clinically concerning features would include a rapidly enlarging mass or associated symptoms. Any soft tissue mass suspicious for a possible STS should be assessed with three-dimensional imaging prior to considering a biopsy. The imaging characteristics can assist in determining the probability that the mass represents a STS, prevent post-biopsy changes such as bleeding from confounding the imaging findings, and allow for appropriate planning of the biopsy trajectory. Although ultrasound is inexpensive and does not require intravenous contrast or exposure to radiation, it is also very operator dependent and the field-of-view is limited. Therefore, a CT scan or MRI would be more appropriate for imaging a suspicious soft

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tissue mass [2–4]. Both modalities would accurately define the size of the mass, the true anatomic location (including the relationship to the muscular fascia or intra-abdominal organs), the internal density (such as fluid), associated tumor vascularity, and the proximity to any adjacent critical neurovascular structures. Finally, certain imaging findings may be pathognomonic for a specific diagnosis (e.g., a large retroperitoneal well differentiated liposarcoma), potentially obviating the need for a biopsy.

THE BENEFITS OF PREOPERATIVE BIOPSY Studies have shown that almost 20% of patients with a soft tissue mass that ultimately proves to be a STS will experience a significant delay between the time of presentations/symptoms to diagnosis/referral to a sarcoma specialist (median time 14 months) [5]. Therefore, biopsy of any mass suspicious for a possible STS could expedite the diagnosis and initiation of appropriate therapy. The potential benefits of having a definitive preoperative STS diagnosis are numerous and further elucidated below.

Accurate Staging/Prognostication In addition to size and depth, grade is a significant STS prognostic factor for both local recurrence and survival [6,7]. The specific STS histologic subtype also impacts the risk for developing distant metastatic disease [7]. A preoperative biopsy would provide this information and allow for a more accurate prediction of survival. The risk for harboring hematogenous metastases would also determine the appropriate sensitivity of staging imaging necessary prior to proceeding with wide resection (e.g., chest x-ray vs. CT scan for pulmonary metastases). It would also allow for the imaging of potential atypical metastatic sites based upon the unique biology of certain STS histologies, such as soft tissue or spine metastases from a myxoid liposarcoma.

* Correspondence to: Dr. John M. Kane, Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Fax: 716–845-2320. E-mail: [email protected] Received 11 June 2014; Accepted 8 November 2014 DOI 10.1002/jso.23870 Published online 8 February 2015 in Wiley Online Library (wileyonlinelibrary.com).

Biopsy Techniques for Sarcomas Optimal Planning of Operative Therapy The purpose of surgical wide resection is to obtain negative margins. This can be potentially morbid when extensive muscular or visceral resections are necessary. Extremity limb salvage surgery will often expose bone, blood vessels, and nerves. This is especially problematic in the setting of preoperative radiation, where well vascularized, nonirradiated tissue is necessary to optimize coverage/healing of the surgical defect. In certain clinical situations, resection/reconstruction of critical bony or neurovascular structures is indicated; the extreme situation would be extremity amputation. Consequently, having a definitive preoperative STS diagnosis would optimize the ability to electively plan the most appropriate oncologic resection. It would also allow for early involvement of other members of a multidisciplinary reconstruction team: plastic surgery, orthopedic surgery, or vascular surgery. Potential soft tissue donor sites, including microvascular free flaps, can be determined and discussed with the patient prior to surgery. There are data to support that multidisciplinary discussion between the oncologic resection and reconstruction teams can optimize operative outcome [8]. Finally, there are some unique tumor histologies where a preoperative diagnosis could dramatically alter the surgical therapy, such as considering Mohs excision to ensure negative margins for a dermatofibrosarcoma protuberans (DFSP). It is also worth mentioning the significant negative consequences of an unplanned, positive margin excisional biopsy or “whoops” operation for a STS. In this scenario, either piecemeal or simple excision of a STS is unknowingly performed. The most common complication following a positive margin inadequate excision is hematoma [9]. On multivariate analysis, a complication following an initial inadequate excision was one of the factors associated with a decreased local recurrence-free survival [9]. Given that a negative margin wide resection is the potentially curative treatment for a STS, these patients often require a morbid second re-resection that needs to encompass the entire prior surgical field, drain sites, etc. Between 35% and 77% of these definitive reresection specimens will have residual STS on final pathology and positive resection margins will be present in 12–39% [9–11]. This problem could be completely avoided by having a preoperative STS diagnosis.

Consideration for Preoperative or Intraoperative Radiation Prior to the 1980s, the potentially curative treatment for an extremity STS was amputation. Following publication of the results from the NCI randomized, prospective trial of limb sparing surgery with radiation versus amputation, adjuvant radiation became a critical component in the multimodality treatment of high risk STS [12]. The main advantage of postoperative radiation is that the final pathology, including margin status, is known. Alternatively, postoperative radiation requires a higher dose and a larger field size to encompass the entire surgical site. In addition, if there are postoperative wound healing issues, adjuvant radiation may be delayed or never administered. In order to consider preoperative radiation therapy, a definitive STS diagnosis is necessary. Benefits of preoperative radiation include a defined tumor target, smaller field size, a lower dose/shorter course secondary to better oxygenation, the potential ability to sterilize margins at critical unresectable structures where tumor will be surgically violated, and an opportunity to restage patients at high risk for developing distant metastases prior to undergoing extensive surgical resection. A randomized, prospective study of preoperative versus postoperative radiation for extremity STS performed by the NCIC showed that local recurrence and overall survival were identical [13]. The rate of postoperative wound healing complications was significantly higher in the preoperative radiation group (35% vs. 17%). However, in contrast to postoperative radiation, postoperative wound healing issues following preoperative radiation would not impact the ability to administer all components of the desired Journal of Surgical Oncology

