Practical Issues for Retroperitoneal Sarcoma - PDF Document

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  1. Pathology Report Practical Issues for Retroperitoneal Sarcoma Vicky Pham, MS, Evita Henderson-Jackson, MD, Matthew P. Doepker, MD, Jamie T. Caracciolo, MD, Ricardo J. Gonzalez, MD, Mihaela Druta, MD, Yi Ding, MD, and Marilyn M. Bui, MD, PhD Background: Retroperitoneal sarcoma is rare. Using initial specimens on biopsy, a definitive diagnosis of histological subtypes is ideal but not always achievable. Methods: A retrospective institutional review was performed for all cases of adult retroperitoneal sarcoma from 1996 to 2015. A review of the literature was also performed related to the distribution of retroperitoneal sarcoma subtypes. A meta-analysis was performed. Results: Liposarcoma is the most common subtype (45%), followed by leiomyosarcoma (21%), not otherwise specified (8%), and undifferentiated pleomorphic sarcoma (6%) by literature review. Data from Moffitt Cancer Center demonstrate the same general distribution for subtypes of retroperitoneal sarcoma. A pathology-based algorithm for the diagnosis of retroperitoneal sarcoma is illustrated, and common pitfalls in the pathology of retroperitoneal sarcoma are discussed. Conclusions: An informative diagnosis of retroperitoneal sarcoma via specimens on biopsy is achievable and meaningful to guide effective therapy. A practical and multidisciplinary algorithm focused on the histopathology is helpful for the management of retroperitoneal sarcoma. Introduction Soft-tissue sarcomas are mesenchymal neoplasms that account for up to 1% of all newly diagnosed ma- lignancies at a rate of 3.6 per 100,000 per year.1-3 Com- pared with bone or visceral sarcomas, they make up 58% of all sarcomas.3 Although the extremities rep- resent the most common location of soft-tissue sarco- ma, retroperitoneal sarcoma accounts for 9% to 15% of all adult soft-tissue sarcomas.3,4For surgical pathol- ogists, retroperitoneal tumors will be encountered in daily practice regardless of the practice setting. Ret- roperitoneal sarcoma presents diagnostic challenges due to its rarity, variety of tumor types, a general level of unfamiliarity among surgical pathologists, and lack of generally accepted guidelines in its diagnostic ap- proach. In the era of personalized medicine, pathol- ogists play a critical and central role in patient care. Demand has increased to obtain diagnostic, prognos- tic, and predictive information based on a relatively small amount of tissue obtained on biopsy. In this study, we compare our experience, espe- cially the distribution of histological subtypes, with the literature to develop a better understanding of common and rare tumor types, pertinent ancil- lary testing, diagnostic pitfalls, and refine a practi- cal, multidisciplinary, and algorithmic approach to achieve an informative diagnosis to help guide the therapeutic plan. Methods After obtaining Institutional Review Board approval, the database Transmed (H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida) was retrospec- tively reviewed for all histological subtypes of retro- peritoneal sarcomas from 1996 to 2015. Transmed in- tegrates data from all patients seen at Moffitt Cancer Center since 1996 (approximately 395,000 patients, regardless of diagnosis) as well as other patients not treated at Moffitt Cancer Center but who consented to the Total Cancer Care protocol at one of 17 consor- tium sites (approximately 36,000 patients).This result was cross-checked by sarcoma pathologists as well as the deidentified result of another retroperitoneal sar- coma retrospective institutional review. A systematic review of the English literature was conducted for works published between 2000 and 2015. This yielded 85 search results. Another literature search was conducted yielding an ad- ditional 444 results. After excluding case reports and studies with locations of retroperitoneal sarco- From the University of South Florida Morsani College of Medicine (VP), the Departments of Anatomic Pathology (EH-J, MMB), Sar- coma (EH-J, JTC, RJG, MD, MMB), Surgical Oncology (MPD), and Diagnostic Imaging (JTC), H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, and the Department of Pathology (YD), JiShuiTan Hospital, Beijing, China. Address correspondence to Marilyn M. Bui, MD, PhD, Department of Anatomic Pathology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612. E-mail: Marilyn.Bui@Moffitt.org Submitted August 17, 2015; accepted December 29, 2015. This study received financial assistance from Information Shared Services Department/Collaborative Data Services Core at the H. Lee Moffitt Cancer Center & Research Institute supported under NIH grant P30-CA76292. This research was also supported by an award from the Scholarly Concentrations Program at USF Health Morsani College of Medicine. July 2016, Vol. 23, No. 3 Cancer Control 249

  2. ma mixed with other locations, our search yielded 54 studies from which we extracted information about the distribution of histological subtypes with- in each study patient population. The meta-analysis was conducted using Stats- Direct (Cheshire, United Kingdom). Table 1. — Distribution of Histological Subtypes of Retroperitoneal Soft-Tissue Sarcoma Subtype Distribution From the Literature, % 45.1 23.9 20.9 0.9 0.4 21.3 8.2 6.4 Distribution From Moffitt, % Liposarcoma (all subtypes) Well differentiated Dedifferentiated Myxoid/round cell Pleomorphic Leiomyosarcoma Other Malignant fibrous histiocytoma/ undifferentiated pleomorphic sarcoma Sarcoma not otherwise specified Malignant peripheral nerve sheath tumor Solitary fibrous tumor/ hemangiopericytoma Fibrosarcoma (nondesmoid) Rhabdomyosarcoma Schwannoma Angiosarcoma Anaplastic sarcoma Adenosarcoma Chondrosarcoma Desmoplastic small-round cell tumor Epithelioid sarcoma Extraskeletal osteosarcoma Fibromyxosarcoma Giant cell sarcoma Mesenchymoma Primitive neuroectodermal tumor/ extraskeletal Ewing sarcoma Small cell/embryonal/synovial/ undifferentiated sarcoma Spindle cell sarcoma Undifferentiated round-cell sarcoma 54.6 15.3 15.6 6.8 Results Literature Review A literature search revealed the following list of most to least common histological subtypes of tumors. Per- centages shown are out of all retroperitoneal sarcoma subtypes (Table 1). Our review and data analysis of retroperitoneal sarcoma studies concluded that the most common subtype of retroperitoneal sarcoma is liposarcoma, which constitutes 45.1% of all retro- peritoneal sarcoma (Fig 1). The next most common subtypes are leiomyosarcoma (21.3%), other (8.2%), and malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma (6.4%; see Table 1). Well-differ- entiated liposarcoma and dedifferentiated liposarco- ma constituted 45.8% and 44.8% of all retroperitoneal liposarcomas, respectively (Fig 2). The less common subtypes were myxoid/round cell liposarcoma and pleomorphic liposarcoma. 