Abdominopelvic and Retroperitoneal Low-Grade Fibromyxoid Sarcoma: A Clinicopathologic Study of 13 Cases

Abdominopelvic and Retroperitoneal Low-Grade Fibromyxoid Sarcoma: A Clinicopathologic Study of 13... Abstract Objectives Low-grade fibromyxoid sarcoma (LGFMS) is a rare tumor often arising in the lower extremities. Only rare examples in the abdominal cavity, pelvis, and retroperitoneum have been reported. Methods cases of abdominopelvic and retroperitoneal LGFMS were retrieved. MUC4, Actin, ALK, β-catenin, desmin, DOG1, KIT, S100 protein, and STAT6 testing was performed, and a subset was tested for FUS rearrangement. Results Sites included intra-abdominal/abdominal wall (four cases), retroperitoneum (three cases), pelvis (three cases), small bowel (two cases), and kidney (one case) (median size, 15 cm; age range, 5-61 years). Tumors harbored spindled cells with mild to moderate atypia, displaying alternating myxoid nodules and hyalinized areas. All cases were positive for MUC4, and five (of five) cases tested harbored FUS rearrangement. Variable positivity for DOG1 (four of 10) and actin (two of 10) was identified. Six tumors recurred, and one patient developed metastasis. Conclusion LGFMS arising in these central locations exhibits similar clinicopathologic features to its counterpart in the extremities. LGFMS at these sites may show limited immunoreactivity for DOG1 and actin. Low-grade fibromyxoid sarcoma, Abdomen, Pelvis, Retroperitoneal, MUC4 Low-grade fibromyxoid sarcoma (LGFMS) is a rare fibroblastic neoplasm that most commonly occurs in the deep soft tissues of the lower extremities, particularly the thigh, chest wall, axilla, shoulder, inguinal region, buttocks and neck.1 Rare examples occurring in the abdominopelvic region and retroperitoneum, including those arising from enteric viscera, have been described, and because of their unusual location, such tumors have often been misdiagnosed as other mesenchymal entities including desmoid-type fibromatosis, peripheral nerve sheath tumors and gastrointestinal stromal tumors.2-18 Herein, we describe the clinicopathologic features of 13 cases of LGFMS confirmed with MUC4 immunostaining and fluorescence in situ hybridization (FISH) for FUS occurring in the abdominopelvic and retroperitoneal region, with emphasis on diagnostic pitfalls at these sites. Materials and Methods Approval for this study was granted by the institutional review boards of the participating institutions. The surgical pathology and consultation archives of Mayo Clinic and Aga Khan University Hospital were searched for previously unreported cases of “low-grade fibromyxoid sarcoma” arising in the abdominal cavity, including from the abdominal wall, pelvis, or retroperitoneum. H&E slides were reviewed to confirm the diagnosis. A representative paraffin block from each tumor, when available, was selected to perform immunohistochemical and molecular studies. Immunohistochemistry Immunohistochemistry for ALK (rabbit monoclonal antibody, Cell Signaling Technology, Danvers, MA), β-catenin (mouse monoclonal antibody, Cell Marque, Rocklin, CA), desmin (mouse monoclonal antibody, Leica Biosystems, Newcastle Upon Tyne, United Kingdom), DOG1 (mouse monoclonal antibody, Leica Biosystems, Newcastle Upon Tyne, UK), KIT (rabbit monoclonal primary antibody, Cell Marque), MUC4 (mouse monoclonal antibody, Biocare Medical, Concord, CA), smooth muscle actin (mouse monoclonal antibody, Dako, Glostrup, Denmark), STAT6 (purified rabbit polyclonal antibody, Santa Cruz Biotechnology, Dallas, TX), S100 protein (polyclonal rabbit anti-S100, Dako, Carpinteria, CA) was performed on 4-μm thick sections prepared from formalin-fixed, paraffin-embedded tissue sections. FISH Unstained 4-μm-thick sections from a representative formalin-fixed paraffin-embedded tissue block were analyzed by FISH using dual-color break-apart probes against the FUS gene (16p11) as previously described,19 using established laboratory protocol. Results Thirteen cases of LGFMS were identified from sites including the abdomen/abdominal wall musculature (four cases), retroperitoneum (three cases), pelvis (three cases), small bowel wall (two cases), and kidney (one case), including 11 primary tumors and two recurrences Table 1 . Tumor size, when available, ranged from 4 cm to 21 cm (median, 15 cm). The age of the patients ranged from 5 to 61 years (mean, 40.8 years; median, 42 years) with seven tumors occurring in females and six in males. A medical chart review revealed that two cases were initially diagnosed as gastrointestinal stromal tumors, and one was previously interpreted as neurofibroma. Six of the 13 cases were submitted for consultation before definitive diagnosis was rendered. Table 1 Clinicopathologic Features of Low-Grade Fibromyoid Sarcoma (LGFMS) Case   Age (y)/Sex   Site   Size (cm)  Primary or Recurrence   MUC4   FISH for FUS  Margins   Adverse Event (Time to First Event)  Length of Follow-up (mo)  Original Diagnosis   Last Known Status   1  39/F  Ileum wall  4  Recurrence  +  ND  −  R (unknown)  Unknown  Neurofibroma  Died of unknown causes  2  29/F  Retroperitoneum  21  Primary  +  ND  +  R (128 mo)  204  LGFMS  Alive with disease  3  46/F  Iliopsoas/iliacus  15  Recurrence  +  ND  −  R (132 mo) M (240 mo)  384  LGFMS  Alive with disease  4  60/M  Pelvis  18  Primary  +  ND  −  R (10 mo)  17  GIST  Alive without disease  5  55/F  Small bowel and mesentery  8  Primary  +  ND  −  R (156 mo)  156  GIST  Alive with