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multimodality therapy. In a parallel study of late radiation morbidity from the same randomized trial, significant fibrosis, joint stiffness, or edema were associated with a decreased extremity functionality scores [14]. Secondary to the larger field size, patients undergoing postoperative radiation tended to have greater fibrosis. It was suggested that the smaller field size associated with preoperative radiation therapy may result in improved long-term limb functionality as compared to postoperative radiation. For retroperitoneal/intra-abdominal STS, conventional radiation doses can lead to significant GI tract, other intra-abdominal organ, and spinal cord toxicity [15]. Consequently, it has been technically challenging to safely administer postoperative external beam radiation. Adhesions can result in the viscera becoming trapped in the tumor resection bed, further increasing the radiation toxicity as these structures cannot move out of the radiation field. For similar reasons, postoperative brachytherapy radiation has also been associated with increased adjacent organ toxicity, especially in the upper abdomen [16]. Finally, intraabdominal dissemination of viable microscopic tumor from a positive resection margin on a critical structure can lead to sarcomatosis. Although there are no prospective, randomized studies to definitively support the role of preoperative radiation therapy for intra-abdominal/ retroperitoneal sarcomas (one is currently underway through the EORTC), most institutions, including ours, that utilize external beam radiation in this situation favor a preoperative approach [16]. The primary tumor acts as a natural “tissue expander,” displacing the majority of the intra-abdominal viscera out of the radiation field, thus minimizing toxicity. Contiguous irradiated portions of the GI tract are typically resected. Similar to extremity and truncal STS, preoperative radiation therapy for intra-abdominal/retroperitoneal STS cannot be considered without a definitive preoperative diagnosis. For institutions with the appropriate resources, a definitive preoperative STS diagnosis would also allow for either intraoperative radiation therapy or postoperative brachytherapy radiation. Intraoperative radiation can be an effective way to deliver very high doses of radiation to critical margins while sparing toxicity to adjacent uninvolved structures, especially in the abdomen/retroperitoneum [15,17]. At our institution, we will often plan for an intraoperative boost dose of 10–12 Gy Iridium-192 brachytherapy radiation for an anticipated microscopically positive margin on a non-resectable bony or vascular structure in the setting of prior external beam radiation. There are also prospective, randomized data supporting the use of postoperative brachytherapy radiation via catheters placed at the time of surgical wide resection to improve local control for a high-grade extremity STS [18]. It would be difficult logistically to plan for either of these radiation modalities in the absence of a preoperative STS diagnosis.

Consideration for Neoadjuvant Systemic Therapy/Clinical Trials Theoretical benefits of neoadjuvant systemic chemotherapy for “high risk” STS include the ability to monitor effectiveness through the in vivo primary tumor response, early treatment of potential microscopic hematogenous metastatic disease, and possible tumor down-staging to allow for a less radical limb salvage resection. Although several studies have examined the role of neoadjuvant chemotherapy, the positive impact on overall survival remains unclear [19–23]. There are some data showing that the response to neoadjuvant chemotherapy can predict the risk for local recurrence and even STS survival [24]. Therefore, some centers utilize neoadjuvant chemotherapy as part of their multimodality treatment approach for high risk STS. In addition, novel approaches combining neoadjuvant chemotherapy with regional hyperthermia have recently shown significant promise [25]. Neoadjuvant systemic chemotherapy would frequently be a component of the standard treatment for certain STS histologic

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subtypes (e.g., extraskeletal Ewing’s sarcoma, non-osseous osteogenic sarcoma, rhabdomyosarcoma). Neoadjuvant imatinib therapy can be used to potentially downstage a locally advanced gastrointestinal stromal tumor (GIST) to reduce the morbidity of surgical resection. There are also increasing data to support the role of sulindac/ antiestrogens, or even a course of clinical observation, as first-line therapy for a newly diagnosed, asymptomatic desmoid/aggressive fibromatosis [26]. Finally, given the rarity of STS, consideration should always be given to clinical trial participation, including investigational neoadjuvant agents. All of these scenarios would require a preoperative tissue diagnosis.

Psychosocial Expectations Although difficult to quantify, having a definitive STS diagnosis prior to subjecting a patient to surgical resection should better allow him/her to psychologically prepare for surgery, the anticipated postoperative recovery, and long-term functional consequences. STS wide resection will typically cause more body image deformity as compared to a simple excision for a benign tumor. Preoperative emotional counseling and the ability to interact with other STS patients through support groups can be provided. Preoperative physical therapy education can be more effective, especially with the elderly or in the setting of concomitant postoperative narcotic analgesics. For an intraabdominal/retroperitoneal STS, nephrectomy, major GI resections, and even ostomies are occasionally necessary as a component of the optimal surgical resection. Adequate preoperative assessment of medical comorbidities, renal function, and preoperative enterostomal therapy counseling would be ideal. Anticipating time off of work for a prolonged recovery and early planning for family/friend support at home or rehabilitation needs can be extremely beneficial. There are a few potential cons to performing a preoperative biopsy. Post-biopsy complications such as bleeding, infection, or wound healing issues could delay or negatively alter the optimal treatment of a STS. Tumor spillage or seeding of the biopsy tract is also a real consideration. Finally, there is an additional cost associated with performing a biopsy, especially under image guidance. However, it is our opinion that the benefits of having a definitive preoperative STS diagnosis as outlined above outweigh the downsides to performing a biopsy in most clinical situations.

PREOPERATIVE BIOPSY TECHNIQUES The goal of a preoperative biopsy is to obtain representative tissue to make a definitive pathologic diagnosis with low morbidity and in a manner that does not compromise subsequent therapies. A diagnosis of “sarcoma” is generally not adequate. Ideally, the specific STS histologic subtype and grade should also be determined from the biopsy to assist in decisions regarding the role of neoadjuvant radiation or chemotherapy. The pros and cons of the various biopsy techniques will be addressed in greater detail.

