Practical Issues for Retroperitoneal Sarcoma Vicky Pham, MS, Evita Henderson-Jackson, MD, Matthew P

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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 tic, and predictive information based on a relatively Soft-tissue sarcomas are mesenchymal neoplasms small amount of tissue obtained on biopsy. that account for up to 1% of all newly diagnosed ma- In this study, we compare our experience, espe- lignancies at a rate of 3.6 per 100,000 per year.1-3 Com- cially the distribution of histological subtypes, with pared with bone or visceral sarcomas, they make up the literature to develop a better understanding of 58% of all sarcomas.3 Although the extremities rep- common and rare tumor types, pertinent ancil- resent the most common location of soft-tissue sarco- lary testing, diagnostic pitfalls, and refine a practi- ma, retroperitoneal sarcoma accounts for 9% to 15% cal, multidisciplinary, and algorithmic approach to of all adult soft-tissue sarcomas.3,4 For surgical pathol- achieve an informative diagnosis to help guide the ogists, retroperitoneal tumors will be encountered in therapeutic plan. daily practice regardless of the practice setting. Ret- roperitoneal sarcoma presents diagnostic challenges Methods due to its rarity, variety of tumor types, a general level After obtaining Institutional Review Board approval, of unfamiliarity among surgical pathologists, and lack the database Transmed (H. Lee Moffitt Cancer Center of generally accepted guidelines in its diagnostic ap- & Research Institute, Tampa, Florida) was retrospec- proach. In the era of personalized medicine, pathol- tively reviewed for all histological subtypes of retro- ogists play a critical and central role in patient care. peritoneal sarcomas from 1996 to 2015. Transmed in- Demand has increased to obtain diagnostic, prognos- tegrates data from all patients seen at Moffitt Cancer Center since 1996 (approximately 395,000 patients, From the University of South Florida Morsani College of Medicine regardless of diagnosis) as well as other patients not (VP), the Departments of Anatomic Pathology (EH-J, MMB), Sar- treated at Moffitt Cancer Center but who consented to coma (EH-J, JTC, RJG, MD, MMB), Surgical Oncology (MPD), and the Total Cancer Care protocol at one of 17 consor- Diagnostic Imaging (JTC), H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, and the Department of Pathology (YD), tium sites (approximately 36,000 patients). This result JiShuiTan Hospital, Beijing, China. was cross-checked by sarcoma pathologists as well as Address correspondence to Marilyn M. Bui, MD, PhD, Department the deidentified result of another retroperitoneal sar- of Anatomic Pathology, Moffitt Cancer Center, 12902 Magnolia coma retrospective institutional review. Drive, Tampa, FL 33612. E-mail: [email protected] Submitted August 17, 2015; accepted December 29, 2015. A systematic review of the English literature This study received financial assistance from Information Shared was conducted for works published between 2000 Services Department/Collaborative Data Services Core at the H. Lee and 2015. This yielded 85 search results. Another Moffitt Cancer Center & Research Institute supported under NIH literature search was conducted yielding an ad- grant P30-CA76292. This research was also supported by an award from the Scholarly Concentrations Program at USF Health Morsani ditional 444 results. After excluding case reports College of Medicine. and studies with locations of retroperitoneal sarco-

July 2016, Vol. 23, No. 3 Cancer Control 249 ma mixed with other locations, our search yielded 54 studies from which we extracted information Table 1. — Distribution of Histological Subtypes of Retroperitoneal Soft-Tissue Sarcoma about the distribution of histological subtypes within each study patient population. Subtype Distribution Distribution From the From The meta-analysis was conducted using Stats- Literature, Moffitt, % Direct (Cheshire, United Kingdom). % Liposarcoma (all subtypes) 45.1 54.6 Results Well differentiated 23.9 15.3 Literature Review A literature search revealed the following list of most Dedifferentiated 20.9 15.6 to least common histological subtypes of tumors. Per- Myxoid/round cell 0.9 6.8 centages shown are out of all retroperitoneal sarcoma Pleomorphic 0.4 1 subtypes (Table 1). Our review and data analysis of Leiomyosarcoma 21.3 26.1 retroperitoneal sarcoma studies concluded that the Other 8.2 0 most common subtype of retroperitoneal sarcoma Malignant fibrous histiocytoma/ 6.4 1 is liposarcoma, which constitutes 45.1% of all retro- undifferentiated pleomorphic peritoneal sarcoma (Fig 1). The next most common sarcoma subtypes are leiomyosarcoma (21.3%), other (8.2%), Sarcoma not otherwise specified 1.6 4.9 and malignant fibrous histiocytoma/undifferentiated Malignant peripheral nerve sheath 1.3 1 pleomorphic sarcoma (6.4%; see Table 1). Well-differ- tumor Well differentiated entiated liposarcoma and dedifferentiated liposarco- Solitary fibrous tumor/ 0.8 0 Dedifferentiated hemangiopericytoma ma constituted 45.8% and 44.8% of all retroperitoneal Myxoid/round cell liposarcomas, respectively (Fig 2). The less common Fibrosarcoma (nondesmoid) 0.5 1 Pleomorphic subtypes were myxoid/round cell liposarcoma and Rhabdomyosarcoma 0.4 1 pleomorphic liposarcoma. Schwannoma 0.3 0 Angiosarcoma 0.1 0 Institutional Results Anaplastic sarcoma < 0.1 0 A review of Transmed, which represents single-institution data, is summarized in Table 1. Our data for Adenosarcoma < 0.1 0 retroperitoneal sarcoma subtypes are consistent with Chondrosarcoma < 0.1 0 our literature search. Liposarcomas of all subtypes at Desmoplastic small-round cell tumor < 0.1 0 Moffitt Cancer Center make up 54.6% (168 cases) of all Epithelioid sarcoma < 0.1 0 retroperitoneal sarcoma (307 cases), followed by leio- Extraskeletal osteosarcoma < 0.1 1 myosarcomas (80 cases), sarcoma not otherwise spec- Fibromyxosarcoma < 0.1 1 ified (15 cases), malignant peripheral nerve tumor Giant cell sarcoma < 0.1 3 (3 cases), and other less common subtypes (1–2 cases; see Table 1). The trend for most to least common tu- Mesenchymoma < 0.1 0 mor types appears to be similar (Fig 3). In Fig 4, data Primitive neuroectodermal tumor/ < 0.1 1 extraskeletal Ewing sarcoma from Moffitt Cancer Center on the histological subtypes of retroperitoneal liposarcomas are compared Small cell/embryonal/synovial/ < 0.1 0 undifferentiated sarcoma with the data found during our literature search. Spindle cell sarcoma < 0.1 1 The median age of the patients in all 54 studies was 58 years. The percentages of those who were men Undifferentiated round-cell < 0.1 1 sarcoma and women were 53.2% and 46.8%, respectively.