1 26.1 0 1 1.6 1.3 4.9 1 0.8 0 0.5 0.4 0.3 0.1 1 1 0 0 0 0 0 0 0 1 1 3 0 1 Institutional Results A review of Transmed, which represents single-insti- tution data, is summarized in Table 1. Our data for retroperitoneal sarcoma subtypes are consistent with our literature search. Liposarcomas of all subtypes at Moffitt Cancer Center make up 54.6% (168 cases) of all retroperitoneal sarcoma (307 cases), followed by leio- myosarcomas (80 cases), sarcoma not otherwise spec- ified (15 cases), malignant peripheral nerve tumor (3 cases), and other less common subtypes (1–2 cases; see Table 1). The trend for most to least common tu- mor types appears to be similar (Fig 3). In Fig 4, data from Moffitt Cancer Center on the histological sub- types of retroperitoneal liposarcomas are compared with the data found during our literature search. The median age of the patients in all 54 studies was 58 years. The percentages of those who were men and women were 53.2% and 46.8%, respectively. < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 0 < 0.1 < 0.1 1 1 Gap Between Practice and Literature Most of the literature we reviewed describes sarcoma in categories based on histological type and morpho- logical pattern.5 Morphological features are evaluated to determine the differential diagnosis, ranking pos- sible diagnoses from most likely to least likely in con- junction with clinical and radiological clues, and then applying ancillary testing to narrow down the diagno- sis. Thus, it is important to understand the common and rare types of retroperitoneal sarcoma. Some sarcomas have molecular and immunohis- tochemical hallmarks and characteristics that can be diagnosed with a small amount of tissue acquired on biopsy; however, commonly, sarcoma does not have such a signature and morphologically overlaps with other tumors. Ancillary tests can be performed to narrow the diagnosis, with the understanding that it may not be possible to achieve a definitive diagno- sis. However, it is important to realize that, when a definitive diagnosis is not achievable, an alternative option is to provide useful, diagnostic information to guide the clinical team in the next appropriate step 250 Cancer Control July 2016, Vol. 23, No. 3

  3. Liposarcoma 45.1 Leiomyosarcoma 21.3 Histological Subtype Other 8.2 Malignant fibrous histiocytoma/ undifferentiated pleomorphic sarcoma Sarcoma not otherwise specified 6.4 1.6 Malignant peripheral nerve sheath tumor 1.3 Solitary fibrous tumor/hemangiopericytoma 0.8 Rhabdomyosarcoma 0.4 10 15 20 25 30 35 40 45 50 0 5 Percentage Fig 1. — Distribution of histological subtypes of retroperitoneal sarcoma. Histological Subtype Well differentiated 45.8 Dedifferentiated 44.8 Myxoid/round cell 4.7 Pleomorphic 0.8 10 15 20 25 30 35 40 45 50 0 5 Percentage Fig 2. — Distribution of histological subtypes of retroperitoneal liposarcoma. for the patient’s care. In such situations, being aware of the management plan for various diagnoses is criti- cal. Some diagnoses are managed according to estab- lished institutional pathways. The literature often fo- cuses on achieving a definitive diagnosis, rather than realizing an informative diagnosis. and higher-grade tumors being more appropriate for treatment.1 Future research may enable more histolo- gy-specific decisions. We speculate that new data may suggest no role exists for radiotherapy in the treatment of leiomyosarcoma. However, histological subtypes play a role in che- motherapy. Some subtypes may respond better to certain chemotherapeutic agents or regimens and, conversely, several different sarcoma subtypes will similarly respond to identical chemotherapy treat- ments (Fig 5; Table 2).7-18 The role of chemotherapy in the management of retroperitoneal sarcoma is not well defined. The 2 most important determinants of overall survival (OS) are tumor grade and extent of re- section, with subtypes having a less important role in determining prognosis.6,19 Therefore, when consider- ing whether to pursue a definitive diagnosis for a tu- mor subtype, the relative costs and turnaround time of ancillary tests vs the importance or relevance of the test results in the larger context of the interdisciplin- ary management of retroperitoneal sarcoma must be considered; therefore, pathologists must make judi- cious use of their tissue samples, time, and institutional resources. Multidisciplinary Approach to Pathology-Focused Management The interdisciplinary management of retroperitoneal sarcoma involves chemotherapy, radiotherapy, and surgery, along with providing prognostic, predictive, and diagnostic information to the clinical team and the patient. The mainstay of treatment for retroperitoneal sarcoma is surgical resection. Complete resection with a microscopically negative margin (R0) remains the po- tential likelihood for cure.6 Surgical decision-making in retroperitoneal sarcoma is not solely based on his- tological subtypes, but rather on factors such as per- formance status, patient comorbidities, and extent of tumor involvement into adjacent organs and vascular structures.1 Adjunctive therapies such as perioperative radiotherapy and chemotherapy are also selectively used within the context of interdisciplinary review on a case-by-case basis. At this time, use of radiotherapy does not depend on histological subtypes but rather on tissue tolerance and tumor grades, with intermediate- Neoadjuvant Chemotherapy The role of neoadjuvant chemotherapy is not well de- July 2016, Vol. 23, No. 3 Cancer Control 251

  4. All liposarcoma subtypes Histological Subtype All leiomyosarcoma subtypes Sarcoma not otherwise specified Malignant peripheral nerve sheath tumor 0 10 20 30 40 50 60 Percentage Data Source Malignant Peripheral Nerve Sheath Tumor 1.0 1.3 Sarcoma Not Otherwise Specified 4.9 1.6 All Subtypes of Leiomyosarcoma 26.1 21.3 All Subtypes of Liposarcoma 54.7 45.1 Moffitt Literature Fig 3. — Comparison of retroperitoneal sarcoma subtypes demonstrates a consistent distribution at Moffitt Cancer Center vs literature search. Histological Subtype Dedifferentiated Well differentiated Myxoid/round cell Pleomorphic 5 10 15 20 25 30 0 Percentage Data Source Moffitt Literature Pleomorphic 1.0 0.4 Myxoid/Round Cell 6.8 0.9 Well Differentiated 15.3 23.9 Dedifferentiated 15.6 20.9 Fig 4. — Comparison of liposarcoma subtypes distribution at Moffitt Cancer Center vs literature search. Percentages take into account all retroperi- toneal sarcoma subtypes. fined in retroperitoneal sarcoma due to the rarity of the disease; therefore, its role is often extrapolated from studies that include extremity sarcoma. Several case series have been reported, but no definitive prospec- tive trials have examined OS differences in those re- ceiving preoperative vs postoperative chemotherapy.1 Similarly, to date, no randomized trials exist of neoad- juvant chemotherapy vs resection alone for retroperi- toneal sarcoma.7 Although data are limited, preopera- tive chemotherapy appears to be safe and occasionally induces a modest radiographic response, which may impact surgical outcomes in select patients.20-23 The theoretical advantage of preoperative chemothera- py focuses on the potential to reduce the complex- ity of potential surgery for the tumor subtypes that re- spond to systemic therapy, especially intermediate- or high-grade tumors.1,8 Opportunity also exists to deter- mine the response to chemotherapy in the neoadjuvant setting as a determinant of therapy continuation in the adjuvant setting. The administration of systemic therapy in the neo- adjuvant setting is often combination therapy with doxorubicin and ifosfamide, a regimen with potential for renal toxicity but with a higher response rate (31% vs 14% in the single-arm doxorubicin alone).24 As a con- sequence of resection, nephrectomy is often required, so chemotherapy in the neoadjuvant setting allows for use of ifosfamide, which, in combination with doxo- rubicin, may have a larger effect on tumor response when compared with doxorubicin alone.24 Localized Treatment (Curative Intent) Retroperitoneal sarcoma is a heterogeneous group of tumors with multiple histological subtypes and grades that vary in chemosensitivity. For localized treatment, doxorubicin and ifosfamide are commonly used.25 Among the liposarcomas, well-differentiated liposar- coma does not respond (response rate = 0%) to che- motherapy and dedifferentiated liposarcoma responds poorly (response rate = 25%).9 Myxoid liposarcoma has 252 Cancer Control July 2016, Vol. 23, No. 3