Fine Needle Aspiration Biopsy Fine-needle aspiration (FNA) biopsy is the least morbid of all techniques. Patient discomfort and the risks for bleeding, infection, or adjacent organ injury are minimal. However, FNA biopsy only provides cytology, not true histology. Therefore, interpretation of the specimen requires significant cytopathology expertise. At institutions with this expertise, diagnostic accuracy can be as high as 95% [27]. In a review of 140 patients undergoing 145 FNA biopsies, Kilpatrick et al. found that a diagnosis sufficient to initiate therapy was made in 83% of STS patients [28]. Limitations included the ability to determine tumor grade and the specific histologic subtype [28]. Costa et al. also noted that a correct histologic subtype diagnosis could only be made from an FNA Journal of Surgical Oncology

biopsy in 20.9% of STS patients [29]. However, the biopsy results were at least suspicious enough to warrant further biopsy or treatment in 88.4%. FNA biopsy can also have difficulty differentiating between benign and low-grade malignant tumors [27]. In the setting of a known STS, FNA biopsy would be adequate to diagnose a possible local recurrence or distant metastatic disease. In light of the required cytopathology expertise, FNA biopsy will not be a practical preoperative biopsy approach for most centers.

Core Needle Biopsy Core needle biopsy (CNB) for the evaluation of soft tissue tumors dates back to the 1970s. For unclear reasons, it has been slow to gain broad acceptance. In contrast to FNA biopsy, CNB provides a specimen for true histopathologic analysis. There is typically adequate tissue for all of the pathologic modalities utilized to diagnose a STS, including both immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). It is less invasive than an incisional or excisional biopsy. There are also data showing a cost savings of CNB over open surgical biopsy [30]. Standard needle sizes are 14–18-gauge, although up to 8 gauge needles are available. Four to ten biopsies are usually performed; more specimens result in greater diagnostic accuracy. Complication rates have been very low at 0–6%, primarily hemorrhage or infection [31–34]. For superficial tumors, simple percutaneous core needle biopsy under local anesthesia is appropriate. For larger, heterogeneous, or deep tumors, many institutions will perform CNB under image guidance: ultrasound or CT. There are several advantages to image guidance. First, there is confirmation that the tumor is being biopsied, not the surrounding normal soft tissues. Second, adjacent vessels and nerves can be avoided, reducing the risk for complications. Third, cystic changes or necrotic tumor can also be avoided, improving the biopsy quality and diagnostic yield. Finally, multiple areas of a heterogeneous tumor can be sampled, including the most radiographic suspicious regions. The overall accuracy for CNB for suspicious soft tissue masses ranges from 68–100% [31,33–40]. In approximately 90% of cases, one set of CNB is adequate to make a diagnosis; open biopsy is rarely necessary [31,33,35,36]. The tumor grade and specific histologic subtype can be determined from CNB in 76–87% and 68–78%, respectively [31,33–35]. For a definitive STS diagnosis, false positives are almost nonexistent, but the false negative rate varies from 5–50% [31,32,35,36]. The most challenging diagnoses are for a low grade STS, primarily differentiating between a lipoma and a well-differentiated liposarcoma. The largest series of CNB for the evaluation of suspicious soft tissue masses deserves specific mention. The Royal Marsden Hospital reported on 530 consecutive patients with a previously undiagnosed suspicious soft tissue mass who underwent CNB using only local anesthesia and without image guidance [41]. The complication rate requiring hospitalization was only 0.4%; both secondary to hemorrhage. One set of CNB was adequate to make a diagnosis in 93% of patients. The remaining 7% underwent repeat CNB. The breakdown of tumors based upon final diagnosis was 225 STS, 201 benign soft tissue tumors, 68 malignant non-STS tumors, and 36 benign conditions mimicking a soft tissue tumor. The accuracy of CNB to differentiate between a STS and a benign soft tissue tumor was 97.6%. The accuracy for histologic subtype was 89.5% for benign tumors and 88% for STS. For a STS diagnosis, the accuracy for grade (confirmed at the time of resection) was 86.3%. There was only one false positive and eight false negatives. Similar to other studies, 63% of the false negatives were an atypical lipomatous tumor/well-differentiated liposarcoma initially felt to be a benign lipoma on CNB. We have a well-defined institutional algorithm that utilizes CNB for all suspicious soft tissue tumors. Blind percutaneous biopsy is

Biopsy Techniques for Sarcomas performed only for superficial, readily palpable tumors that are internally homogeneous on pre-biopsy imaging. Otherwise, image guided CNB is utilized. There is a direct discussion with the radiologist who will be performing the biopsy regarding the proposed biopsy location as it relates to the tumor, the anatomic muscular compartments, and the orientation of the future surgical resection incision. If technically possible, ultrasound guidance is our first choice. This allows for rapid identification of associated vasculature by utilizing duplex and real-time, direct visualization of the biopsy needle. For anatomic locations where ultrasound is not possible, CT guided CNB is otherwise performed. The majority of biopsies are performed with only local anesthesia. However, if there is concern that the soft tissue mass may be a neurogenic tumor, arrangements are made for conscious sedation secondary to the potential for significant biopsy associated discomfort. Typically, four to six 18-gauge biopsies are performed. The pathologist also plays a critical role in the CNB process. Our cytopathologist is present at all of the image guided biopsies to ensure the quality and adequacy of the specimens. If the rapid pathologic assessment suggests the possibility of lymphoma, additional biopsies are performed for flow cytometry/cytogenetics. Real-time pathologic examination of the CNB should reduce the number of nondiagnostic samples and need for repeat biopsy (with the associated increased cost). At some point shortly after the CNB has been completed, the patient is seen again in clinic for India ink tattooing of the biopsy site. This will make the biopsy site readily identifiable at the time of future wide resection for incorporation into the planned incision, especially with the significant skin changes that can occur following preoperative radiation therapy. There is some ongoing controversy surrounding the optimal management of well-differentiated liposarcoma (WDLPS), both extremity/truncal and retroperitoneal. Some institutions perform more limited surgical resections for what is classified as an atypical lipomatous tumor/WDLPS and do not consider radiation [42–44]. With this approach, there would be no benefit to obtaining a preoperative pathologic diagnosis as the imaging alone is often diagnostic and the proposed extent of surgery would be the same regardless of the biopsy results. In contrast, other sarcoma centers will selectively utilize radiation, including preoperative, in situations where a WDLPS local recurrence would be very morbid (such as adjacent to critical neurovascular structures or in the retroperitoneum) [13,16]. Clinical scenarios where a definitive diagnosis of WDLPS could result in considering the role of preoperative radiation, a pathologic distinction between these two entities becomes clinical relevant. Given the diagnostic challenge of a large lipoma versus WDLPS, when clinically appropriate, we obtain a minimum of six 18-gauge or larger biopsies for a lipomatous soft tissue mass. Multiple areas of the lipomatous mass are sampled, including targeting regions of stranding or nonfat density. We also routinely perform FISH for MDM2 amplification. MDM2 is expressed in up to 97% of atypical lipomatous tumors/WDLPS as compared to only 5% of benign adipocytic tumors [45]. Unpublished quality review data from our institution for 94 patients undergoing image guided CNB for a suspicious soft tissue mass are similar to that reported in the literature. The overall diagnostic accuracy was 91% and a specific histologic diagnosis was made in 87%. Pathology requested additional tissue to refine the diagnosis in only 8.5%; 3 patients underwent repeat image guided CNB and 5 underwent incisional biopsy. Based upon the CNB diagnosis, 43% of patients were spared a surgical resection as it was not clinically indicated. Post biopsy complications were rare (1 hematoma and 1 infection).