Gap Between Practice and Literature tochemical hallmarks and characteristics that can be Most of the literature we reviewed describes sarcoma diagnosed with a small amount of tissue acquired on in categories based on histological type and morpho- biopsy; however, commonly, sarcoma does not have logical pattern.5 Morphological features are evaluated such a signature and morphologically overlaps with to determine the differential diagnosis, ranking pos- other tumors. Ancillary tests can be performed to sible diagnoses from most likely to least likely in con- narrow the diagnosis, with the understanding that it junction with clinical and radiological clues, and then may not be possible to achieve a definitive diagno- applying ancillary testing to narrow down the diagnosis. However, it is important to realize that, when a sis. Thus, it is important to understand the common definitive diagnosis is not achievable, an alternative and rare types of retroperitoneal sarcoma. option is to provide useful, diagnostic information to Some sarcomas have molecular and immunohis- guide the clinical team in the next appropriate step

250 Cancer Control July 2016, Vol. 23, No. 3 Liposarcoma 45.1 Leiomyosarcoma 21.3

Other 8.2 Malignant fibrous histiocytoma/ 6.4 undifferentiated pleomorphic sarcoma Sarcoma not otherwise specified 1.6 Malignant peripheral nerve sheath tumor 1.3

Histological Subtype Solitary fibrous tumor/hemangiopericytoma 0.8 Rhabdomyosarcoma 0.4

0 5 10 15 20 25 30 35 40 45 50 Percentage

Fig 1. — Distribution of histological subtypes of retroperitoneal sarcoma.

Well differentiated 45.8 Dedifferentiated 44.8 Myxoid/round cell 4.7 Pleomorphic 0.8 Histological Subtype 0 5 10 15 20 25 30 35 40 45 50 Percentage

Fig 2. — Distribution of histological subtypes of retroperitoneal liposarcoma. for the patient’s care. In such situations, being aware and higher-grade tumors being more appropriate for of the management plan for various diagnoses is criti- treatment.1 Future research may enable more histolo- cal. Some diagnoses are managed according to estab- gy-specific decisions. We speculate that new data may lished institutional pathways. The literature often fo- suggest no role exists for radiotherapy in the treatment cuses on achieving a definitive diagnosis, rather than of leiomyosarcoma. realizing an informative diagnosis. However, histological subtypes play a role in chemotherapy. Some subtypes may respond better to Multidisciplinary Approach to certain chemotherapeutic agents or regimens and, Pathology-Focused Management conversely, several different sarcoma subtypes will The interdisciplinary management of retroperitoneal similarly respond to identical chemotherapy treat- sarcoma involves chemotherapy, radiotherapy, and ments (Fig 5; Table 2).7-18 The role of chemotherapy surgery, along with providing prognostic, predictive, in the management of retroperitoneal sarcoma is not and diagnostic information to the clinical team and the well defined. The 2 most important determinants of patient. The mainstay of treatment for retroperitoneal overall survival (OS) are tumor grade and extent of re- sarcoma is surgical resection. Complete resection with section, with subtypes having a less important role in a microscopically negative margin (R0) remains the po- determining prognosis.6,19 Therefore, when consider- tential likelihood for cure.6 Surgical decision-making ing whether to pursue a definitive diagnosis for a tu- in retroperitoneal sarcoma is not solely based on his- mor subtype, the relative costs and turnaround time tological subtypes, but rather on factors such as per- of ancillary tests vs the importance or relevance of the formance status, patient comorbidities, and extent of test results in the larger context of the interdisciplin- tumor involvement into adjacent organs and vascular ary management of retroperitoneal sarcoma must be structures.1 Adjunctive therapies such as perioperative considered; therefore, pathologists must make judi- radiotherapy and chemotherapy are also selectively cious use of their tissue samples, time, and institutional used within the context of interdisciplinary review on resources. a case-by-case basis. At this time, use of radiotherapy does not depend on histological subtypes but rather on Neoadjuvant Chemotherapy tissue tolerance and tumor grades, with intermediate- The role of neoadjuvant chemotherapy is not well de-

July 2016, Vol. 23, No. 3 Cancer Control 251 All liposarcoma subtypes

All leiomyosarcoma subtypes

Sarcoma not otherwise specified Malignant peripheral nerve

Histological Subtype sheath tumor

0 10 20 30 40 50 60 Percentage

Data Source Malignant Peripheral Sarcoma Not Otherwise All Subtypes of All Subtypes of Nerve Sheath Tumor Specified Leiomyosarcoma Liposarcoma Moffitt 1.0 4.9 26.1 54.7 Literature 1.3 1.6 21.3 45.1 Fig 3. — Comparison of retroperitoneal sarcoma subtypes demonstrates a consistent distribution at Moffitt Cancer Center vs literature search.