  5. Chemotherapy for Metastatic or Advanced Soft-Tissue Sarcoma (Palliative Intent) Chemotherapy has an established role in the palliative management of metastatic or advanced soft-tissue sar- coma.6,14 In the metastatic setting, use of single-agent doxorubicin or combination doxorubicin/ifosfamide has shown a consistent response.24 However, some subtypes the highest response rate at 48%.9 Round cell liposarco- ma, a high-grade spectrum of myxoid liposarcoma, has a response rate of 17%.9 Pleomorphic liposarcoma has a response rate of 33%.1 The response rate of leiomyo- sarcoma to chemotherapy is 25%.10-12 For the remain- ing retroperitoneal sarcoma subtypes, response rates range from 21% to 31% (see Fig 5).7,9,11-14,16,26 Table 2. — Use of Chemotherapy for the Management of Retroperitoneal Soft-Tissue Sarcomas Clinical and radiological information (including contrast-enhanced abdominopelvic CT or MRI to evaluate local extent of disease and CT of the chest to evaluate for distant metastases) assessed by interdisciplinary teama Patients with Li-Fraumeni syndrome should be referred for further genetic assessment11,16 Subtype Chemotherapy Response Rate,a % Myxoid: 48 Round cell: 179 Type of Chemotherapy Neoadjuvant Setting Doxorubicin/ifosfamide for localized treatment Metastatic Setting Single-agent doxorubicin Adjuvant Setting Adjuvant chemotherapy determined on case-by-case basis; with large high-grade tumors, adjuvant chemotherapy increases metastasis-free survival rate8 Myxoid/round cell liposarcoma Dedifferentiated liposarcoma Leiomyosarcoma Pleomorphic liposarcoma Undifferentiated pleomorphic sarcoma Other subtypes 21–3310-12 Well-Differentiated Liposarcoma (24%) Further biopsy not mandatory depending on cross-sectional imaging Complete resection is mainstay of treatment Unresponsive to anthracycline- based chemotherapy or radiotherapy9 Most locoregionally occur rather than metastasize9,14 Image-Guided Core Biopsy Preferred to open surgical biopsy Angiosarcomab Solitary fibrous tumorb Hemangiopericytomab Ewing/primitive neuroectodermal tumorb Nonpleomorphic rhabdomyosarcomab,c Histological specific treatment (not anthracycline-based) recommended16 Differential Diagnoses GIST Desmoid tumor (aggressive fibromatosis) Metastatic lesion Lipoma Lymphoma Primary neoplasm arising from pancreas, adrenal glands, kidneys, duodenum Adenopathy from testicles in a young male Other Retroperitoneal Soft-Tissue Sarcoma Subtypes — Surgery = Mainstay Treatment If tumor is partially resect- able, then neoadjuvant radiotherapy/chemotherapy becomes more important to treat periphery of lesion as it abuts critical structures with intent of consolidating peritumoral reactive zone and rendering the close margin sterile Neoadjuvant chemotherapy also important for chemosensitive histologies7,11 New evidence may suggest no role for radiotherapy in treating leiomyosarcoma Synovial Sarcoma Responds best to ifosfamide-based first-line therapy (doxorubicin/ ifosfamide)10,12; also sensitive to radiotherapy15 MPSNT Responds best to doxorubicin/ifosfamide in metastatic setting13 Synovial sarcoma/ MPNST Synovial sarcoma: 25–3110,12 MPNST: 2113 May Not Require Surgery as First Approach Examples: lymphoma, GIST, Ewing sarcoma Preoperative Radiotherapy: External beam radiotherapy used for intermediate- to high-grade tumors, especially in more radiosensitive tumors (eg, extraosseous Ewing sarcoma, primitive neuroectodermal tumor). The more common subtypes, such as well-differentiated liposarcoma and leiomyosarcoma, are generally unresponsive to radiotherapy.18 Postoperative Radiotherapy: Not commonly used due to toxic effects to adjacent organs with no apparent benefit.17 aIn general, response rates extracted from studies of soft-tissue sarcomas (not restricted to retroperitoneum). bComprises < 0.8% of all subtypes. cMost studies reviewed list rhabdomyosarcoma as a general subtype without denoting more specific subtypes. MPNST = malignant peripheral nerve sheath tumor. Refer to Table 2 Fig 5. — Proposed algorithm for the pathology-focused management of retroperitoneal soft-tissue sarcoma. aTeam is made up of a surgical oncologist, radiologist, oncologist, and pathologist. CT = computed tomography, GIST = gastrointestinal stromal tumor, MRI = magnetic resonance imaging. July 2016, Vol. 23, No. 3 Cancer Control 253

  6. (eg, solitary fibrous tumor, well-differentiated liposarco- ma) are resistant to anthracycline-based therapy, while others show a differential response to cytotoxic system- ic therapy.9,27 Thus, the concept of histology-driven treat- ment has arisen, rather than a one-size-fits-all or all-in- clusive approaches to therapy in patients with metastatic soft-tissue sarcoma. Angiosarcomas have been shown to respond to paclitaxel and pegylated liposomal doxo- rubicin, leiomyosarcomas to combination gemcitabine/ docetaxel, desmoid tumors to liposomal doxorubicin, and synovial sarcoma and malignant peripheral nerve sheath tumor (MPNST) respond best to doxorubicin/ ifosfamide.10-15,26-28 Pazopanib, a multitargeted tyrosine kinase inhibitor, has demonstrated single-agent activity in patients with advanced soft-tissue sarcoma subtypes, except for liposarcoma.16 Consensus-based recommen- dations for the treatment of metastatic soft-tissue sarco- ma from the National Comprehensive Cancer Network provide specific therapy regimen recommendations for the following retroperitoneal sarcoma subtypes: soft-tissue sarcoma with nonspecific histologies, angio- sarcoma, solitary fibrous tumor/hemangiopericytoma, Ewing sarcoma/primitive neuroectodermal tumor, non- pleomorphic rhabdomyosarcoma, and desmoid tumors (see Fig 5).7,9,11,14,16 Although select patients with sarcoma do derive substantial clinical benefit from chemothera- py, most patients develop metastatic disease that is in- curable.29 In a study of 488 participants with advanced soft-tissue sarcoma who were treated with first-line che- motherapy at a single institution, 45% of them derived clinical benefit from treatment in terms of partial re- sponse (PR) or prolonged disease stabilization; the me- dian rate of OS was 12 months.30 Furthermore, in the past decade, greater empha- sis has been placed on identifying the underlying mo- lecular drivers of sarcomas.31 Several potential novel, systemic therapies for soft-tissue sarcoma have been identified, including MDM2 targets, cyclin-dependent kinase 4 inhibitors, peroxisome proliferator-activated receptors (critical regulators of normal adipocyte dif- ferentiation), and tyrosine