disease  6  42/M  Kidney  16.5  Primary  +  ND  −  −  6  LGFMS  Alive without disease  7  5/M  Abdominal wall  8.5  Primary  +  ND  +  Unknown  Unknown  LGFMS  Unknown  8  55/F  Abdominal wall  Unknown  Primary  +  +  Unknown  Unknown  Unknown  Submitted for consultation  Unknown  9  41/M  Abdomen  Unknown  Primary  +  +  −  −  13  Submitted for consultation  Alive without disease  10  18/F  Retroperitoneal  15  Primary  +  ND  −  −  36  Submitted for consultation  Alive without disease  11  61/M  Retroperitoneal  8.5  Primary  +  +  −  −  55  Submitted for consultation  Alive without disease  12  46/M  Pelvis  20.2  Primary  +  +  +  Unknown  Unknown  Submitted for consultation  Unknown  13  34/F  Pelvis  6.7  Primary  +  +  +  R (27 mo)  58  Submitted for consultation  Alive without disease  Case   Age (y)/Sex   Site   Size (cm)  Primary or Recurrence   MUC4   FISH for FUS  Margins   Adverse Event (Time to First Event)  Length of Follow-up (mo)  Original Diagnosis   Last Known Status   1  39/F  Ileum wall  4  Recurrence  +  ND  −  R (unknown)  Unknown  Neurofibroma  Died of unknown causes  2  29/F  Retroperitoneum  21  Primary  +  ND  +  R (128 mo)  204  LGFMS  Alive with disease  3  46/F  Iliopsoas/iliacus  15  Recurrence  +  ND  −  R (132 mo) M (240 mo)  384  LGFMS  Alive with disease  4  60/M  Pelvis  18  Primary  +  ND  −  R (10 mo)  17  GIST  Alive without disease  5  55/F  Small bowel and mesentery  8  Primary  +  ND  −  R (156 mo)  156  GIST  Alive with disease  6  42/M  Kidney  16.5  Primary  +  ND  −  −  6  LGFMS  Alive without disease  7  5/M  Abdominal wall  8.5  Primary  +  ND  +  Unknown  Unknown  LGFMS  Unknown  8  55/F  Abdominal wall  Unknown  Primary  +  +  Unknown  Unknown  Unknown  Submitted for consultation  Unknown  9  41/M  Abdomen  Unknown  Primary  +  +  −  −  13  Submitted for consultation  Alive without disease  10  18/F  Retroperitoneal  15  Primary  +  ND  −  −  36  Submitted for consultation  Alive without disease  11  61/M  Retroperitoneal  8.5  Primary  +  +  −  −  55  Submitted for consultation  Alive without disease  12  46/M  Pelvis  20.2  Primary  +  +  +  Unknown  Unknown  Submitted for consultation  Unknown  13  34/F  Pelvis  6.7  Primary  +  +  +  R (27 mo)  58  Submitted for consultation  Alive without disease  FISH, fluorescence in situ hybridization; GIST, gastrointestinal stromal tumor; M, metastasis; ND, not done; R, recurrence. View Large Gross examination typically revealed firm, solid grey cut surfaces with a circumscribed but lobular appearance Image 1 . Histologically, all cases displayed characteristic alternating myxoid and hyalinized zones, usually with an abrupt transition between the two architectures. The lesional cells were arranged in short fascicles or occasionally in a storiform pattern, containing ovoid to elongated normochromatic nuclei and indistinct cytoplasm Image 2A , Image 2B , and Image 2C . Mild to focal moderate cytologic atypia was appreciated, but mitotic activity was sparse. Arcades of curvilinear thin-walled vessels were best appreciated within the myxoid areas. Scattered giant collagen rosettes were seen in five cases Image 2D . Image 1 View largeDownload slide Gross features of low-grade fibromyxoid sarcoma (LGFMS). A, Recurrent LGFMS from the small bowel wall shows a firm fibrous gross appearance, with multiple smaller nodules identified in the omentum (B). C, Examination of case 6 reveals a large tumor arising from the renal pelvis with a whorled cut surface. D, A subset of tumors showed myxoid change on gross examination. Image 1 View largeDownload slide Gross features of low-grade fibromyxoid sarcoma (LGFMS). A, Recurrent LGFMS from the small bowel wall shows a firm fibrous gross appearance, with multiple smaller nodules identified in the omentum (B). C, Examination of case 6 reveals a large tumor arising from the renal pelvis with a whorled cut surface. D, A subset of tumors showed myxoid change on gross examination. Image 2 View largeDownload slide A, Low-power histologic examination of low-grade fibromyxoid sarcoma shows alternating myxoid and hyalinized zones. B, Arcades of medium-sized blood vessels are characteristic in the myxoid zones. C, Most cases harbored only minimal cytologic atypia in the lesional spindle cells. D, Giant collagen rossettes were noted in five cases. (H&E) Image 2 View largeDownload slide A, Low-power histologic examination of low-grade fibromyxoid sarcoma shows alternating myxoid and hyalinized zones. B, Arcades of medium-sized blood vessels are characteristic in the myxoid zones. C, Most cases harbored only minimal cytologic atypia in the lesional spindle cells. D, Giant collagen rossettes were noted in five cases. (H&E) Immunohistochemical analysis revealed strong and diffuse cytoplasmic MUC4 staining in all 13 cases analyzed (Table 1) Image 3A . Focal to diffuse DOG1 staining was present in four of 10 cases Image 3B , while patchy, weak immunoreactivity for smooth muscle actin was observed in two of 10 cases. KIT staining was appreciated in the primary resection specimen in one case by report (slides not available for review), but this marker was negative in the subsequent recurrence. The remaining nine cases were negative for KIT. No case showed nuclear β-catenin expression (zero of nine); however, seven cases exhibited nonspecific cytoplasmic staining. ALK, desmin, STAT6 and S100 were negative in all cases tested. FISH studies detected FUS rearrangement in all cases evaluated (five