Dedifferentiated

Well differentiated

Myxoid/round cell

Pleomorphic Histological Subtype

0 5 10 15 20 25 30 Percentage

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

252 Cancer Control July 2016, Vol. 23, No. 3 the highest response rate at 48%.9 Round cell liposarco- Chemotherapy for Metastatic or Advanced ma, a high-grade spectrum of myxoid liposarcoma, has Soft-Tissue Sarcoma (Palliative Intent) a response rate of 17%.9 Pleomorphic liposarcoma has Chemotherapy has an established role in the palliative a response rate of 33%.1 The response rate of leiomyo- management of metastatic or advanced soft-tissue sar- sarcoma to chemotherapy is 25%.10-12 For the remain- coma.6,14 In the metastatic setting, use of single-agent ing retroperitoneal sarcoma subtypes, response rates doxorubicin or combination doxorubicin/ifosfamide has range from 21% to 31% (see Fig 5).7,9,11-14,16,26 shown a consistent response.24 However, some subtypes

Table 2. — Use of Chemotherapy for the Management of Clinical and radiological information (including contrast-enhanced Retroperitoneal Soft-Tissue Sarcomas abdominopelvic CT or MRI to evaluate local extent of disease and CT of the chest to evaluate for distant metastases) a Subtype Chemotherapy Type of assessed by interdisciplinary team Response Chemotherapy Patients with Li-Fraumeni syndrome should be referred for Rate,a % further genetic assessment11,16 Myxoid/round cell Myxoid: 48 Neoadjuvant Setting liposarcoma Round cell: 179 Doxorubicin/ifosfamide for localized treatment

Well-Differentiated Dedifferentiated 21–3310-12 Metastatic Setting Liposarcoma (24%) liposarcoma Single-agent doxorubicin Further biopsy not mandatory Leiomyosarcoma Adjuvant Setting Adjuvant chemotherapy depending on cross-sectional Pleomorphic imaging determined on Image-Guided Core Biopsy liposarcoma Complete resection is case-by-case basis; with mainstay of treatment Preferred to open surgical Undifferentiated large high-grade tumors, biopsy pleomorphic sarcoma adjuvant chemotherapy Unresponsive to anthracycline- Other subtypes increases metastasis-free based chemotherapy or 8 radiotherapy9 survival rate Most locoregionally occur rather than metastasize9,14 Angiosarcomab Histological specific Solitary fibrous treatment (not tumorb anthracycline-based) recommended16 Hemangiopericytomab Other Retroperitoneal Differential Diagnoses Ewing/primitive — Soft-Tissue Sarcoma Subtypes GIST neuroectodermal Desmoid tumor tumorb (aggressive fibromatosis) Nonpleomorphic Metastatic lesion Surgery = Mainstay rhabdomyosarcomab,c Treatment Lipoma Lymphoma Synovial sarcoma/ Synovial Synovial Sarcoma If tumor is partially resect- MPNST sarcoma: Responds best to Primary neoplasm arising able, then neoadjuvant 25–3110,12 ifosfamide-based radiotherapy/chemotherapy from pancreas, adrenal 13 first-line therapy becomes more important glands, kidneys, duodenum MPNST: 21 to treat periphery of lesion as (doxorubicin/ Adenopathy from testicles ifosfamide)10,12; it abuts critical structures in a young male with intent of consolidating also sensitive to peritumoral reactive zone radiotherapy15 and rendering the close MPSNT margin sterile Responds best to Neoadjuvant chemotherapy doxorubicin/ifosfamide May Not Require Surgery also important for in metastatic setting13 chemosensitive histologies7,11 as First Approach New evidence may suggest Examples: lymphoma, GIST, Preoperative Radiotherapy: External beam radiotherapy used for no role for radiotherapy in Ewing sarcoma intermediate- to high-grade tumors, especially in more radiosensitive treating leiomyosarcoma 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 Refer to Table 2 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 Fig 5. — Proposed algorithm for the pathology-focused management of (not restricted to retroperitoneum). retroperitoneal soft-tissue sarcoma. bComprises < 0.8% of all subtypes. aTeam is made up of a surgical oncologist, radiologist, oncologist, and cMost studies reviewed list rhabdomyosarcoma as a general subtype pathologist. without denoting more specific subtypes. CT = computed tomography, GIST = gastrointestinal stromal tumor, MPNST = malignant peripheral nerve sheath tumor. MRI = magnetic resonance imaging.