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Fig. 1. A postoperative wound infection and exophytic tumor growth from the biopsy scar that precluded preoperative radiation therapy following an incisional biopsy for a large, deep, high-grade left thigh sarcoma.

grade and histologic subtype. Although overall complication rates are often less than 2%, complications that force a change in what would have otherwise been the appropriate STS treatment plan can be as high as 18–19% [46–48]. In addition, cost and patient discomfort are greater for surgical biopsy as compared to CNB. Given the high implantation potential of STS, meticulous hemostasis is critical to prevent tumor dissemination within a postoperative hematoma. Tumor seeding of the superficial biopsy scar (especially for a deeper tumor) can also lead to exophytic tumor growth with bleeding or contamination of the overlying subcutaneous tissues. A postoperative wound infection can lead to a significant delay in initiating preoperative radiation or proceeding with definitive surgical wide resection. (Fig. 1). It is also imperative that the biopsy site is oriented in a manner so that noninvolved muscular compartments are not violated and the biopsy scar can be incorporated into any future wide resection incision. In light of the previously noted advantages of CNB, incisional biopsy should be reserved for obtaining additional tissue when prior, less invasive biopsy attempts have been non-diagnostic.

Excisional Biopsy Excisional biopsy has almost no role in the diagnostic workup of a suspicious soft tissue mass. It is appropriate only for very small, superficial masses where CNB would be technically difficult [49]. However, it will be non-therapeutic if the final pathology returns as a STS (akin to a “whoops” procedure, leaving residual microscopic tumor). Consequently, excisional biopsy is suboptimal for larger or deep tumors as the patient will require a second, more extensive surgical resection that will need to include the entire previous excisional biopsy site. The same concerns as for an incisional biopsy regarding hemostasis, infection, and appropriate biopsy site selection/orientation also apply.

Incisional Biopsy Historically, incisional biopsy of a suspicious soft tissue mass was the standard of care. This approach will almost certainly provide adequate tissue to make a definitive pathologic diagnosis, including Journal of Surgical Oncology

GENERAL BIOPSY PRINCIPLES Biologically, STS can have high implantation potential [50–52]. Theoretically, this could lead to seeding of microscopic tumor cells into

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the biopsy tract. Consequently, the biopsy site should be considered as part of the primary tumor in terms of future treatment planning (radiation field, surgical resection). There are several general principles for planning the biopsy of a potential STS. The biopsy site should be in close proximity to the primary tumor. If possible, the biopsy tract should not traverse uninvolved muscular compartments. Disruption of fascial planes should be minimized as they are a good barrier to tumor penetration. The fascia underlying a superficial soft tissue mass should not be violated. If technically possible, an effort should be made to avoid contamination of free spaces such as the abdominal cavity. There should be minimal dissection of the uninvolved tissues surrounding the mass. Meticulous hemostasis is imperative. Ideally, the biopsy site should also be anatomically situated to allow for incorporation into the future wide resection incision. Surgical drains should be avoided. If necessary, they should exit at a location that will also allow for future en bloc excision of the drain tract. Finally, if extensive soft tissue dissection is required, the periphery of the biopsy site should be marked with metallic clips for future radiographic identification. Secondary to the risk for tumor implantation, traditional dogma has been that the STS biopsy tract be excised en bloc with the surgical wide resection specimen. However, there is actually a paucity of data in the literature on this subject. In a systematic review by Mello et al., only 11 published articles contained adequate information on biopsy tract tumor seeding [53]. When limited to studies of bone or STS, biopsy tract contamination rates ranged from 0–57% for open biopsy and 0–22% for percutaneous core needle. In the two studies with no biopsy tract contamination, the previous biopsy sites had not been resected. A recent study by Letson et al. has also challenged the need for routine biopsy tract excision, especially in the setting of adjuvant therapy [54]. In 59 patients with a large, deep, high-grade extremity STS, the core needle biopsy tract was not excised at the time of wide resection. The authors noted that the local recurrence rate was only 9%, which is comparable to other reports in the literature. However, 97% of patients received radiation and 83% received systemic chemotherapy. Although the risk for biopsy tract recurrence may be nominal when adjuvant therapies are utilized, one cannot necessarily extrapolate these findings to clinical situations where only wide resection will be performed. With appropriate biopsy planning, there is typically minimal morbidity to excising the biopsy tract en bloc with the wide resection specimen. Therefore, we routinely resect the biopsy tract for most of our STS patients. However, there are scenarios where technical aspects of the biopsy preclude en bloc excision of the biopsy tract (especially for intra-abdominal and retroperitoneal tumors). In light of the limited scientific data, leaving the biopsy tract in situ in certain situations would still be clinically appropriate, especially if adjuvant therapy will be administered.