of five). Image 3 View largeDownload slide A, MUC4 immunohistochemical stain shows strong cytoplasmic staining in the tumor cells of low-grade fibromyxoid sarcoma. B, DOG1 staining was seen in a subset of cases in our study. Image 3 View largeDownload slide A, MUC4 immunohistochemical stain shows strong cytoplasmic staining in the tumor cells of low-grade fibromyxoid sarcoma. B, DOG1 staining was seen in a subset of cases in our study. The margin status was available in 12 cases: four cases were incompletely excised with positive margins, while margins for the remaining eight cases were reported as negative. Follow-up was available in 10 patients, ranging from 6 months to 384 months (median, 55 months). Six patients experienced local recurrence (median time to recurrence, 128 months; range, 10-156 months). One of these patients also developed liver metastasis 20 years after the initial resection followed by bone and lung metastases. Two of the six patients with local recurrence had positive margins at the time of the original surgery. At the time of last clinical follow-up, six patients were alive without disease, and three patients were alive with disease (two local disease, one with bone and lung metastases). One patient died of unknown causes, and the remaining three patients were lost to follow-up. Discussion LGFMS are rare mesenchymal tumors that often occur in the deep soft tissues of the extremities and are characterized by deceptively bland spindled cells growing in heavily collagenized, hypocellular zones and distinctive myxoid nodules, often displaying a “curvilinear” vascular pattern. At the genetic level, the great majority of LGFMS show rearrangements involving the FUS locus, most often with the CREB3L2 gene.19-21 More recently, MUC4 has been shown to be a highly sensitive and specific immunohistochemical marker of genetically confirmed LGFMS, and some authors have suggested that MUC4 expression alone is a sufficient adjunct in the diagnosis of LGFMS, even without confirmatory FISH studies.22 Abdominopelvic and retroperitoneal LGFMS, including those arising from gastrointestinal viscera, are extremely uncommon tumors, with only 26 cases previously described in the literature, the majority as single case reports or small series.2-18 The largest group of seven cases was reported as part of a series of 33 LGFMS cases with long-term follow-up by Evans in 2011.8 However, MUC4 immunohistochemistry and/or molecular studies for FUS rearrangement were performed in only minority of these cases, and except for Evans’ series, follow-up is limited.8,18 The results of this study, the largest series to date of LGFMS occurring in the abdominal cavity and retroperitoneum, suggest that the morphological, immunohistochemical and molecular genetic features of LGFMS in this location are essentially identical to their counterparts in more common locations, including the presence of giant collagen rosettes (“hyalinizing spindle cell tumor with giant rosettes”) in some. The natural history of LGFMS in these unusual anatomical locations also appears to be similar to that of their counterparts elsewhere, with potential for local recurrence and late distant metastases. In our series, nearly half of the patients (six of 13) experienced local recurrence, but only one instance of metastatic disease was reported. To date, no patients have died of disease. In our cohort, only one of the six recurrences occurred before the 2-year follow-up mark. The recurrence rate in our series echoed findings by Evans who found 21 of 33 patients experienced recurrence (median time to recurrence, 42 months) in his series of LGFMS cases with long-term follow-up.8 In fact, six of seven patients with either abdominopelvic or retroperitoneal LGFMS in Evans’ study experienced local recurrence. These findings coupled with ours suggest that LGFMS in this location have high rates of recurrence, although many recurrences occur after several years. Interestingly, Evans reported metastasis in 15 of 33 patients (median time to metastasis, 60 months), and 14 of 33 patients died of disease (median time to death, 15 years). When focusing on intraabdominal/pelvic/retroperitoneal cases, two of seven patients developed metastasis and five of seven died of disease. Explanations for the discordance between rate of death from disease in Evans’ work and our study include the limited number of patients in both series and selection bias. Alternatively, even though our median follow-up time was nearly 5 years, it is possible that patients in our study will continue to develop adverse events as we follow them over time, as LGFMS is notorious for late (greater than 10 years) recurrence and metastasis. Given the similarity of LGFMS in abdominal/ retroperitoneal locations to those elsewhere, it is not surprising that only four of 13 cases in the present series were initially correctly diagnosed as representing LGFMS, with the remainder either misdiagnosed as representing gastrointestinal stromal tumors or nerve sheath tumors or submitted for consultation before definitive diagnosis. This very likely reflects both pathologists’ lack of familiarity with the typical morphological features of this very rare sarcoma and the extreme rarity of LGFMS in these anatomical locations. These problems are compounded in occasional cases of LGFMS showing unexpected immunoreactivity for markers such as DOG1 and smooth muscle actin, and by misinterpretation of cytoplasmic