July 2016, Vol. 23, No. 3 Cancer Control 253 (eg, solitary fibrous tumor, well-differentiated liposarco- nal damage, secondary cancers, cardiomyopathy, and ma) are resistant to anthracycline-based therapy, while overall impairment of quality of life.16 others show a differential response to cytotoxic systemic therapy.9,27 Thus, the concept of histology-driven treat- Radiotherapy ment has arisen, rather than a one-size-fits-all or all-in- The overall benefit of radiotherapy for use with retro- clusive approaches to therapy in patients with metastatic peritoneal sarcoma has yet to be established, with most soft-tissue sarcoma. Angiosarcomas have been shown of the data being extrapolated from studies of soft-tissue to respond to paclitaxel and pegylated liposomal doxo- sarcoma of the extremities.33 However, concern remains rubicin, leiomyosarcomas to combination gemcitabine/ about the increased risk of treatment-related toxicity to docetaxel, desmoid tumors to liposomal doxorubicin, highly radiosensitive visceral structures due to their rap- and synovial sarcoma and malignant peripheral nerve idly proliferating mucosa and rich blood supply.34 The sheath tumor (MPNST) respond best to doxorubicin/ relatively low rate of radiation tolerance for surrounding ifosfamide.10-15,26-28 Pazopanib, a multitargeted tyrosine normal tissues (liver, kidney, gastrointestinal tract, spi- kinase inhibitor, has demonstrated single-agent activity nal cord) predisposes patients to risks of intestinal per- in patients with advanced soft-tissue sarcoma subtypes, foration, peritonitis, and peripheral neuropathy.35 except for liposarcoma.16 Consensus-based recommen- Use of preoperative radiotherapy is currently being dations for the treatment of metastatic soft-tissue sarco- investigated in an accruing, prospective, randomized, ma from the National Comprehensive Cancer Network multicenter trial (NCT01344018). This type of trial is in- provide specific therapy regimen recommendations vestigating the potential for external beam radiotherapy for the following retroperitoneal sarcoma subtypes: (EBRT) to reduce local regional failure.36 Proponents of soft-tissue sarcoma with nonspecific histologies, angio- preoperative radiation cite the potential benefits of posarcoma, solitary fibrous tumor/hemangiopericytoma, tentially using lower doses, while the tumor displaces Ewing sarcoma/primitive neuroectodermal tumor, non- radiosensitive viscera outside the field of radiation.37 pleomorphic rhabdomyosarcoma, and desmoid tumors Proponents also claim gross tumor volume can be more (see Fig 5).7,9,11,14,16 Although select patients with sarcoma adequately defined, which would allow for more accu- do derive substantial clinical benefit from chemothera- rate preoperative treatment planning.37 py, most patients develop metastatic disease that is in- Use of postoperative EBRT has been studied but curable.29 In a study of 488 participants with advanced largely abandoned due to its toxic effects of the remain- soft-tissue sarcoma who were treated with first-line che- ing organs within the tissue bed after resection, with no motherapy at a single institution, 45% of them derived apparent improvement in survival.17 Another concern clinical benefit from treatment in terms of partial re- with postoperative radiation suggests the difficulty in sponse (PR) or prolonged disease stabilization; the me- defining a precise area of the tumor bed to apply EBRT.17 dian rate of OS was 12 months.30 Our experience at Moffitt Cancer Center favors use Furthermore, in the past decade, greater empha- of preoperative EBRT for intermediate- to high-grade sis has been placed on identifying the underlying mo- tumors, especially in more radiosensitive tumors, such lecular drivers of sarcomas.31 Several potential novel, as extraosseous Ewing sarcoma/primitive neuroecto- systemic therapies for soft-tissue sarcoma have been dermal tumor. The more common subtypes, such as identified, including MDM2 targets, cyclin-dependent well-differentiated liposarcoma and leiomyosarcoma, kinase 4 inhibitors, peroxisome proliferator-activated are generally unresponsive to radiation.18 Thus, concern receptors (critical regulators of normal adipocyte dif- remains about the increased risk of treatment-related ferentiation), and tyrosine kinase receptors.32 Other toxicity to visceral structures. targets reported but not yet tested include YEATS4, c-Jun, and JNK.32 Pathological Prognostic Factors The most important prognostic factors for survival are Adjuvant Chemotherapy extent of tumor resection and histological grade, al- Several prospective, randomized trials of study pa- though histological subtype is also emphasized as an tients who received adjuvant regimens following sur- important factor.38 Other factors influencing prognosis gical resection have demonstrated decreased local re- include tumor stage, patient age, tumor size, and mul- currence rates, but the effect on OS is less clear.1 The tifocality. Nomograms have been developed and vali- benefits of adjuvant chemotherapy must be addressed dated to more accurately predict postoperative survival based on the individual while simultaneously taking based on these and other factors.39 Well-differentiated into consideration performance status, disease loca- liposarcomas have the most favorable outcome, where- tion, tumor size, comorbid factors (including age), and as leiomyosarcomas, pleomorphic sarcoma/malignant histological subtype. The potential for benefit must be fibrous histiocytoma, MPNST, and dedifferentiated li- discussed in the context of expected treatment-related posarcomas exhibit the least favorable outcomes.38 toxicities, including sterility in younger individuals, re- Other prognostic concerns include risks for locore-

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

Table 3. — Risk by Subtype for Local Regional Relapse, Metastasis, and OS Rates Subtype Risk for Locoregional Relapse42 OS Metastasis8 Leiomyosarcoma Piecemeal resection predictive Adjacent organ involvement associated Exceptions to typical pattern of of relapse with worst OS metastatic disease Associated with high risk of competitive Commonly metastasizes to liver, lung 42 systemic relapse High risk of metastatic disease14 Well-differentiated Piecemeal resection predictive Adjacent organ involvement associated Nearly all recur locoregionally, not via liposarcoma of relapse with worst OS metastasis14 Multifocality significantly associated with worse survival42 Dedifferentiated Surgeon specialization and periopera- Grade 3 associated with worst OS42 Nearly all recur locoregionally, not via liposarcoma tive radiotherapy associated with lower metastasis14 risk of relapse OS = overall survival.