kinase receptors.32 Other targets reported but not yet tested include YEATS4, c-Jun, and JNK.32 nal damage, secondary cancers, cardiomyopathy, and overall impairment of quality of life.16 Radiotherapy The overall benefit of radiotherapy for use with retro- peritoneal sarcoma has yet to be established, with most of the data being extrapolated from studies of soft-tissue sarcoma of the extremities.33 However, concern remains about the increased risk of treatment-related toxicity to highly radiosensitive visceral structures due to their rap- idly proliferating mucosa and rich blood supply.34 The relatively low rate of radiation tolerance for surrounding normal tissues (liver, kidney, gastrointestinal tract, spi- nal cord) predisposes patients to risks of intestinal per- foration, peritonitis, and peripheral neuropathy.35 Use of preoperative radiotherapy is currently being investigated in an accruing, prospective, randomized, multicenter trial (NCT01344018). This type of trial is in- vestigating the potential for external beam radiotherapy (EBRT) to reduce local regional failure.36 Proponents of preoperative radiation cite the potential benefits of po- tentially using lower doses, while the tumor displaces radiosensitive viscera outside the field of radiation.37 Proponents also claim gross tumor volume can be more adequately defined, which would allow for more accu- rate preoperative treatment planning.37 Use of postoperative EBRT has been studied but largely abandoned due to its toxic effects of the remain- ing organs within the tissue bed after resection, with no apparent improvement in survival.17 Another concern with postoperative radiation suggests the difficulty in defining a precise area of the tumor bed to apply EBRT.17 Our experience at Moffitt Cancer Center favors use of preoperative EBRT for intermediate- to high-grade tumors, especially in more radiosensitive tumors, such as extraosseous Ewing sarcoma/primitive neuroecto- dermal tumor. The more common subtypes, such as well-differentiated liposarcoma and leiomyosarcoma, are generally unresponsive to radiation.18 Thus, concern remains about the increased risk of treatment-related toxicity to visceral structures. Pathological Prognostic Factors The most important prognostic factors for survival are extent of tumor resection and histological grade, al- though histological subtype is also emphasized as an important factor.38 Other factors influencing prognosis include tumor stage, patient age, tumor size, and mul- tifocality. Nomograms have been developed and vali- dated to more accurately predict postoperative survival based on these and other factors.39 Well-differentiated liposarcomas have the most favorable outcome, where- as leiomyosarcomas, pleomorphic sarcoma/malignant fibrous histiocytoma, MPNST, and dedifferentiated li- posarcomas exhibit the least favorable outcomes.38 Other prognostic concerns include risks for locore- Adjuvant Chemotherapy Several prospective, randomized trials of study pa- tients who received adjuvant regimens following sur- gical resection have demonstrated decreased local re- currence rates, but the effect on OS is less clear.1 The benefits of adjuvant chemotherapy must be addressed based on the individual while simultaneously taking into consideration performance status, disease loca- tion, tumor size, comorbid factors (including age), and histological subtype. The potential for benefit must be discussed in the context of expected treatment-related toxicities, including sterility in younger individuals, re- 254 Cancer Control July 2016, Vol. 23, No. 3

  7. gional recurrence and metastasis. Local regional relapse is the main cause of disease-related death and, in con- junction with retroperitoneal sarcoma, the risk for de- veloping abdominal sarcomatosis also results in death, even in the absence of systemic dissemination.40,41 Tu- mor grade and histological subtypes are major prognos- tic factors related to metastatic occurrence.19,42 Toule- monde et al42 reviewed the data of 586 study patients with retroperitoneal sarcoma during a multicenter anal- ysis, looking at patterns of care at diagnosis and prog- nostic factors, with a focus on main histological sub- types. Those findings are summarized in Table 3.8,14,42 Other symptoms such as hematuria, uncontrollable hypertension, or early satiety may raise concern for a primary tumor of a retroperitoneal origin rather than primary retroperitoneal sarcoma.1 Findings on cross-sectional imaging may also help assess the internal composition of the tumor, allowing for the preoperative prediction of tumor histopathol- ogy and assessment of local extent of disease; these may have an impact on neoadjuvant treatment, surgical planning, or both. Tumor staging should include imag- ing of the chest to evaluate for pulmonary metastatic disease and is typically performed with CT. Of all the retroperitoneal sarcoma subtypes, well- differentiated liposarcomas make up 24% and are com- prised of simple-appearing fat that has a characteristic appearance on cross-sectional imaging (Fig 6).1 For lesions demonstrating typical imaging findings of well-differentiated retroperitoneal liposarcoma, biopsy is typically not indicated given the high rate of diagnostic sensitivity of CT for low-grade adipo- cytic lesions and no role for neoadjuvant therapy with these tumors.1 If imaging findings do not suggest well-differen- tiated liposarcoma, then image-guided core needle bi- opsy or fine needle aspiration (FNA) is required and is preferred to open surgical biopsy.16 However, core needle biopsy is preferred to FNA due to the difficulty that exists in discerning histological subtype by FNA. If results on biopsy suggest retroperitoneal sar- coma, then surgery is the mainstay treatment for all subtypes (see Fig 5). If the tumor is partially resectable, then neoadjuvant radiotherapy and chemotherapy be- come more important for treating the periphery of the lesion because it will abut critical structures; both types of therapy have the intent of consolidating the peritu- moral reactive zone and rendering close margins sterile. Neoadjuvant chemotherapy is also important for tumors with chemosensitive histologies.7,11 For the palliative management of metastatic or advanced soft-tissue sar- coma, chemotherapy has an established role.6 Proposed Algorithm for Management A patient’s clinical and radiological information is first assessed by an interdisciplinary team that generally in- cludes a surgical oncologist, radiologist, medical and radiation oncologists, and a pathologist — preferably all of whom have expertise in soft-tissue sarcoma (see Fig 5). Cross-sectional imaging, including computed to- mography (CT) or magnetic resonance imaging (MRI), preferably with intravenous contrast, can demonstrate predictable displacement of retroperitoneal structures, allowing for localization of a tumor to the retroperito- neum rather than the peritoneal cavity. When a mass is detected in the retroperitoneum, the differential diagnoses may include primary retroperitoneal soft- tissue sarcomas, metastatic disease, including lymph- adenopathy from primary sites of disease elsewhere, lymphoma, primary neoplasms arising from retroperi- toneal viscera such as the pancreas, kidneys, ureters, adrenal glands, duodenum, or ascending/descending colon