Fig. 2. A poorly oriented transverse incisional biopsy for a superficial, high-grade sarcoma of the medial right thigh. Wide resection to incorporate the previous biopsy scar required a generous, transversely oriented excision. amputation may occasionally be necessary for a proximal extremity STS, the biopsy site should never be placed on the trunk (as this would potentially disseminate tumor out of the extremity). In contrast to the extremities, most STS wide resections on the trunk will be transversely oriented. This needs to be considered when planning the biopsy of a mass on the body wall.

Retroperitoneal and Intra-Abdominal Tumors

SPECIFIC ANATOMIC CONSIDERATIONS Extremity and Truncal Tumors In general, muscle groups, lymphatics, and neurovascular structures run longitudinally within the extremities. Therefore, most STS wide resections will be longitudinally oriented on the arms or legs. This will aid in the identification/dissection of critical structures, minimize disruption of lymphatics/nerves (reducing long-term morbidity), and potentially facilitate primary closure. Although this would be counter to the lines of Langer, the biopsy site for a suspicious soft tissue mass on the extremities should also be longitudinally oriented. This will facilitate incorporation of the biopsy site into the planned wide resection incision. Figure 2 shows the consequences of a poorly oriented transverse biopsy scar for a sarcoma of the medial thigh. As the transverse placement obligated that a component of the wide resection incision be transversely oriented, significantly more lymphatics and sensory nerves were transected at the time of wide resection. Given that Journal of Surgical Oncology

Suspicious soft tissue masses of the retroperitoneum and intraabdominal cavity fall into three general situations; retroperitoneal/ preperitoneal, true intra-abdominal visceral, and a high clinical suspicion for a gastrointestinal stromal tumor (GIST). The optimal biopsy approach will vary somewhat based upon these categories. A limitation of biopsy for any of these locations will be that it is rarely technically possible to excise the biopsy tract en bloc at the time of future wide resection if the final pathology returns as a STS. Therefore, decisions regarding the biopsy approach will be based primarily upon minimizing morbidity, reducing the risk for tumor dissemination, and providing adequate tissue for a definitive diagnosis. Secondary to a slightly higher likelihood for post-biopsy hemorrhage as compared to extremity/truncal masses, image guided biopsies for these tumors are typically performed with surgical backup available in case there is uncontrolled bleeding. Up to 80% of retroperitoneal tumors will be some form of malignancy [55]. Therefore, having a tissue diagnosis would be ideal

Biopsy Techniques for Sarcomas given the widely differing treatments for the various possibilities. A STS would require wide resection with consideration for preoperative/ intraoperative radiation therapy. Renal cell carcinoma or adrenocortical carcinoma would also be treated surgically, but not necessarily a STS type resection. Surgical resection would not be therapeutic for lymphoma. Metastatic testicular cancer would typically be treated with systemic chemotherapy first. Observation or simple excision would be appropriate for a neuroendocrine soft tissue tumor, but a biochemical workup would often be performed prior to surgical manipulation. An asymptomatic, benign neurogenic tumor could be followed clinically with serial imaging. Figure 3 shows four different intra-abdominal/retroperitoneal tumors with a similar radiographic appearance, highlighting the importance of making a preoperative tissue diagnosis. In the retroperitoneal/preperitoneal location, it is frequently technically possible to perform image guided CNB without traversing the free intra-abdominal space. This will not only reduce the risk for persistent post-biopsy hemorrhage, but would also minimize the chance for peritoneal tumor seeding. A situation where avoiding the intra-abdominal space may not be possible is tumors located anterior to distal great vessels/aortic bifurcation. In that location, a transabdominal biopsy trajectory may be necessary. In terms of imaging modality, ultrasound or CT guided CNB are equivalent. In addition to standard pathologic assessment, flow cytometry should also be performed if there is clinical suspicion for lymphoma. Based upon institutional expertise, endoscopic ultrasound-guided FNA or small gauge CNB would also be a potential low morbidity biopsy approach for tumors in the deep pelvis or upper retroperitoneum. Transvaginal ultrasound guided CNB is also an option for pelvic tumors in a female patient. Surgical incisional or excisional biopsy, either laparoscopically or via a laparotomy, should be avoided unless there is no other way to make a definitive pathologic diagnosis. These approaches are morbid

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for the patient (larger incisions, require general anesthesia) and are more expensive than CNB. They also have a much greater risk for hemorrhage and tumor spillage, especially if the surgical biopsy is performed across the free intra-abdominal space. Figure 4 illustrates the negative consequences of performing a transabdominal excisional biopsy of a right retroperitoneal sarcoma, resulting in intraoperative tumor spillage. Our institutional algorithm has been to repeat the image guided CNB if the original biopsies are non-diagnostic. Using this approach, formal surgical biopsy is almost never necessary. The technical approach to the biopsy of free intra-abdominal tumors (e.g., gynecologic or visceral leiomyosarcomas, mesenteric desmoid, etc.) will be similar to that for retroperitoneal/preperitoneal tumors, except that the free intra-abdominal space will often be traversed. Clinically, it is our opinion that the small risks for hemorrhage or spillage of microscopic tumor cells following image guided CNB are still outweighed by the advantages of having a definitive pathologic diagnosis. As the management of desmoid/aggressive fibromatosis is evolving into more conservative, initial nonsurgical management in the absence of symptoms, this option would not be possible without a tissue diagnosis [26,56]. Previously thought to be rare, GIST has become one of the most common STS subtypes. A high clinical suspicion for this diagnosis will alter the biopsy approach as compared to other intra-abdominal soft tissue masses. This is due to the fact that a GIST is extremely friable; minimal trauma can lead to major tumor spillage and hemorrhage. Based upon the imaging and endoscopic workup, if the overall clinical picture is most consistent with a primary GIST that is readily amenable to surgical resection with minimal morbidity, then there is no strong indication for obtaining a preoperative tissue diagnosis. If the GIST appears to be locally advanced where surgery would require a morbid, multivisceral resection, there are data to support downstaging with neoadjuvant imatinib therapy [57,58] For this to be considered, a