July 2016, Vol. 23, No. 3 Cancer Control 255 Fig 5 summarizes relevant information regard- ing subtypes and perioperative therapy considerations.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 significantly differs from that undertaken for adult-type soft-tissue sarcoma. Subsequent surgery is then considered for responsive tumors to achieve complete resection of all visible tumors; however, adjacent viscera is only included if true invasion is evident.14 Our experience with GIST is that neoadjuvant tyrosine ki- Fig 6. — Axial contrast-enhanced computed tomography demonstrates nase inhibitor therapy for large lesions and abutting a large, round, adipocytic left retroperitoneal mass (dashed circle) that displaces the descending colon and compresses the left kidney with critical structures should be used to reduce tumor size minimal fat stranding and few thin septations consistent with well-dif- and limit the complexity of the procedure. Reduction ferentiated liposarcoma. of tumor size due to effective preoperative imatinib occurs in the majority of patients.44,45 In such a sce- and CDK4 are present in most cases and are in keeping nario, proper therapy is warranted for larger tumors with gene amplification.49 Molecular, cytogenetic, and that may require multivisceral resection. immunohistochemistry applications help distinguish well-differentiated liposarcoma from benign adipose Determination of Tumor Types With tumors. Well-differentiated liposarcoma is locally ag- Radiological and Histological Correlation gressive and lacks metastatic potential.47 Unless it be- Well-Differentiated and Dedifferentiated comes dedifferentiated (dedifferentiated liposarcoma), Liposarcoma well-differentiated liposarcoma is potentially curable CT or MRI can be used to recognize well-differentiated with complete excision when located in the extremities; liposarcoma (see Fig 6). Histomorphological findings however, sites like the retroperitoneum and mediasti- that support a diagnosis of well-differentiated liposar- num pose difficulty in obtaining a microscopically neg- coma include proliferation of mature adipocytes with ative margin (R0).46,51 The differential diagnosis of well- marked variation in cell size and a focal nuclear atypia differentiated liposarcoma from benign adipose tumors in both adipocytes and stromal cells. Identification of in a limited specimen, such as specimens from core lipoblasts does not make (or is required for) a diagno- needle biopsies, can be difficult. MDM2 fluorescence sis of liposarcoma.46 Lipoblasts may be seen in benign in situ hybridization is sensitive and specific to iden- lesions such as lipoblastoma, pleomorphic lipoma, and tify MDM2 amplification in morphologically atypical chondroid lipoma. and typical lesional cells.51 The immunohistochemistry Based on morphology, 4 main subtypes exist: adi- performance of MDM2 decreases when working with pocytic (lipoma-like), sclerosing, inflammatory, and limited specimens on biopsy, a rate typically attributed spindle cell. The sclerosing subtype of well-differen- to the focal staining seen within the majority of well- tiated liposarcoma tends to occur in the retroperito- differentiated liposarcoma on whole-tissue sections.51 neum and microscopically demonstrate scattered, MDM2 has been useful in identifying dedifferen- hyperchromatic, bizarre stromal cells set in extensive tiated liposarcomas in addition to well-differentiated fibrillary collagenous stroma. With the exception of the liposarcoma. Several studies have reported that most spindle-cell subtype, well-differentiated liposarcoma poorly differentiated sarcomas arising in the retroperi- has been found by molecular and cytogenetic studies toneum are, in fact, dedifferentiated liposarcoma and to harbor a characteristic ring and giant marker chro- can be diagnosed on the basis of MDM2 amplification mosomes containing amplification of the 12q13-15 re- even without an atypical adipocytic component.52-54 gion, including MDM2.47-50 Several other genes located Like well-differentiated liposarcoma, dedifferentiated in the 12q14-15 region, including CDK4 and HMGA2, liposarcoma harbors the ring or giant marker chromo- are frequently coamplified with MDM2.46 somes, whereas MDM2 (12q15) is consistently ampli- Immunohistochemically, expressions of MDM2 fied and overexpressed.46,49,55-58

256 Cancer Control July 2016, Vol. 23, No. 3 Histologically, dedifferentiated liposarcoma con- sarcoma constitute 0.9% and 0.4% of all retroperitoneal tains a well-differentiated liposarcoma component jux- soft-tissue sarcomas, respectively (see Table 1). Myxoid taposed to areas of either low- or high-grade nonlipo- liposarcoma demonstrates areas of myxomatous tis- genic sarcoma (dedifferentiation). The dedifferentiated sue that appear similar to fluid (low density on CT; component may exhibit a wide variety of morphology high signal intensity on T2-weighted MRI) prior to from high-grade sarcoma resembling undifferentiated pleomorphic sarcoma or high-grade myxofibrosar- A coma to low-grade dedifferentiation resembling fibromatosis or fibrosarcoma.59-62 Historically, many dedifferentiated liposarcomas were diagnosed as malignant fibrous histiocytoma, particularly de novo dedifferentiated liposarcomas.54 Dedifferentiated liposarcoma commonly occurs in the retroperitoneum, with more than 90% arising de novo, whereas less than 10% represent recurrences.46,58 Radiologically, the presence of a nonlipogenic soft-tissue mass within an otherwise fatty tumor would be consistent with dedifferentiation (Fig 7). Given the internal heterogeneity, it is important to correlate 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 B 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 rarely excised with margins free of well-differentiated liposarcoma. 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 dedifferentiated liposarcoma appears in Fig 8.