such as adenocarcinoma or gastrointestinal stro- mal tumor (GIST), paraspinal neurogenic tumors, and retroperitoneal fibrosis. Clinical symptomatology, such as B symptoms in cases of lymphoma or findings on physical examination such as a palpable testicular ab- normality, which may be associated with retroperito- neal lymphadenopathy, will direct diagnostic consid- eration away from primary retroperitoneal sarcoma. Table 3. — Risk by Subtype for Local Regional Relapse, Metastasis, and OS Rates Subtype Leiomyosarcoma Risk for Locoregional Relapse42 Piecemeal resection predictive of relapse OS Metastasis8 Adjacent organ involvement associated with worst OS Associated with high risk of competitive systemic relapse42 Exceptions to typical pattern of metastatic disease Commonly metastasizes to liver, lung High risk of metastatic disease14 Nearly all recur locoregionally, not via metastasis14 Well-differentiated liposarcoma Piecemeal resection predictive of relapse Adjacent organ involvement associated with worst OS Multifocality significantly associated with worse survival42 Grade 3 associated with worst OS42 Dedifferentiated liposarcoma Surgeon specialization and periopera- tive radiotherapy associated with lower risk of relapse Nearly all recur locoregionally, not via metastasis14 OS = overall survival. July 2016, Vol. 23, No. 3 Cancer Control 255

  8. Fig 5 summarizes relevant information regard- ing subtypes and perioperative therapy consider- ations.7,9,11,14,16 Myxoid/round cell liposarcoma as a primary malignancy is rare in the retroperitoneum (< 0.9% of all retroperitoneal sarcoma subtypes), and physical examination and imaging of the extremities to rule out a primary site in an extremity with distant retroperitoneal metastasis are indicated.6,43 Primitive neuroectodermal tumors, Ewing sarcoma, and alveo- lar/embryonal rhabdomyosarcoma are radiosensitive and chemosensitive, so they should not be considered for first-line surgery. Because primary chemotherapy is always given, the strategy for these tumors signifi- cantly differs from that undertaken for adult-type soft-tissue sarcoma. Subsequent surgery is then con- sidered for responsive tumors to achieve complete resection of all visible tumors; however, adjacent vis- cera is only included if true invasion is evident.14 Our experience with GIST is that neoadjuvant tyrosine ki- nase inhibitor therapy for large lesions and abutting critical structures should be used to reduce tumor size and limit the complexity of the procedure. Reduction of tumor size due to effective preoperative imatinib occurs in the majority of patients.44,45 In such a sce- nario, proper therapy is warranted for larger tumors that may require multivisceral resection. Fig 6. — Axial contrast-enhanced computed tomography demonstrates a large, round, adipocytic left retroperitoneal mass (dashed circle) that displaces the descending colon and compresses the left kidney with minimal fat stranding and few thin septations consistent with well-dif- ferentiated liposarcoma. and CDK4 are present in most cases and are in keeping with gene amplification.49 Molecular, cytogenetic, and immunohistochemistry applications help distinguish well-differentiated liposarcoma from benign adipose tumors. Well-differentiated liposarcoma is locally ag- gressive and lacks metastatic potential.47 Unless it be- comes dedifferentiated (dedifferentiated liposarcoma), well-differentiated liposarcoma is potentially curable with complete excision when located in the extremities; however, sites like the retroperitoneum and mediasti- num pose difficulty in obtaining a microscopically neg- ative margin (R0).46,51 The differential diagnosis of well- differentiated liposarcoma from benign adipose tumors in a limited specimen, such as specimens from core needle biopsies, can be difficult. MDM2 fluorescence in situ hybridization is sensitive and specific to iden- tify MDM2 amplification in morphologically atypical and typical lesional cells.51 The immunohistochemistry performance of MDM2 decreases when working with limited specimens on biopsy, a rate typically attributed to the focal staining seen within the majority of well- differentiated liposarcoma on whole-tissue sections.51 MDM2 has been useful in identifying dedifferen- tiated liposarcomas in addition to well-differentiated liposarcoma. Several studies have reported that most poorly differentiated sarcomas arising in the retroperi- toneum are, in fact, dedifferentiated liposarcoma and can be diagnosed on the basis of MDM2 amplification even without an atypical adipocytic component.52-54 Like well-differentiated liposarcoma, dedifferentiated liposarcoma harbors the ring or giant marker chromo- somes, whereas MDM2 (12q15) is consistently ampli- fied and overexpressed.46,49,55-58 Determination of Tumor Types With Radiological and Histological Correlation Well-Differentiated and Dedifferentiated Liposarcoma CT or MRI can be used to recognize well-differentiated liposarcoma (see Fig 6). Histomorphological findings that support a diagnosis of well-differentiated liposar- coma include proliferation of mature adipocytes with marked variation in cell size and a focal nuclear atypia in both adipocytes and stromal cells. Identification of lipoblasts does not make (or is required for) a diagno- sis of liposarcoma.46 Lipoblasts may be seen in benign lesions such as lipoblastoma, pleomorphic lipoma, and chondroid lipoma. Based on morphology, 4 main subtypes exist: adi- pocytic (lipoma-like), sclerosing, inflammatory, and spindle cell. The sclerosing subtype of well-differen- tiated liposarcoma tends to occur in the retroperito- neum and microscopically demonstrate scattered, hyperchromatic, bizarre stromal cells set in extensive fibrillary collagenous stroma. With the exception of the spindle-cell subtype, well-differentiated liposarcoma has been found by molecular and cytogenetic studies to harbor a characteristic ring and giant marker chro- mosomes containing amplification of the 12q13-15 re- gion, including MDM2.47-50 Several other genes located in the 12q14-15 region, including CDK4 and HMGA2, are frequently coamplified with MDM2.46 Immunohistochemically, expressions of MDM2 256 Cancer Control July 2016, Vol. 23, No. 3