β-catenin expression as diagnostically relevant (eg, supportive of the diagnosis of desmoid-type fibromatosis). From a morphological perspective, desmoid-type fibromatosis is perhaps the tumor most likely to be confused with LGFMS, particularly in the abdomen and abdominal wall. Desmoid-type fibromatosis consists of a diffusely infiltrative proliferation of “active-appearing,” uniform fibroblasts and myofibroblasts growing in long, sweeping fascicles, arrayed about a thin-walled, dilated vasculature, with perivascular edema. Although myxoid change may be seen in fibromatosis, the “abrupt” transition into myxoid nodules that typifies LGFMS is not seen, nor are arcades of curvilinear vessels. Desmoid-type fibromatoses often show aberrant nuclear accumulation of β-catenin protein, reflecting mutations in either CTNNB1 or APC.23,24 In contrast, cytoplasmic expression of β-catenin in LGFMS is wholly nonspecific and is not associated with CTNNB1 or APC aberrations. Other entities in the differential diagnosis of abdominal, pelvic or retroperitoneal LGFMS include gastrointestinal stromal tumors, peripheral nerve sheath tumors such as perineurioma, smooth muscle neoplasms, solitary fibrous tumor, dedifferentiated liposarcoma and inflammatory myofibroblastic tumor Table 2 . Table 2 Key Histologic and Immunophenotypic Features of Low-Grade Fibromyxoid Sarcoma and Its Mimics Tumor  Key Histologic Features   MUC4   Most Useful Immunohistochemical Marker(s) or Molecular Studies   Low-grade fibromyxoid sarcoma  Alternating myxoid and hyalinized zones; m ild to focal moderate cytologic atypia ; collagen rosettes  +  MUC4 (IHC), FUS rearrangement (FISH)  Desmoid-type fibromatosis  Long sweeping fascicles ; infiltrative growth pattern ; lacks cytologic atypia  −  β-Catenin (nuclear) (IHC)  Gastrointestinal stromal tumor, spindled type  Fascicles of spindled cells with pale eosinophilic and fibrillary cytoplasm  −  KIT, DOG1 (IHC)  Smooth muscle tumor  Brightly eosinophilic cytoplasm; b lunt-ended nuclei  −  Smooth muscle actin, desmin (IHC)  Peripheral nerve sheath tumor  Hyperchromatic and wavy nuclei; nuclear palisading  −  Schwannoma/neurofibroma: S100, SOX10 (IHC); p erineurioma: EMA, claudin, GLUT-1 (IHC)  Dedifferentiated liposarcoma  High-grade sarcoma juxtaposed to well- differentiated liposarcoma  No data  MDM2 amplification (FISH)  Inflammatory myofibroblastic tumor  Spindled to stellate shaped cells; myxoid or hyalinized background; inflammatory cells  −  Smooth muscle actin, ALK (IHC)  Solitary fibrous tumor  Uniform ovoid to spindled cells; branching and hyalinized blood vessels  −  STAT6 (IHC)  Tumor  Key Histologic Features   MUC4   Most Useful Immunohistochemical Marker(s) or Molecular Studies   Low-grade fibromyxoid sarcoma  Alternating myxoid and hyalinized zones; m ild to focal moderate cytologic atypia ; collagen rosettes  +  MUC4 (IHC), FUS rearrangement (FISH)  Desmoid-type fibromatosis  Long sweeping fascicles ; infiltrative growth pattern ; lacks cytologic atypia  −  β-Catenin (nuclear) (IHC)  Gastrointestinal stromal tumor, spindled type  Fascicles of spindled cells with pale eosinophilic and fibrillary cytoplasm  −  KIT, DOG1 (IHC)  Smooth muscle tumor  Brightly eosinophilic cytoplasm; b lunt-ended nuclei  −  Smooth muscle actin, desmin (IHC)  Peripheral nerve sheath tumor  Hyperchromatic and wavy nuclei; nuclear palisading  −  Schwannoma/neurofibroma: S100, SOX10 (IHC); p erineurioma: EMA, claudin, GLUT-1 (IHC)  Dedifferentiated liposarcoma  High-grade sarcoma juxtaposed to well- differentiated liposarcoma  No data  MDM2 amplification (FISH)  Inflammatory myofibroblastic tumor  Spindled to stellate shaped cells; myxoid or hyalinized background; inflammatory cells  −  Smooth muscle actin, ALK (IHC)  Solitary fibrous tumor  Uniform ovoid to spindled cells; branching and hyalinized blood vessels  −  STAT6 (IHC)  EMA, epithelial membrane antigen; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry. View Large In conclusion, we report the clinicopathologic features of 13 cases of abdominopelvic and retroperitoneal LGFMS. The morphological features of LGFMS at these sites are comparable to their counterparts arising in the extremities. However, due to the relative rarity of this entity at these locations compared to other spindle cell neoplasms, the diagnosis can be challenging. These tumors appear to exhibit similar recurrence rates to their somatic counterparts with risk for late distant metastasis. However, prognosis is predicated on accurate diagnosis, and misclassification may lead to undertreatment and increased adverse events. Pathologists should be aware that LGFMS may arise within the abdomen, pelvis, and retroperitoneum, and when confronted with a spindle cell neoplasm in these sites, careful morphological examination and targeted immunohistochemical panel, including MUC4, will aid in appropriate classification and treatment. Acknowledgments: The authors thank Brian P. Rubin and Renee Slaw, Department of Pathology and Laboratory Medicine, Cleveland Clinic, for arranging MUC4 staining of these cases. References 1. Goldblum JR, Folpe AL, Weiss SW, eds. Enzinger and Weiss’s Soft Tissue Tumors . 6th ed. Philadelphia PA: Elsevier Saunders; 2013: 324- 332. 2. Folpe AL, Lane KL, Paull Get al.   Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes: a clinicopathologic study of 73 cases supporting their identity and assessing the impact of high-grade areas. Am J Surg Pathol . 