Other Subtypes of Liposarcoma Myxoid/round cell liposarcoma and pleomorphic lipo-

Fig 7. — Axial contrast-enhanced computed tomography demonstrates Fig 8A–C. — Dedifferentiated liposarcoma. (A) Nonlipogenic malignancy is a large infiltrative retroperitoneal mass encasing the right kidney (K), revealed on core biopsy. Hematoxylin and eosin stain, × 400. (B) Nuclear- displacing the ascending colon (C) with lipogenic elements (large arrow), positive MDM2. Immunohistochemistry, × 400. (C) Amplification of MDM2 thick septations (small arrow), and nonadipocytic soft-tissue masses (*) (red signals). Green signals are chromosome 17 and confirm dedifferenti- anterior to the inferior vena cava and aorta (A). ated liposarcoma. Fluorescent in situ hybridization, × 1000.

July 2016, Vol. 23, No. 3 Cancer Control 257 administering intravenous contrast. However, myx- Retroperitoneal leiomyosarcoma shows a high pro- oid elements will be enhanced as opposed to non- pensity of occurrence in women. When arising from enhanced fluid in areas of cystic degeneration or large blood vessels, it commonly occurs from the in- tumor necrosis. Occasionally, liposarcoma may dem- ferior vena cava and its major tributaries.65 Grossly, onstrate areas of mineralization or ossification. More leiomyosarcomas may exhibit either a grey-to-white than 95% of cases of myxoid liposarcoma demon- whorled appearance or form fleshy, tan-white masses strate a classical t(12;16)(q13;p11) or t(12;22)(q13;q12) with hemorrhage, necrosis, and/or cystic change in- translocation, which results in fusion of FUS-CHOP distinguishable from other sarcomas.66 Typical his- or EWSR1-CHOP, respectively.46 A diagnosis of pri- tomorphology consists of intersecting fascicles of mary retroperitoneal myxoid liposarcoma should spindle cells with elongated and blunt-ended nuclei made with caution, because such cases represent and eosinophilic cytoplasm. Nuclear hyperchroma- either metastatic myxoid liposarcoma or well-differ- sia and pleomorphism (ranging from mild to severe) entiated/dedifferentiated liposarcoma with myxoid can be observed. Pleomorphism in leiomyosarcoma stromal change.43,63 Round cell liposarcoma is not an may resemble undifferentiated pleomorphic sarco- independent subtype but rather a high-grade spec- ma.66 Mitoses, including atypical mitotic figures, are trum of myxoid liposarcoma. Round cell liposarcoma usually present. Occasionally, retroperitoneal leio- shares the same molecular change as myxoid liposar- myosarcoma may have areas exhibiting epithelioid coma but is morphologically composed of blue round cytomorphology, multinucleated giant cells, promi- tumor cells. nent inflammatory infiltrate, or exuberant myxoid Pleomorphic liposarcoma often presents as a non- change.67-70 Rarely, leiomyosarcoma contains granular specific soft-tissue mass without obvious fat evident by cytoplasmic change.71 Leiomyosarcoma, specifically results on imaging mimicking other high-grade retro- of soft-tissue origin, is considered malignant when peritoneal sarcomas. Pleomorphic liposarcoma exhib- some degree of nuclear atypia and mitotic activity, its pleomorphic lipoblasts without well differentiation which may be very low (< 1/10 hpf), are present.66 An- or other types of liposarcoma.46 This is a rare type of tibodies to smooth-muscle actin, desmin, and caldes- high-grade liposarcoma that can be differentiated from mon are positive in most types of leiomyosarcoma.72-74 dedifferentiated liposarcoma by the absence of MDM2 Smooth-muscle, myosin heavy chain is less sensitive amplification. Pleomorphic liposarcoma also has a dif- and may be expressed in myoepithelial cells.75-77 Ab- ferent clinical metastatic rate than other pleomorphic errant cytokeratin is frequent and epithelial mem- or high-grade sarcoma types (Table 4).46 brane antigen expression may also be seen.78-81 S100, CD34, estrogen, and progesterone receptors may also Retroperitoneal Leiomyosarcoma be positive in leiomyosarcoma.46,82 Hormone-receptor Retroperitoneal leiomyosarcomas typically arise expression can be seen in leiomyosarcoma of a uter- from smooth muscle within the soft tissues of the ret- ine origin but is not specific for leiomyosarcoma of a roperitoneum itself or within the walls of large ret- gynecological origin.66 roperitoneal vessels such as the inferior vena cava, aorta, or gonadal veins.64 Radiographically, the most Undifferentiated Pleomorphic Sarcoma helpful diagnostic clue may be identification of a Undifferentiated pleomorphic sarcoma was previ- mass associated with one of these vascular struc- ously referred to as malignant fibrous histiocytoma. tures. Typically, retroperitoneal leiomyosarcomas are It has no identifiable line of differentiation when hypervascular solid tumors with minimal necrosis analyzed by current technologies and represents a and a notable absence of internal fat compared with diagnosis of exclusion.66 Undifferentiated pleomor- liposarcomas. Mineralization is rarely seen. Com- phic sarcoma typically presents as a large, nonspe- pression of the underlying vessel may result in ve- cific, heterogeneous, enhancing soft-tissue mass with nous thrombosis, and intraluminal extension of dis- internal necrosis and intratumoral hemorrhage, of- ease is not uncommon. ten with lobulated morphology and well-defined margins due to the presence of a pseudocapsule. Table 4. — Sarcoma Types and Clinical Metastatic Rates Occasionally, internal fibrous tissue may be identified as areas of low signal intensity on T1- and Type Incidence, % T2-weighted MRI (Fig 9).64 Myxoid elements may be Dedifferentiated liposarcoma 15–20 seen as regions of increased T2-weighted signal with High-grade myxofibrosarcoma 25–30 enhanced intravenous contrast. Tumor heterogene- Pleomorphic liposarcoma 30–50 ity, including hemorrhage, is typical of undifferenti- Pleomorphic leiomyosarcoma 70 ated pleomorphic sarcoma. Given the propensity for Pleomorphic rhabdomyosarcoma 90 hemorrhage, underlying neoplasms, including undifferentiated pleomorphic sarcoma, must be consid-