Fig. 3. Four different intra-abdominal/retroperitoneal tumors with a similar radiographic appearance: A. Dedifferentiated liposarcoma. B. Metastatic testicular cancer. C. Gastrointestinal stromal tumor. D. Lymphoma. Journal of Surgical Oncology

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Fig. 4. Inappropriate transabdominal excisional biopsy of a right retroperitoneal dedifferentiated liposarcoma: A. The primary tumor on the preoperative CT scan. B. The postoperative tumor bed approximately 8 weeks later on restaging imaging. C. A discontiguous right lower quadrant sarcomatous implant on the small bowel (arrow) approximately 8 weeks later on restaging imaging. This occurred secondary to tumor spillage at the time of the excisional biopsy.

preoperative diagnosis is necessary. The preferred biopsy approach would be endoscopic transmural, as opposed to transabdominal [59]. This would reduce the risk for tumor spillage leading to sarcomatosis. Endoscopic ultrasound-guided needle biopsy has been shown to be highly accurate and minimally morbid [60,61]. Transabdominal image guided CNB would be reserved for failed endoscopically guided biopsies or if a diagnosis is required in the setting of widespread metastatic disease, especially sarcomatosis.

CONCLUSIONS The ideal treatment of an STS requires a thorough understanding of sarcoma tumor biology, the appropriate role and sequencing of the various multimodality treatment options (surgery, radiation, chemotherapy), and surgical expertise in multiorgan resection with reconstruction to maximize functionality. Having a definitive preoperative STS diagnosis would allow for consideration for neoadjuvant therapy (including preoperative radiation or systemic chemotherapy) as well as optimal surgical treatment planning and patient counseling. Conversely, many rare, but benign soft tissue tumors can be managed with nonsurgical therapies or even observation. The technical aspects of how the diagnostic biopsy is performed and expertise in soft tissue pathology are important components of the evaluation of a suspicious soft tissue mass. A poorly planned biopsy resulting in tumor seeding into otherwise uninvolved anatomic locations can increase the morbidity of subsequent wide resection or even render a patient with a previous localized STS “incurable.” Two different studies by the Musculoskeletal Tumor Society compared treatment outcomes when the diagnostic biopsy was performed at the referring institution versus the definitive treatment center [46,47]. In 18–19% of patients, problems related to the biopsy led to a different or Journal of Surgical Oncology

more complex operation or obligated the use of adjuvant radiation or chemotherapy. In addition, unnecessary amputation secondary to biopsy issues was performed in 8–10% of patients. These negative outcomes were 2–12 times more likely when the original diagnostic biopsy was done at the referring institution as compared to the treatment center (P < 0.001). Consequently, although there may be some gratification for the local physician to make the “diagnosis” prior to referral of a patient with a suspicious soft tissue mass, strong consideration should be given to having the entire workup, including the diagnostic biopsy, performed at a center with multidisciplinary STS and other soft tissue tumor expertise.

REFERENCES 1. Rydholm A, Berg NO: Size, site and clinical incidence of lipoma. factors in the differential diagnosis of lipoma and sarcoma. Acta Orthop Scand 1983;54:929–934. 2. Berquist TH, Ehman RL, King BF, et al.: Value of MR imaging in differentiating benign from malignant soft-tissue masses: Study of 95 lesions. AJR Am J Roentgenol 1990;155:1251–1255. DOI:10.2214/ajr.155.6.2122675 . 3. Kransdorf M, Murphey M: Radiologic evaluation of soft-tissue masses: A current perspective. AJR Am J Roentgenol 2000;175:575–587.DOI:10.2214/ajr.175.3.1750575 . 4. Aga P, Singh R, Parihar A, et al.: Imaging spectrum in soft tissue sarcomas. Indian. J Surg Oncol 2011;2:271–279.DOI:10.1007/ s13193-011-0095-1 . 5. Clark MA, Thomas JM: Delay in referral to a specialist soft-tissue sarcoma unit. Eur J Surg Oncol 2005;31:443–448.DOI:10.1016/j. ejso.2004.11.016 . 6. Guillou L, Coindre JM, Bonichon F, et al.: Comparative study of the national cancer institute and french federation of cancer centers

Biopsy Techniques for Sarcomas

7.

8. 9.

10. 11.

12.

13.

14.

15. 16.

17.

18. 19. 20.

21.

22.

23.

24.