  9. Histologically, dedifferentiated liposarcoma con- tains a well-differentiated liposarcoma component jux- taposed to areas of either low- or high-grade nonlipo- genic sarcoma (dedifferentiation). The dedifferentiated component may exhibit a wide variety of morphology from high-grade sarcoma resembling undifferentiated pleomorphic sarcoma or high-grade myxofibrosar- coma to low-grade dedifferentiation resembling fibro- matosis or fibrosarcoma.59-62 Historically, many dedif- ferentiated liposarcomas were diagnosed as malignant fibrous histiocytoma, particularly de novo dedifferen- tiated liposarcomas.54 Dedifferentiated liposarcoma commonly occurs in the retroperitoneum, with more than 90% arising de novo, whereas less than 10% rep- resent recurrences.46,58 Radiologically, the presence of a nonlipogen- ic soft-tissue mass within an otherwise fatty tumor would be consistent with dedifferentiation (Fig 7). Given the internal heterogeneity, it is important to cor- relate the histopathological findings with radiological imaging because results on tissue sampling may yield low-grade lipomatous tissue or high-grade sarcoma depending on the target of the biopsy. Surgically, the dedifferentiated part of the tumor is regarded as the only part needed to be excised, whereas surrounding well-differentiated liposarcoma is regarded as normal tissue. Therefore, dedifferentiated liposarcoma is rare- ly excised with margins free of well-differentiated li- posarcoma. Dedifferentiation is associated with a 15% to 20% metastatic rate; however, the mortality rate is more often related to uncontrolled local recurrences than to metastatic spread.50 A case illustration of de- differentiated liposarcoma appears in Fig 8. sarcoma constitute 0.9% and 0.4% of all retroperitoneal soft-tissue sarcomas, respectively (see Table 1). Myxoid liposarcoma demonstrates areas of myxomatous tis- sue that appear similar to fluid (low density on CT; high signal intensity on T2-weighted MRI) prior to A B Other Subtypes of Liposarcoma Myxoid/round cell liposarcoma and pleomorphic lipo- C Fig 8A–C. — Dedifferentiated liposarcoma. (A) Nonlipogenic malignancy is revealed on core biopsy. Hematoxylin and eosin stain, × 400. (B) Nuclear- positive MDM2. Immunohistochemistry, × 400. (C) Amplification of MDM2 (red signals). Green signals are chromosome 17 and confirm dedifferenti- ated liposarcoma. Fluorescent in situ hybridization, × 1000. Fig 7. — Axial contrast-enhanced computed tomography demonstrates a large infiltrative retroperitoneal mass encasing the right kidney (K), displacing the ascending colon (C) with lipogenic elements (large arrow), thick septations (small arrow), and nonadipocytic soft-tissue masses (*) anterior to the inferior vena cava and aorta (A). July 2016, Vol. 23, No. 3 Cancer Control 257

  10. administering intravenous contrast. However, myx- oid elements will be enhanced as opposed to non- enhanced fluid in areas of cystic degeneration or tumor necrosis. Occasionally, liposarcoma may dem- onstrate areas of mineralization or ossification. More than 95% of cases of myxoid liposarcoma demon- strate a classical t(12;16)(q13;p11) or t(12;22)(q13;q12) translocation, which results in fusion of FUS-CHOP or EWSR1-CHOP, respectively.46 A diagnosis of pri- mary retroperitoneal myxoid liposarcoma should made with caution, because such cases represent either metastatic myxoid liposarcoma or well-differ- entiated/dedifferentiated liposarcoma with myxoid stromal change.43,63 Round cell liposarcoma is not an independent subtype but rather a high-grade spec- trum of myxoid liposarcoma. Round cell liposarcoma shares the same molecular change as myxoid liposar- coma but is morphologically composed of blue round tumor cells. Pleomorphic liposarcoma often presents as a non- specific soft-tissue mass without obvious fat evident by results on imaging mimicking other high-grade retro- peritoneal sarcomas. Pleomorphic liposarcoma exhib- its pleomorphic lipoblasts without well differentiation or other types of liposarcoma.46 This is a rare type of high-grade liposarcoma that can be differentiated from dedifferentiated liposarcoma by the absence of MDM2 amplification. Pleomorphic liposarcoma also has a dif- ferent clinical metastatic rate than other pleomorphic or high-grade sarcoma types (Table 4).46 Retroperitoneal leiomyosarcoma shows a high pro- pensity of occurrence in women. When arising from large blood vessels, it commonly occurs from the in- ferior vena cava and its major tributaries.65 Grossly, leiomyosarcomas may exhibit either a grey-to-white whorled appearance or form fleshy, tan-white masses with hemorrhage, necrosis, and/or cystic change in- distinguishable from other sarcomas.66 Typical his- tomorphology consists of intersecting fascicles of spindle cells with elongated and blunt-ended nuclei and eosinophilic cytoplasm. Nuclear hyperchroma- sia and pleomorphism (ranging from mild to severe) can be observed. Pleomorphism in leiomyosarcoma may resemble undifferentiated pleomorphic sarco- ma.66 Mitoses, including atypical mitotic figures, are usually present. Occasionally, retroperitoneal leio- myosarcoma may have areas exhibiting epithelioid cytomorphology, multinucleated giant cells, promi- nent inflammatory infiltrate, or exuberant myxoid change.67-70 Rarely, leiomyosarcoma contains granular cytoplasmic change.71 Leiomyosarcoma, specifically of soft-tissue origin, is considered malignant when some degree of nuclear atypia and mitotic activity, which may be very low (< 1/10 hpf), are present.66 An- tibodies to smooth-muscle actin, desmin, and caldes- mon are positive in most types of leiomyosarcoma.72-74 Smooth-muscle, myosin heavy chain is less sensitive and may be expressed in myoepithelial cells.75-77 Ab- errant cytokeratin is frequent and epithelial mem- brane antigen expression may also be seen.78-81 S100, CD34, estrogen, and progesterone receptors may also be positive in leiomyosarcoma.46,82 Hormone-receptor expression can be seen in leiomyosarcoma of a uter- ine origin but is not specific for leiomyosarcoma of a gynecological origin.66 Retroperitoneal Leiomyosarcoma Retroperitoneal leiomyosarcomas typically arise from smooth muscle within the soft tissues of the ret- roperitoneum itself or within the walls of large ret- roperitoneal vessels such as the inferior vena cava, aorta, or gonadal veins.64 Radiographically, the most helpful diagnostic clue may be identification of a mass associated with one of these vascular struc- tures. Typically, retroperitoneal leiomyosarcomas are hypervascular solid tumors with minimal necrosis and a notable absence of internal fat compared with liposarcomas. Mineralization is rarely seen. Com- pression of the underlying vessel may result in ve- nous thrombosis, and intraluminal extension of dis- ease is not uncommon. Undifferentiated Pleomorphic Sarcoma Undifferentiated pleomorphic sarcoma was previ- ously referred to as malignant fibrous histiocytoma. It has no identifiable line of differentiation when analyzed by current technologies and represents a diagnosis of exclusion.66 Undifferentiated pleomor- phic sarcoma typically presents as a large, nonspe- cific, heterogeneous, enhancing soft-tissue mass with internal necrosis and intratumoral hemorrhage, of- ten with lobulated morphology and well-defined margins due to the presence of a pseudocapsule. Occasionally, internal fibrous tissue may be iden- tified as areas of low signal intensity on T1- and T2-weighted MRI (Fig 9).64 Myxoid elements may be seen as regions of increased T2-weighted signal with enhanced intravenous contrast. Tumor heterogene- ity, including hemorrhage, is typical of undifferenti- ated pleomorphic sarcoma. Given the propensity for hemorrhage, underlying neoplasms, including undif- ferentiated pleomorphic sarcoma, must be consid- Table 4. — Sarcoma Types and Clinical Metastatic Rates Type Dedifferentiated liposarcoma High-grade myxofibrosarcoma Pleomorphic liposarcoma Pleomorphic leiomyosarcoma Pleomorphic rhabdomyosarcoma Incidence, % 15–20 25–30 30–50 70 90 258 Cancer Control July 2016, Vol. 23, No. 3