2000; 24: 1353- 1360. Google Scholar CrossRef Search ADS PubMed  3. Harish K, Ashok AC, Alva NK. Low grade fibromyxoid sarcoma of the falciform ligament: a case report. BMC Surg . 2003; 3: 7. Google Scholar CrossRef Search ADS PubMed  4. Koishi A, Gomibuchi H, Inoue Jet al.   Hyalinizing spindle cell tumor with giant rosettes of the omentum. J Obstet Gynaecol Res . 2003; 29: 388- 391. Google Scholar CrossRef Search ADS PubMed  5. Park IJ, Kim HC, Yu CSet al.   Low-grade fibromyxoid sarcoma of the colon. Dig Liver Dis . 2007; 39: 274- 277. Google Scholar CrossRef Search ADS PubMed  6. Fujii S, Kawawa Y, Horiguchi Set al.   Low-grade fibromyxoid sarcoma of the small bowel mesentery: computed tomography and magnetic resonance imaging findings. Radiat Med . 2008; 26: 244- 247. Google Scholar CrossRef Search ADS PubMed  7. Laurini JA, Zhang L, Goldblum JRet al.   Low-grade fibromyxoid sarcoma of the small intestine: report of 4 cases with molecular cytogenetic confirmation. Am J Surg Pathol . 2011; 35: 1069- 1073. Google Scholar CrossRef Search ADS PubMed  8. Evans HL. Low-grade fibromyxoid sarcoma: a clinicopathologic study of 33 cases with long-term follow-up. Am J Surg Pathol . 2011; 35: 1450- 1462. Google Scholar CrossRef Search ADS PubMed  9. Lee AF, Yip S, Smith ACet al.   Low-grade fibromyxoid sarcoma of the perineum with heterotopic ossification: case report and review of the literature. Hum Pathol . 2011; 42: 1804- 1809. Google Scholar CrossRef Search ADS PubMed  10. Alevizopoulos A, Mygdalis V, Tyritzis Set al.   Low-grade fibromyxoid sarcoma of the renal pelvis: first report. Case Rep Nephrol Urol . 2012; 2: 87- 91. Google Scholar CrossRef Search ADS PubMed  11. Singh K, Singh S, Pal Net al.   Low-grade fibromyxoid sarcoma of anterior abdominal wall. Indian J Surg . 2012; 74: 351- 353. Google Scholar CrossRef Search ADS PubMed  12. Alatise OI, Oke OA, Olaofe OOet al.   A huge low-grade fibromyxoid sarcoma of small bowel mesentery simulating hyper immune splenomegaly syndrome: a case report and review of literature. Afr Health Sci . 2013; 13: 736- 740. Google Scholar PubMed  13. Vasudevan G, Shivamurthy A. Low grade fibromyxoid sarcoma of the mesentery, an under recognised entity: a case report. J Interdiscipl Histopathol . 2014; 2: 228- 231. Google Scholar CrossRef Search ADS   14. Kim KJ, Seo JW. Intra-abdominal low-grade fibromyxoid sarcoma of the transverse mesocolon mimicking lymphoma. Jpn J Radiol . 2014; 32: 360- 364. Google Scholar CrossRef Search ADS PubMed  15. Rubinstein JC, Visa A, Zhang Let al.   Primary low-grade fibromyxoid sarcoma of the kidney in a child with the alternative EWSR1-CREB3L1 gene fusion. Pediatr Dev Pathol . 2014; 17: 321- 326. Google Scholar CrossRef Search ADS PubMed  16. Mendoza AS, O’Leary MP, Peng SKet al.   Low-grade fibromyxoid sarcoma of the sigmoid colon. Exp Mol Pathol . 2015; 98: 300- 303. Google Scholar CrossRef Search ADS PubMed  17. Konecna J, Liberale G, Haddad Jet al.   Diffuse intra-abdominal low grade fibromyxoid sarcoma with hepatic metastases: case report and review of the literature. Int J Surg Case Rep . 2015; 14: 40- 43. Google Scholar CrossRef Search ADS PubMed  18. Thway K, Ng W, Benson Cet al.   DOG1 expression in low-grade fibromyxoid sarcoma: a study of 11 cases, with molecular characterization. Int J Surg Pathol . 2015; 23: 454- 460. Google Scholar CrossRef Search ADS PubMed  19. Guillou L, Benhattar J, Gengler Cet al.   Translocation-positive low-grade fibromyxoid sarcoma: clinicopathologic and molecular analysis of a series expanding the morphologic spectrum and suggesting potential relationship to sclerosing epithelioid fibrosarcoma: a study from the French Sarcoma Group. Am J Surg Pathol . 2007; 31: 1387- 1402. Google Scholar CrossRef Search ADS PubMed  20. Matsuyama A, Hisaoka M, Shimajiri Set al.   DNA-based polymerase chain reaction for detecting FUS-CREB3L2 in low-grade fibromyxoid sarcoma using formalin-fixed, paraffin-embedded tissue specimens. Diagn Mol Pathol . 2008; 17: 237- 240. Google Scholar CrossRef Search ADS PubMed  21. Mertens F, Fletcher CD, Antonescu CRet al.   Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma, and cloning of a novel FUS/CREB3L1 fusion gene. Lab Invest . 2005; 85: 408- 415. Google Scholar CrossRef Search ADS PubMed  22. Doyle LA, Wang WL, Dal Cin Pet al.   MUC4 is a sensitive and extremely useful marker for sclerosing epithelioid fibrosarcoma: association with FUS gene rearrangement. Am J Surg Pathol . 2012; 36: 1444- 1451. Google Scholar CrossRef Search ADS PubMed  23. Miyaki M, Konishi M, Kikuchi-Yanoshita Ret al.   Coexistence of somatic and germ-line mutations of APC gene in desmoid tumors from patients with familial adenomatous polyposis. Cancer Res . 1993; 53: 5079- 5082. Google Scholar PubMed  24. Lazar AJ, Tuvin D, Hajibashi Set al.   Specific mutations in the beta-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors. Am J Pathol . 2008; 173: 1518- 1527. Google Scholar CrossRef Search ADS PubMed  © American Society for Clinical Pathology, 2018. All rights reserved. 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Abdominopelvic and Retroperitoneal Low-Grade Fibromyxoid Sarcoma: A Clinicopathologic Study of 13 Cases

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Abstract