sarcoma group grading systems in a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol 1997;15:350– 362. Zagars GK, Ballo MT, Pisters PWT, et al.: Prognostic factors for patients with localized soft-tissue sarcoma treated with conservation surgery and radiation therapy: An analysis of 1225 patients. Cancer 2003;97:2530–2543.DOI: 10.1002/cncr.11365 . Moreira-Gonzalez A, Djohan R, Lohman. R: Considerations surrounding reconstruction after resection of musculoskeletal sarcomas. Clevel Clin J Med 2010;77:S18–S22.DOI: 10.3949/ccjm.77.s1.04 . Van Geel AN, Eggermont AMM, Hanssens et al PEJ, et al.: Factors influencing prognosis after initial inadequate excision (IIE) for soft tissue sarcoma. Sarcoma 2003;7:159–165.DOI: 10.1080/ 13577140310001650321 . Noria S, Davis A, Kandel R, et al.: Residual disease following unplanned excision of a soft-tissue sarcoma of an extremity. J Bone Jt Surg Ser A 1996;78:650–655. Zagars GK, Ballo MT, Pisters PWT, et al.: Surgical margins and reresection in the management of patients with soft tissue sarcoma using conservative surgery and radiation therapy. Cancer 2003;97:2544–2553.DOI:10.1002/cncr.11367 . Rosenberg SA, Tepper J, Glatstein E, et al.: Wesley. The treatment of soft-tissue sarcomas of the extremities. prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982;196:305–315. O’Sullivan B, Davis AM, Turcotte R, et al.: Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: A randomised trial. Lancet 2002;359:2235–2241.DOI:10.1016/ S0140–6736(02) 09292–9 . Davis AM, O’Sullivan B, Turcotte R, et al.: Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 2005;75:48–53.DOI:10.1016/j.radonc.2004.12.020 Sindelar WF, Kinsella TJ, Chen PW, et al.: Intraoperative radiotherapy in retroperitoneal sarcomas: Final results of a prospective, randomized, clinical trial. Arch Surg 1993;128:402–410. Jones JJ, Catton CN, O’Sullivan B, et al.: Initial results of a trial of preoperative external-beam radiation therapy and postoperative brachytherapy for retroperitoneal sarcoma. Ann Surg Oncol 2002;9:346–354.DOI:10.1245/aso.2002.9.4.346 Ove R, Wallner K, Badiozamani K, et al.: Long-term results of intraoperative electron beam radiotherapy for primary and recurrent retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol Phys 2001;131:127–131.DOI:10.1016/S0360-3016(00) 01589–3 . Pisters PW, Harrison LB, Leung DH, et al.: Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996;14:859–868. Grobmyer SR, Maki RG, Demetri GD, et al.: Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma. Ann Oncol 2004;15:1667–1672.DOI:10.1093/annonc/mdh431 Italiano A, Penel N, Robin Y,-, et al.: Neo/adjuvant chemotherapy does not improve outcome in resected primary synovial sarcoma: A study of the french sarcoma group. Ann Oncol 2009;20:425–430. DOI:10.1093/annonc/mdn678 Kraybill WG, Harris J, Spiro IJ, et al.: Phase II study of neoadjuvant chemotherapy and radiation therapy in the management of highrisk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation therapy oncology group trial 9514. J Clin Oncol. 2006;02:619–625. DOI:10.1200/JCO.;1; 2005.02.5577 . Cormier JN, Huang X, Xing Y, et al.: Cohort analysis of patients with localized, high-risk, extremity soft tissue sarcoma treated at two cancer centers: Chemotherapy-associated outcomes. J Clin Oncol 2004;22:4567–4574.DOI:10.1200/JCO.2004.02.057 DeLaney TF, Spiro IJ, Suit HD, et al.: Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 2003;56:1117–1127.DOI:10.1016/S0360– 3016(03) 00186-X . Meric F, Hess KR, Varma DGK, et al.: Radiographic response to neoadjuvant chemotherapy is a predictor of local control and survival in soft tissue sarcomas. Cancer 2002;95:1120–1126. DOI:10.1002/cncr.10794

Journal of Surgical Oncology

511

25. Issels RD, Lindner LH, Verweij J, et al.: Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk softtissue sarcoma: A randomised phase 3 multicentre study. Lancet Oncol 2010;11:561–570.DOI:10.1016/S1470–2045(10) 70071–1 . 26. Escobar C, Munker R, Thomas JO, et al.: Update on desmoid tumors. Ann Oncol 2012;23:562–569.DOI:10.1093/annonc/mdr386 27. Singh HK, Kilpatrick SE, Silverman JF: Fine needle aspiration biopsy of soft tissue sarcomas: Utility and diagnostic challenges. Adv Anat Pathol 2004;11:24–37.DOI:10.1097/00125480–200401000-00003 . 28. Kilpatrick SE, Cappellari JO, Bos GD, et al.: Is fine-needle aspiration biopsy a practical alternative to open biopsy for the primary diagnosis of sarcoma? experience with 140 patients. Am J Clin Pathol 2001;115:59–68.DOI:10.1309/YN14-K8U4–5FLJ-DGJE . 29. Costa MJ, Campman SC, Davis RL, et al.: Fine-needle aspiration cytology of sarcoma: Retrospective review of diagnostic utility and specificity. Diagn Cytopathol 1996;15:23–32.DOI:10.1002/(SICI) 1097–0339(199607) 15:1 3.0.CO;2-R . 30. Skrzynski MC, Biermann JS, Montag A, et al.: Diagnostic accuracy and charge-savings of outpatient core needle biopsy compared with open biopsy of musculoskeletal tumors. J Bone Jt Surg SER A 1996;78:644–649. 31. Welker JA, Henshaw RM, Jelinek J, et al.: The percutaneous needle biopsy is safe and recommended in the diagnosis of musculoskeletal masses: Outcomes analysis of 155 patients at a sarcoma referral center. Cancer 2000;89:2677–2686.DOI:10.1002/1097–0142 (20001215) 89:12 < 2677::AID-CNCR22> 3.0.CO;2-L . 32. Ray-Coquard I, Ranchère-Vince D, Thiesse P, et al.: Evaluation of core needle biopsy as a substitute to open biopsy in the diagnosis of soft-tissue masses. Eur J Cancer 2003;39:2021–2025. DOI:10.1016/S0959–8049(03) 00430–1 . 33. Mitsuyoshi G, Naito N, Kawai A, et al.: Accurate diagnosis of musculoskeletal lesions by core needle biopsy. J Surg Oncol 2006;94:21–27.DOI:10.1002/jso.20504 34. Madhavan VP, Smile SR, Chandra S : Value of core needle biopsy in the diagnosis of soft tissue tumours. Indian J Pathol Microbiol 2002;45:165–168. 35. Heslin MJ, Lewis JJ, Woodruff JM, et al.: Core needle biopsy for diagnosis of extremity soft tissue sarcoma. Ann Surg Oncol 1997;4:425–431. 36. Pohlig F, Kirchhoff C, Lenze U, et al.: Percutaneous core needle biopsy versus open biopsy in diagnostics of bone and soft tissue sarcoma: A retrospective study. Eur J Med Res 2012;17:29. 37. Kachroo P, Pak PS, Sandha HS, et al.: Chest wall sarcomas are accurately diagnosed by image-guided core needle biopsy. J Thorac Oncol 2012;7:151–156.DOI:10.1097/JTO.0b013e3182307f4c 38. Altuntas AO, Slavin J, Smith P, et al.: Accuracy of computed tomography guided core needle biopsy of musculoskeletal tumours. ANZ J Surg 2005;75:187–191.DOI:10.1111/j.1445– 2197.2005.03332.x . 39. Soudack M, Nachtigal A, Vladovski E, et al.: Sonographically guided percutaneous needle biopsy of soft tissue masses with histopathologic correlation. J Ultrasound Med 2006;25:1271–1277. 40. Issakov J, Flusser G, Kollender Y, et al.: Computed tomographyguided core needle biopsy for bone and soft tissue tumors. Isr Med Assoc J 2003;5:28–30. 41. Strauss DC, Qureshi YA, Hayes AJ, et al.: The role of core needle biopsy in the diagnosis of suspected soft tissue tumours. J Surg Oncol 2010;102:523–529.DOI:10.1002/jso.21600 42. Azumi N, Curtis J, Kempson RL, et al.: Atypical and malignant neoplasms showing lipomatous differentiation. A study of 111 cases. Am J Surg Pathol 1987;11:161–183. 43. Kooby DA, Antonescu CR, Brennan MF, et al.: Atypical lipomatous tumor/well-differentiated liposarcoma of the extremity and trunk wall: Importance of histological subtype with treatment recommendations. Ann Surg Oncol 2004;11:78–84. 44. Sommerville SM, Patton JT, Luscombe JC, et al.: Clinical outcomes of deep atypical lipomas (well-differentiated lipoma-like liposarcomas) of the extremities. ANZ J Surg 2005;75:803–806.DOI: 10.1111/j.1445-2197.2005.03519.x. 45. Binh MBN, Sastre-Garau X, Guillou L, et al.: MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing welldifferentiated and dedifferentiated liposarcoma subtypes: A