  11. of undifferentiated pleomorphic sarcoma with promi- nent myxoid stroma and features such as multinodular growth pattern and prominent curvilinear vasculature, even focally, should be diagnosed as high-grade myxo- fibrosarcoma.66 Immunohistochemistry serves as a method to ex- clude other pleomorphic tumors. Undifferentiated pleomorphic sarcoma often shows patchy to rare cells positive for cytokeratin, actin, desmin, or epithelial membrane antigen. Vimentin and CD34 may be posi- tive but are of no diagnostic value.46 Over the years, complex cytogenetic aberrations have been identified in undifferentiated pleomorphic sarcoma, but they are nonspecific.84,85 Similarities between undifferentiated pleomorphic sarcoma and leiomyosarcoma have been reported from comparative genomic hybridization analyses, suggesting a possible shared lineage.86,87 Fur- thermore, Carneiro et al87 reported that losses of 4q13 (encompassing SMAD1) and 18q22 were independent predictors of metastasis. Fig 9. — Axial contrast-enhanced computed tomography demonstrates a heterogeneous nonadipocytic, largely necrotic upper retroperitoneal mass along the aorta (stent graft in place) and pulmonary metastases. Although nonspecific, imaging characteristics would favor undiffer- entiated pleomorphic sarcoma rather than liposarcoma or leiomyo- sarcoma. Neurogenic Tumors Neurogenic tumors, including nerve sheath tumors (both benign and malignant), are more common in the extremities, but they have been known to occur in the retroperitoneum, often in paraspinal or pre- sacral locations. Neurogenic tumors tend to demon- strate a fusiform shape, increased T2-weighted sig- nal intensity, and intravenous contrast enhancement. Bony erosions and scalloping, including widening of the neural foramina, are commonly associated osse- ous findings. Differentiation of benign and malignant neoplasms can be difficult, but increased size, rapid growth, internal necrosis, and increased vascularity all favor malignancy. Malignant neurogenic tumors also tend to demonstrate greater fluorodeoxyglucose uptake than benign tumors on positron emission to- mography/CT. Malignant tumors are often seen in the setting of type 1 neurofibromatosis.64 Ganglioneuroma is a rare, benign, differentiat- ed neoplasm of the sympathetic nervous system that contains no immature neuroblastic elements.66,88 Gan- glioneuromas predominantly arise within the poste- rior mediastinum and retroperitoneum.66,89 They are well-circumscribed tumors with a fibrous capsule, and cut sections are gray to yellow with a whorled-like pat- tern similar to leiomyoma.66 Histologically, this tumor consists of Schwann cells with scattered deposits of gan- glion cells, isolated, or small clusters. Surgical excision is appropriate. Ganglioneuromas rarely recur. Malignant transformation into MPNST has been reported.90,91 Schwannoma, a peripheral nerve sheath tumor consisting of well-differentiated Schwann cells, is usu- ally encapsulated, and its cut surfaces have a pink, white, or yellow appearance.66 Retroperitoneal tumors are large and may have areas of cystic degeneration ered in any patient presenting with spontaneous he- matoma. When arising in the retroperitoneum, these tumors tend to be larger than when they occur in the extremities. Adjacent bone invasion is more common than in liposarcoma or leiomyosarcoma and may help suggest the diagnosis. Undifferentiated pleomorphic sarcoma represents the most common soft-tissue sarcoma following prior radiotherapy. When encountering a retroperitoneal soft-tissue tumor with the appearance of undifferentiated pleo- morphic sarcoma, pathologists must exclude possible pleomorphic sarcoma of a specific type (eg, pleomor- phic leiomyosarcoma, pleomorphic liposarcoma), a de- differentiated component of another type of sarcoma (eg, dedifferentiated liposarcoma), and other sarcoma- toid carcinomas. Rarely, sarcomatoid mesothelioma, dedifferentiated melanoma, and anaplastic lymphoma can also occur.66 The histology of undifferentiated pleomorphic sar- coma is variable and may reveal several morphologi- cal patterns, from storiform areas composed of spindle cells to pleomorphic areas composed of large, round- ed, fibroblastic-like cells with marked nuclear atypia and bizarre, multinucleated-tumor giant cells.46,66 Mi- totic activity is prominent with atypical mitotic fig- ures. The background stroma is usually collagenous, but, rarely, the stroma may have metaplastic osteoid or chondroid material. Some cases of undifferentiated pleomorphic sarcoma have prominent background xanthomatous and neutrophilic infiltrates.83 Prominent stromal myxoid change may be pres- ent in undifferentiated pleomorphic sarcoma, either focally within the tumor or as large areas abutting cel- lular zones. Tumors with cytomorphology indicative July 2016, Vol. 23, No. 3 Cancer Control 259

  12. and calcification. Classic histology shows a pattern of alternating Antoni A (cellular areas of spindle cells with occasional palisading) and Antoni B (loose myx- oid areas with scattered spindle cells and thick-walled, hyalinized vessels) areas. Retroperitoneal schwannomas may be exclusive- ly or predominantly composed of Antoni A tissue.92,93 Schwannomas with increased cellularity and occasion- al mitoses are referred to as cellular schwannomas, a variant of schwannoma.92-96 Degenerative changes such as cyst formation, calcification, hemorrhage, and hya- linization may be present in retroperitoneal schwanno- mas, especially if the tumor has been present for a long time. Marked nuclear atypia characterized by Schwann cells with large, hyperchromatic nuclei are usually as- sociated with schwannomas with degenerative change (ancient schwannoma). They behave similar to con- ventional schwannomas. S100 is strongly and diffuse- ly expressed in schwannomas.97SOX10, a marker of neural crest differentiation, exhibits nuclear staining in schwannomas.98 Of note, retroperitoneal schwanno- mas may express cytokeratin AE1/3 due to cross-reac- tivity with GFAP.46 MPNST is an aggressive sarcoma arising from a peripheral nerve (eg, sciatic nerve, brachial plexus, sacral plexus) or preexisting benign nerve sheath tu- mor (eg, neurofibroma). Nearly 50% of MPNSTs occur in patients with type 1 neurofibromatosis and the re- mainder sporadically occurs.46,66 Retroperitoneal in- volvement is rare.99,100 Grossly, MPNSTs arising from a nerve form a large fusiform mass and often measure more than 5 cm and have a tan-white, fleshy cut sur- face with areas of hemorrhage and necrosis.46 Tumor histomorphology is diverse. Classic cases of MPNST exhibit spindle cells arranged in densely cellular fas- cicles alternating with less cellular, myxoid areas, creat- ing a marble-like effect.66 The cells can have a whorling or, rarely, palisading architecture with large areas of necrosis. The spindle cells have hyperchromatic nuclei and pale cytoplasm. Mitoses are readily seen. Occa- sionally, MPNSTs demonstrate marked pleomorphism, simulating high-grade, undifferentiated pleomorphic sarcoma. Skeletal muscle differentiation, glandular dif- ferentiation, and heterologous elements have been re- ported in MPNSTs.101,102 Between 50% and 90% of cases of MPNST are positive for S100, which demonstrates focal staining, and 2% to 15% show weak expression of TLE1.97,103-108SOX10 has recently been reported to show better sensitivity and specificity for the diagno- sis of MPNST than S100.109 A rare variant, epithelioid MPNST, is not associated with type 1 neurofibromato- sis and commonly arises from preexisting schwanno- ma.46 Histologically, epithelioid MPNST is composed of short cords of large