Abstract Objectives Low-grade fibromyxoid sarcoma (LGFMS) is a rare tumor often arising in the lower extremities. Only rare examples in the abdominal cavity, pelvis, and retroperitoneum have been reported. Methods cases of abdominopelvic and retroperitoneal LGFMS were retrieved. MUC4, Actin, ALK, β-catenin, desmin, DOG1, KIT, S100 protein, and STAT6 testing was performed, and a subset was tested for FUS rearrangement. Results Sites included intra-abdominal/abdominal wall (four cases), retroperitoneum (three cases), pelvis (three cases), small bowel (two cases), and kidney (one case) (median size, 15 cm; age range, 5-61 years). Tumors harbored spindled cells with mild to moderate atypia, displaying alternating myxoid nodules and hyalinized areas. All cases were positive for MUC4, and five (of five) cases tested harbored FUS rearrangement. Variable positivity for DOG1 (four of 10) and actin (two of 10) was identified. Six tumors recurred, and one patient developed metastasis. Conclusion LGFMS arising in these central locations exhibits similar clinicopathologic features to its counterpart in the extremities. LGFMS at these sites may show limited immunoreactivity for DOG1 and actin. Low-grade fibromyxoid sarcoma, Abdomen, Pelvis, Retroperitoneal, MUC4 Low-grade fibromyxoid sarcoma (LGFMS) is a rare fibroblastic neoplasm that most commonly occurs in the deep soft tissues of the lower extremities, particularly the thigh, chest wall, axilla, shoulder, inguinal region, buttocks and neck.1 Rare examples occurring in the abdominopelvic region and retroperitoneum, including those arising from enteric viscera, have been described, and because of their unusual location, such tumors have often been misdiagnosed as other mesenchymal entities including desmoid-type fibromatosis, peripheral nerve sheath tumors and gastrointestinal stromal tumors.2-18 Herein, we describe the clinicopathologic features of 13 cases of LGFMS confirmed with MUC4 immunostaining and fluorescence in situ hybridization (FISH) for FUS occurring in the abdominopelvic and retroperitoneal region, with emphasis on diagnostic pitfalls at these sites. Materials and Methods Approval for this study was granted by the institutional review boards of the participating institutions. The surgical pathology and consultation archives of Mayo Clinic and Aga Khan University Hospital were searched for previously unreported cases of “low-grade fibromyxoid sarcoma” arising in the abdominal cavity, including from the abdominal wall, pelvis, or retroperitoneum. H&E slides were reviewed to confirm the diagnosis. A representative paraffin block from each tumor, when available, was selected to perform immunohistochemical and molecular studies. Immunohistochemistry Immunohistochemistry for ALK (rabbit monoclonal antibody, Cell Signaling Technology, Danvers, MA), β-catenin (mouse monoclonal antibody, Cell Marque, Rocklin, CA), desmin (mouse monoclonal antibody, Leica Biosystems, Newcastle Upon Tyne, United Kingdom), DOG1 (mouse monoclonal antibody, Leica Biosystems, Newcastle Upon Tyne, UK), KIT (rabbit monoclonal primary antibody, Cell Marque), MUC4 (mouse monoclonal antibody, Biocare Medical, Concord, CA), smooth muscle actin (mouse monoclonal antibody, Dako, Glostrup, Denmark), STAT6 (purified rabbit polyclonal antibody, Santa Cruz Biotechnology, Dallas, TX), S100 protein (polyclonal rabbit anti-S100, Dako, Carpinteria, CA) was performed on 4-μm thick sections prepared from formalin-fixed, paraffin-embedded tissue sections. FISH Unstained 4-μm-thick sections from a representative formalin-fixed paraffin-embedded tissue block were analyzed by FISH using dual-color break-apart probes against the FUS gene (16p11) as previously described,19 using established laboratory protocol. Results Thirteen cases of LGFMS were identified from sites including the abdomen/abdominal wall musculature (four cases), retroperitoneum (three cases), pelvis (three cases), small bowel wall (two cases), and kidney (one case), including 11 primary tumors and two recurrences Table 1 . Tumor size, when available, ranged from 4 cm to 21 cm (median, 15 cm). The age of the patients ranged from 5 to 61 years (mean, 40.8 years; median, 42 years) with seven tumors occurring in females and six in males. A medical chart review revealed that two cases were initially diagnosed as gastrointestinal stromal tumors, and one was previously interpreted as neurofibroma. Six of the 13 cases were submitted for consultation before definitive diagnosis was rendered. Table 1 Clinicopathologic Features of Low-Grade Fibromyoid Sarcoma (LGFMS) Case   Age (y)/Sex   Site   Size (cm)  Primary or Recurrence   MUC4   FISH for FUS  Margins   Adverse Event (Time to First Event)  Length of Follow-up (mo)  Original Diagnosis   Last Known Status   1  39/F  Ileum wall  4  Recurrence  +  ND  −  R (unknown)  Unknown  Neurofibroma  Died of unknown causes  2  29/F  Retroperitoneum  21  Primary  +  ND  +  R (128 mo)  204  LGFMS  Alive with disease  3  46/F  Iliopsoas/iliacus  15  Recurrence  +  ND  −  R (132 mo) M (240 mo)  384  LGFMS  Alive with disease  4  60/M  Pelvis  18  Primary  +  ND  −  R (10 mo)  17  GIST  Alive without disease  5  55/F  Small bowel and mesentery  8  Primary  +  ND  −  R (156 mo)  156  GIST  Alive with disease  6  42/M  Kidney  16.5  Primary  +  ND  −  −  6  LGFMS  Alive without disease  7  5/M  Abdominal wall  8.5  Primary  +  ND  +  Unknown  Unknown  LGFMS  Unknown  8  55/F  Abdominal wall  Unknown  Primary  +  +  Unknown  Unknown  Unknown  Submitted for consultation  Unknown  9  41/M  Abdomen  Unknown  Primary  +  +  −  −  13  Submitted for consultation  Alive without disease  10  18/F  Retroperitoneal  