512

46. 47. 48. 49. 50. 51. 52. 53.

54.

Tuttle and Kane comparative analysis of 559 soft tissue neoplasms with genetic data. Am J Surg Pathol 2005;29:1340–1347.DOI:10.1097/01. pas.0000170343.09562.39 Mankin HJ, Lange TA, Spanier SS: The hazards of biopsy in patients with malignant primary bone and soft-tissue tumors. J Bone Jt Surg SER A 1982;64:1121–1127. Mankin HJ, Mankin CJ, Simon MA: The hazards of the biopsy, revisited: For the members of the musculoskeletal tumor society. J Bone Jt Surg Ser A 1996;78:656–663. Clayer M: Open incisional biopsy is a safe and accurate technique for soft tissue tumours. ANZ J Surg 2010;80:786–788. DOI:10.1111/j.1445–2197.2010.05340.x . Casali PG, Blay J-: Soft tissue sarcomas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21:v198–v203.DOI: 10.1093/annonc/mdq209 Hughes TM, Thomas JM: Sarcoma metastases due to iatrogenic implantation. Eur J Surg Oncol 2000;26:50–52.DOI:10.1053/ ejso.1999.0740. Schwartz HS, Spengler DM: Needle tract recurrences after closed biopsy for sarcoma: Three cases and review of the literature. Ann Surg Oncol 1997;4:228–236. Walsh GL, Nesbitt JC: Tumor implants after thoracoscopic resection of a metastatic sarcoma. Ann Thorac Surg 1995;59:215–216. Oliveira MP, Lima PM, da Silva HJ, et al.: Neoplasm seeding in biopsy tract of the musculoskeletal system. A systematic review. Acta Ortop Bras 2014;22:106–110.DOI:10.1590/1413– 78522014220200422 Binitie O, Tejiram S, Conway S, et al.: Adult soft tissue sarcoma local recurrence after adjuvant treatment without resection of core

Journal of Surgical Oncology

55. 56.

57.

58.

59.

60.

61.

needle biopsy tract. Clin Orthop Relat Res. 2013;471:891–898. DOI:10.1007/s11999–012-2569-z [doi] . Liles JS, Tzeng C-D, Short JJ, et al.: Retroperitoneal and intraabdominal sarcoma. Curr Probl Surg 2009;46:445–503. DOI:10.1067/j.cpsurg.2009.01.004 . Kasper B, Ströbel P, Hohenberger P: Desmoid tumors: Clinical features and treatment options for advanced disease. Oncologist 2011;16:682–693.DOI:10.1634/theoncologist.2010– 0281 Andtbacka RHI, Ng CS, Scaife CL, et al.: Surgical resection of gastrointestinal stromal tumors after treatment with imatinib. Ann Surg Oncol 2007;14:14–24.DOI:10.1245/s10434–0069034–8 Tielen R, Verhoef C, Van Coevorden F, et al.: Surgical treatment of locally advanced, non-metastatic, gastrointestinal stromal tumours after treatment with imatinib. Eur J Surg Oncol 2013;39:150–155. DOI:10.1016/j.ejso.2012.09.004 DeMatteo RP, Lewis JJ, Leung D, et al.: Two hundred gastrointestinal stromal tumors: Recurrence patterns and prognostic factors for survival. Ann Surg. 2000;231:51–58.DOI:10.1097/ 00000658–200001000-00008 Ito H, Inoue H, Ryozawa S, et al.: Fine-needle aspiration biopsy and endoscopic ultrasound for pretreatment pathological diagnosis of gastric gastrointestinal stromal tumors. Gastroenterol Res Pract 2012;DOI:10.1155/2012/139083 Chatzipantelis P, Salla C, Karoumpalis I, et al.: Endoscopic ultrasound-guided fine needle aspiration biopsy in the diagnosis of gastrointestinal stromal tumors of the stomach. A study of 17 cases. J Gastrointest Liver Dis 2008;17:15–20.