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

July 2016, Vol. 23, No. 3 Cancer Control 259 and calcification. Classic histology shows a pattern ated with myxoid matrix. They can resemble melano- of alternating Antoni A (cellular areas of spindle cells ma or carcinoma. Immunohistochemically, epitheli- with occasional palisading) and Antoni B (loose myxoid MPNSTs show strong and diffuse S100 positivity, oid areas with scattered spindle cells and thick-walled, one-half of cases lack SMARCB1 staining, and rare hyalinized vessels) areas. cases show keratin positivity.110,111 MPNST may also Retroperitoneal schwannomas may be exclusive- have rhabdomyoblastic differentiation (malignant ly or predominantly composed of Antoni A tissue.92,93 triton tumor), which has a worse prognosis than con- Schwannomas with increased cellularity and occasion- ventional MPNST.112 al mitoses are referred to as cellular schwannomas, a Cellular schwannoma may be misdiagnosed as variant of schwannoma.92-96 Degenerative changes such MPNST due to it hypercellularity. Significant institu- as cyst formation, calcification, hemorrhage, and hya- tional data do not exist to address how to differentiate linization may be present in retroperitoneal schwanno- MPNST from cellular schwannoma in the retroperito- mas, especially if the tumor has been present for a long neum. One large study suggested that certain features time. Marked nuclear atypia characterized by Schwann distinguish cellular schwannoma from MPNST, but cells with large, hyperchromatic nuclei are usually as- only in general and not specifically to the retroperito- sociated with schwannomas with degenerative change neum (Table 5).113 (ancient schwannoma). They behave similar to conventional schwannomas. S100 is strongly and diffuse- Solitary Fibrous Tumor/Hemangiopericytoma ly expressed in schwannomas.97 SOX10, a marker of Solitary fibrous tumor is a mesenchymal tumor of fi- neural crest differentiation, exhibits nuclear staining broblastic origin that occurs in deep soft tissue such in schwannomas.98 Of note, retroperitoneal schwanno- as the thigh, pelvis, retroperitoneum, and serosal mas may express cytokeratin AE1/3 due to cross-reac- surfaces.114 Solitary fibrous tumor typically demon- tivity with GFAP.46 strates marked enhancement when viewed with in- MPNST is an aggressive sarcoma arising from a travenous contrast and presents as a solid, enhancing peripheral nerve (eg, sciatic nerve, brachial plexus, soft-tissue mass with prominent tortuous and ser- sacral plexus) or preexisting benign nerve sheath tu- pentine vessels extending to and seen within the pe- mor (eg, neurofibroma). Nearly 50% of MPNSTs occur riphery of the mass. Central necrosis is common. The in patients with type 1 neurofibromatosis and the re- cut surface of the tumor is gray-white to red-brown mainder sporadically occurs.46,66 Retroperitoneal in- in color and hemorrhage or cystic degeneration may volvement is rare.99,100 Grossly, MPNSTs arising from a be seen.66 Histologically, solitary fibrous tumors nerve form a large fusiform mass and often measure more than 5 cm and have a tan-white, fleshy cut sur- 46 face with areas of hemorrhage and necrosis. Tumor Table 5. — Distinguishing Features Between Cellular histomorphology is diverse. Classic cases of MPNST Schwannoma and Malignant Peripheral Nerve Sheath Tumora exhibit spindle cells arranged in densely cellular fas- Cellular Schwannoma Malignant Peripheral Nerve cicles alternating with less cellular, myxoid areas, creat- Sheath Tumor 66 ing a marble-like effect. The cells can have a whorling Benign Malignant or, rarely, palisading architecture with large areas of Free of metastasis necrosis. The spindle cells have hyperchromatic nuclei Disease-specific–related deaths and pale cytoplasm. Mitoses are readily seen. Occa- Schwannian whorls Perivascular hypercellularity sionally, MPNSTs demonstrate marked pleomorphism, Peritumoral capsule Tumor herniation into vascular simulating high-grade, undifferentiated pleomorphic Subcapsular lymphocytes lumens sarcoma. Skeletal muscle differentiation, glandular dif- Macrophage-rich infiltrates Necrosis ferentiation, and heterologous elements have been re- Fascicles absent ported in MPNSTs.101,102 Between 50% and 90% of cases Expression of p75NTR Expression of p75NTR observed in of MPNST are positive for S100, which demonstrates observed in 31% of cellular 80% of tumors* focal staining, and 2% to 15% show weak expression schwannomas* 97,103-108 of TLE1. SOX10 has recently been reported to Complete loss of SOX10* show better sensitivity and specificity for the diagno- Neurofibromin or p16 expression* 109 sis of MPNST than S100. A rare variant, epithelioid Presence of EGFR immunoreactivity MPNST, is not associated with type 1 neurofibromato- is specific* sis and commonly arises from preexisting schwanno- Ki-67 labeling indices > 20% ma.46 Histologically, epithelioid MPNST is composed highly predictive (87% sensitivity, of short cords of large epithelioid cells arranged in a 96% specificity) vague, nodular pattern.66 The cells have large, round aIn general, not specific to the retroperitoneum. *P < .001. nuclei with prominent nucleoli. They may be associ-