15  Primary  +  ND  −  −  36  Submitted for consultation  Alive without disease  11  61/M  Retroperitoneal  8.5  Primary  +  +  −  −  55  Submitted for consultation  Alive without disease  12  46/M  Pelvis  20.2  Primary  +  +  +  Unknown  Unknown  Submitted for consultation  Unknown  13  34/F  Pelvis  6.7  Primary  +  +  +  R (27 mo)  58  Submitted for consultation  Alive without disease  Case   Age (y)/Sex   Site   Size (cm)  Primary or Recurrence   MUC4   FISH for FUS  Margins   Adverse Event (Time to First Event)  Length of Follow-up (mo)  Original Diagnosis   Last Known Status   1  39/F  Ileum wall  4  Recurrence  +  ND  −  R (unknown)  Unknown  Neurofibroma  Died of unknown causes  2  29/F  Retroperitoneum  21  Primary  +  ND  +  R (128 mo)  204  LGFMS  Alive with disease  3  46/F  Iliopsoas/iliacus  15  Recurrence  +  ND  −  R (132 mo) M (240 mo)  384  LGFMS  Alive with disease  4  60/M  Pelvis  18  Primary  +  ND  −  R (10 mo)  17  GIST  Alive without disease  5  55/F  Small bowel and mesentery  8  Primary  +  ND  −  R (156 mo)  156  GIST  Alive with disease  6  42/M  Kidney  16.5  Primary  +  ND  −  −  6  LGFMS  Alive without disease  7  5/M  Abdominal wall  8.5  Primary  +  ND  +  Unknown  Unknown  LGFMS  Unknown  8  55/F  Abdominal wall  Unknown  Primary  +  +  Unknown  Unknown  Unknown  Submitted for consultation  Unknown  9  41/M  Abdomen  Unknown  Primary  +  +  −  −  13  Submitted for consultation  Alive without disease  10  18/F  Retroperitoneal  15  Primary  +  ND  −  −  36  Submitted for consultation  Alive without disease  11  61/M  Retroperitoneal  8.5  Primary  +  +  −  −  55  Submitted for consultation  Alive without disease  12  46/M  Pelvis  20.2  Primary  +  +  +  Unknown  Unknown  Submitted for consultation  Unknown  13  34/F  Pelvis  6.7  Primary  +  +  +  R (27 mo)  58  Submitted for consultation  Alive without disease  FISH, fluorescence in situ hybridization; GIST, gastrointestinal stromal tumor; M, metastasis; ND, not done; R, recurrence. View Large Gross examination typically revealed firm, solid grey cut surfaces with a circumscribed but lobular appearance Image 1 . Histologically, all cases displayed characteristic alternating myxoid and hyalinized zones, usually with an abrupt transition between the two architectures. The lesional cells were arranged in short fascicles or occasionally in a storiform pattern, containing ovoid to elongated normochromatic nuclei and indistinct cytoplasm Image 2A , Image 2B , and Image 2C . Mild to focal moderate cytologic atypia was appreciated, but mitotic activity was sparse. Arcades of curvilinear thin-walled vessels were best appreciated within the myxoid areas. Scattered giant collagen rosettes were seen in five cases Image 2D . Image 1 View largeDownload slide Gross features of low-grade fibromyxoid sarcoma (LGFMS). A, Recurrent LGFMS from the small bowel wall shows a firm fibrous gross appearance, with multiple smaller nodules identified in the omentum (B). C, Examination of case 6 reveals a large tumor arising from the renal pelvis with a whorled cut surface. D, A subset of tumors showed myxoid change on gross examination. Image 1 View largeDownload slide Gross features of low-grade fibromyxoid sarcoma (LGFMS). A, Recurrent LGFMS from the small bowel wall shows a firm fibrous gross appearance, with multiple smaller nodules identified in the omentum (B). C, Examination of case 6 reveals a large tumor arising from the renal pelvis with a whorled cut surface. D, A subset of tumors showed myxoid change on gross examination. Image 2 View largeDownload slide A, Low-power histologic examination of low-grade fibromyxoid sarcoma shows alternating myxoid and hyalinized zones. B, Arcades of medium-sized blood vessels are characteristic in the myxoid zones. C, Most cases harbored only minimal cytologic atypia in the lesional spindle cells. D, Giant collagen rossettes were noted in five cases. (H&E) Image 2 View largeDownload slide A, Low-power histologic examination of low-grade fibromyxoid sarcoma shows alternating myxoid and hyalinized zones. B, Arcades of medium-sized blood vessels are characteristic in the myxoid zones. C, Most cases harbored only minimal cytologic atypia in the lesional spindle cells. D, Giant collagen rossettes were noted in five cases. (H&E) Immunohistochemical analysis revealed strong and diffuse cytoplasmic MUC4 staining in all 13 cases analyzed (Table 1) Image 3A . Focal to diffuse DOG1 staining was present in four of 10 cases Image 3B , while patchy, weak immunoreactivity for smooth muscle actin was observed in two of 10 cases. KIT staining was appreciated in the primary resection specimen in one case by report (slides not available for review), but this marker was negative in the subsequent recurrence. The remaining nine cases were negative for KIT. No case showed nuclear β-catenin expression (zero of nine); however, seven cases exhibited nonspecific cytoplasmic staining. ALK, desmin, STAT6 and S100 were negative in all cases tested. FISH studies detected FUS rearrangement in all cases evaluated (five of five). Image 3 View largeDownload slide A, MUC4 immunohistochemical stain shows strong cytoplasmic staining in the tumor cells of low-grade fibromyxoid sarcoma. B, DOG1 staining was seen in a subset of cases in our study. Image 3 View largeDownload slide A, MUC4 immunohistochemical stain shows strong cytoplasmic staining in the tumor cells of low-grade fibromyxoid sarcoma. B, DOG1 staining was seen in