epithelioid cells arranged in a vague, nodular pattern.66 The cells have large, round nuclei with prominent nucleoli. They may be associ- ated with myxoid matrix. They can resemble melano- ma or carcinoma. Immunohistochemically, epitheli- oid MPNSTs show strong and diffuse S100 positivity, one-half of cases lack SMARCB1 staining, and rare cases show keratin positivity.110,111 MPNST may also have rhabdomyoblastic differentiation (malignant triton tumor), which has a worse prognosis than con- ventional MPNST.112 Cellular schwannoma may be misdiagnosed as MPNST due to it hypercellularity. Significant institu- tional data do not exist to address how to differentiate MPNST from cellular schwannoma in the retroperito- neum. One large study suggested that certain features distinguish cellular schwannoma from MPNST, but only in general and not specifically to the retroperito- neum (Table 5).113 Solitary Fibrous Tumor/Hemangiopericytoma Solitary fibrous tumor is a mesenchymal tumor of fi- broblastic origin that occurs in deep soft tissue such as the thigh, pelvis, retroperitoneum, and serosal surfaces.114 Solitary fibrous tumor typically demon- strates marked enhancement when viewed with in- travenous contrast and presents as a solid, enhancing soft-tissue mass with prominent tortuous and ser- pentine vessels extending to and seen within the pe- riphery of the mass. Central necrosis is common. The cut surface of the tumor is gray-white to red-brown in color and hemorrhage or cystic degeneration may be seen.66 Histologically, solitary fibrous tumors Table 5. — Distinguishing Features Between Cellular Schwannoma and Malignant Peripheral Nerve Sheath Tumora Cellular Schwannoma Malignant Peripheral Nerve Sheath Tumor Malignant Benign Free of metastasis Disease-specific–related deaths Schwannian whorls Peritumoral capsule Subcapsular lymphocytes Macrophage-rich infiltrates Fascicles absent Expression of p75NTR observed in 31% of cellular schwannomas* Perivascular hypercellularity Tumor herniation into vascular lumens Necrosis Expression of p75NTR observed in 80% of tumors* Complete loss of SOX10* Neurofibromin or p16 expression* Presence of EGFR immunoreactivity is specific* Ki-67 labeling indices > 20% highly predictive (87% sensitivity, 96% specificity) aIn general, not specific to the retroperitoneum. *P < .001. 260 Cancer Control July 2016, Vol. 23, No. 3

  13. can demonstrate a variable appearance, from being highly cellular to densely hyalinized and hypocellu- lar tumors. Cellular, solitary fibrous tumors show a patternless architecture composed of tightly packed, bland-appearing, spindle- to fusiform-shaped cells with indistinct cytoplasmic borders arranged around prominent dilated, branched vessels. Myxoid change is common, as is stromal and perivascular hyaliniza- tion. Mitoses are scarce. A solitary fibrous tumor variant, the fat-forming solitary fibrous tumor, often affects the thigh and retroperitoneum.46 It contains a variable amount of mature adipocytes that should not be confused with well-differentiated liposarcoma. Solitary fi- brous tumors can be malignant, and these cases demonstrate dense cellularity, increased mitoses (> 4 mitoses/10 hpf), variable cytological atypia, tu- mor necrosis, and/or infiltrative margins.115,116 Tu- mor cells are typically positive for CD34 (80%–90%), CD99 (70%), BCL2 (30%), epithelial membrane an- tigen (30%), and actin (20%).117-123 Desmin, cyto- keratin, and S100 are usually absent.117 Recently, NAB2/STAT6 was identified in solitary fibrous tu- mors, strongly suggesting that this type of tumor is a translocation-associated neoplasm and that STAT6 immunostain is a sensitive and specific marker for solitary fibrous tumor.124,125 well-differentiated liposarcoma on imaging and findings on biopsies are often inconclusive. Molecu- lar testing is recommended to support a diagnosis of retroperitoneal lipoma confirming the absence of MDM2 amplification; however, a negative result does not exclude the possibility of well-differentiat- ed liposarcoma. Amplification varies in individual tumors and among different cells in the same tumor. Additional research is necessary to understand the etiology and genetic mechanisms of retroperitoneal lipomas. Close and regular follow-up is recommend- ed for such cases. Conclusions When a definitive diagnosis of retroperitoneal sarco- ma, including its histological tumor type and grade, is achievable, then such a diagnosis can help pro- vide useful prognostic and predictive information to help guide effective therapy. However, not all tumors of the retroperitoneum must be biopsied, subjected to work up by ancillary testing, or both methods to achieve a definitive diagnosis. Certain tumor types may call for specific neoadjuvant therapeutic regi- mens that might produce excellent responses, thus warranting a definitive diagnosis with judicious ancil- lary testing. By contrast, other tumor types may share similar therapeutic regimens, but neoadjuvant thera- py may not provide any benefit to the patient. In such cases, an informative diagnosis should be rendered as an alternative, which includes meaningful and use- ful information to guide the next best step in man- agement, especially when there is a small amount of tissue on biopsy available for analysis. A definitive diagnosis can be deferred and then be rendered at resection following a full examination of the entire tumor. This type of multidisciplinary, pathology-fo- cused approach is practical and, in our experience, works well to serve the needs of patients with retro- peritoneal sarcoma. Acknowledgment: Total Cancer Care was enabled in part by the support of the DeBartolo Family, and we thank the many patients who provided data and tissue for Total Cancer Care. We also thank Ambuj Kumar, MD, of USF Health for his assistance with statistical analysis and the continuous commitment to medical education by the staff of the Anatomic Pathology Ed- ucation Program. We also appreciate Julia A. Bridge, MD, from the Nebraska Medical Center for performing the molecular testing. Other Rare Considerations GIST in the retroperitoneum is rare: One case report has been documented in the literature.126 Characteris- tic immunostain pattern of CD117, CD34, and DOG1 immunoreactivity is helpful in confirming the diag- nosis.46 Ewing sarcoma in the retroperitoneum is also rare. Hallmark translation (EWSR1/FLI1 or EWSR1/ ERG) detection is helpful in confirming Ewing sarco- ma in the majority of cases.46 Retroperitoneal desmoid tumor has been de- scribed in 11 articles since 1991.127-137 These tumors are characterized by proliferation of spindle (fibro- blast) cells, with a moderate amount of collagen fi- bers, bland cellular appearance, scant mitosis, and lack of metastasis.130,135 Expression of beta catenin in tumor cells is helpful for confirming the diagnosis.46 Most sporadic cases of aggressive fibromatosis con- tain a somatic mutation in either APC or CTNNB1.128 Lazar et al138 reported 3 discrete mutations (ACC- 41GCC, TCT45TTT, and TCT45CCT) in 2 codons of CTNNB1 exon 3. Targeted therapy for desmoid tumor/ fibromatosis may be a potential treatment option in the future.135 Retroperitoneal lipoma is a rare benign tumor of mature adipocytes occurring in the retroperitoneum. 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