260 Cancer Control July 2016, Vol. 23, No. 3 can demonstrate a variable appearance, from being well-differentiated liposarcoma on imaging and highly cellular to densely hyalinized and hypocellu- findings on biopsies are often inconclusive. Molecu- lar tumors. Cellular, solitary fibrous tumors show a lar testing is recommended to support a diagnosis patternless architecture composed of tightly packed, of retroperitoneal lipoma confirming the absence bland-appearing, spindle- to fusiform-shaped cells of MDM2 amplification; however, a negative result with indistinct cytoplasmic borders arranged around does not exclude the possibility of well-differentiat- prominent dilated, branched vessels. Myxoid change ed liposarcoma. Amplification varies in individual is common, as is stromal and perivascular hyaliniza- tumors and among different cells in the same tumor. tion. Mitoses are scarce. Additional research is necessary to understand the A solitary fibrous tumor variant, the fat-forming etiology and genetic mechanisms of retroperitoneal solitary fibrous tumor, often affects the thigh and lipomas. Close and regular follow-up is recommend- retroperitoneum.46 It contains a variable amount ed for such cases. of mature adipocytes that should not be confused with well-differentiated liposarcoma. Solitary fi- Conclusions brous tumors can be malignant, and these cases When a definitive diagnosis of retroperitoneal sarco- demonstrate dense cellularity, increased mitoses ma, including its histological tumor type and grade, (> 4 mitoses/10 hpf), variable cytological atypia, tu- is achievable, then such a diagnosis can help pro- mor necrosis, and/or infiltrative margins.115,116 Tu- vide useful prognostic and predictive information to mor cells are typically positive for CD34 (80%–90%), help guide effective therapy. However, not all tumors CD99 (70%), BCL2 (30%), epithelial membrane an- of the retroperitoneum must be biopsied, subjected tigen (30%), and actin (20%).117-123 Desmin, cyto- to work up by ancillary testing, or both methods to keratin, and S100 are usually absent.117 Recently, achieve a definitive diagnosis. Certain tumor types NAB2/STAT6 was identified in solitary fibrous tu- may call for specific neoadjuvant therapeutic regi- mors, strongly suggesting that this type of tumor is mens that might produce excellent responses, thus a translocation-associated neoplasm and that STAT6 warranting a definitive diagnosis with judicious ancil- immunostain is a sensitive and specific marker for lary testing. By contrast, other tumor types may share solitary fibrous tumor.124,125 similar therapeutic regimens, but neoadjuvant therapy may not provide any benefit to the patient. In such Other Rare Considerations cases, an informative diagnosis should be rendered GIST in the retroperitoneum is rare: One case report as an alternative, which includes meaningful and use- has been documented in the literature.126 Characteris- ful information to guide the next best step in man- tic immunostain pattern of CD117, CD34, and DOG1 agement, especially when there is a small amount of immunoreactivity is helpful in confirming the diag- tissue on biopsy available for analysis. A definitive nosis.46 Ewing sarcoma in the retroperitoneum is also diagnosis can be deferred and then be rendered at rare. Hallmark translation (EWSR1/FLI1 or EWSR1/ resection following a full examination of the entire ERG) detection is helpful in confirming Ewing sarco- tumor. This type of multidisciplinary, pathology-fo- ma in the majority of cases.46 cused approach is practical and, in our experience, Retroperitoneal desmoid tumor has been de- works well to serve the needs of patients with retro- scribed in 11 articles since 1991.127-137 These tumors peritoneal sarcoma. are characterized by proliferation of spindle (fibro- Acknowledgment: Total Cancer Care was enabled blast) cells, with a moderate amount of collagen fi- in part by the support of the DeBartolo Family, and we bers, bland cellular appearance, scant mitosis, and thank the many patients who provided data and tissue lack of metastasis.130,135 Expression of beta catenin in for Total Cancer Care. We also thank Ambuj Kumar, tumor cells is helpful for confirming the diagnosis.46 MD, of USF Health for his assistance with statistical Most sporadic cases of aggressive fibromatosis con- analysis and the continuous commitment to medical tain a somatic mutation in either APC or CTNNB1.128 education by the staff of the Anatomic Pathology Ed- Lazar et al138 reported 3 discrete mutations (ACC- ucation Program. We also appreciate Julia A. Bridge, 41GCC, TCT45TTT, and TCT45CCT) in 2 codons of MD, from the Nebraska Medical Center for performing CTNNB1 exon 3. Targeted therapy for desmoid tumor/ the molecular testing. fibromatosis may be a potential treatment option in the future.135 References Retroperitoneal lipoma is a rare benign tumor of 1. Mullinax JE, Zager JS, Gonzalez RJ. Current diagnosis and management of retroperitoneal sarcoma. Cancer Control. 2011;18(3):177-187. mature adipocytes occurring in the retroperitoneum. 2. Mastrangelo G, Coindre JM, Ducimetiere F, et al. 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