a subset of cases in our study. The margin status was available in 12 cases: four cases were incompletely excised with positive margins, while margins for the remaining eight cases were reported as negative. Follow-up was available in 10 patients, ranging from 6 months to 384 months (median, 55 months). Six patients experienced local recurrence (median time to recurrence, 128 months; range, 10-156 months). One of these patients also developed liver metastasis 20 years after the initial resection followed by bone and lung metastases. Two of the six patients with local recurrence had positive margins at the time of the original surgery. At the time of last clinical follow-up, six patients were alive without disease, and three patients were alive with disease (two local disease, one with bone and lung metastases). One patient died of unknown causes, and the remaining three patients were lost to follow-up. Discussion LGFMS are rare mesenchymal tumors that often occur in the deep soft tissues of the extremities and are characterized by deceptively bland spindled cells growing in heavily collagenized, hypocellular zones and distinctive myxoid nodules, often displaying a “curvilinear” vascular pattern. At the genetic level, the great majority of LGFMS show rearrangements involving the FUS locus, most often with the CREB3L2 gene.19-21 More recently, MUC4 has been shown to be a highly sensitive and specific immunohistochemical marker of genetically confirmed LGFMS, and some authors have suggested that MUC4 expression alone is a sufficient adjunct in the diagnosis of LGFMS, even without confirmatory FISH studies.22 Abdominopelvic and retroperitoneal LGFMS, including those arising from gastrointestinal viscera, are extremely uncommon tumors, with only 26 cases previously described in the literature, the majority as single case reports or small series.2-18 The largest group of seven cases was reported as part of a series of 33 LGFMS cases with long-term follow-up by Evans in 2011.8 However, MUC4 immunohistochemistry and/or molecular studies for FUS rearrangement were performed in only minority of these cases, and except for Evans’ series, follow-up is limited.8,18 The results of this study, the largest series to date of LGFMS occurring in the abdominal cavity and retroperitoneum, suggest that the morphological, immunohistochemical and molecular genetic features of LGFMS in this location are essentially identical to their counterparts in more common locations, including the presence of giant collagen rosettes (“hyalinizing spindle cell tumor with giant rosettes”) in some. The natural history of LGFMS in these unusual anatomical locations also appears to be similar to that of their counterparts elsewhere, with potential for local recurrence and late distant metastases. In our series, nearly half of the patients (six of 13) experienced local recurrence, but only one instance of metastatic disease was reported. To date, no patients have died of disease. In our cohort, only one of the six recurrences occurred before the 2-year follow-up mark. The recurrence rate in our series echoed findings by Evans who found 21 of 33 patients experienced recurrence (median time to recurrence, 42 months) in his series of LGFMS cases with long-term follow-up.8 In fact, six of seven patients with either abdominopelvic or retroperitoneal LGFMS in Evans’ study experienced local recurrence. These findings coupled with ours suggest that LGFMS in this location have high rates of recurrence, although many recurrences occur after several years. Interestingly, Evans reported metastasis in 15 of 33 patients (median time to metastasis, 60 months), and 14 of 33 patients died of disease (median time to death, 15 years). When focusing on intraabdominal/pelvic/retroperitoneal cases, two of seven patients developed metastasis and five of seven died of disease. Explanations for the discordance between rate of death from disease in Evans’ work and our study include the limited number of patients in both series and selection bias. Alternatively, even though our median follow-up time was nearly 5 years, it is possible that patients in our study will continue to develop adverse events as we follow them over time, as LGFMS is notorious for late (greater than 10 years) recurrence and metastasis. Given the similarity of LGFMS in abdominal/ retroperitoneal locations to those elsewhere, it is not surprising that only four of 13 cases in the present series were initially correctly diagnosed as representing LGFMS, with the remainder either misdiagnosed as representing gastrointestinal stromal tumors or nerve sheath tumors or submitted for consultation before definitive diagnosis. This very likely reflects both pathologists’ lack of familiarity with the typical morphological features of this very rare sarcoma and the extreme rarity of LGFMS in these anatomical locations. These problems are compounded in occasional cases of LGFMS showing unexpected immunoreactivity for markers such as DOG1 and smooth muscle actin, and by misinterpretation of cytoplasmic β-catenin expression as diagnostically relevant (eg, supportive of the diagnosis of desmoid-type fibromatosis). From a morphological perspective, desmoid-type fibromatosis is perhaps the tumor most likely to be confused with LGFMS, particularly in the abdomen and abdominal wall. Desmoid-type fibromatosis consists of a diffusely infiltrative proliferation of “active-appearing,” uniform fibroblasts and myofibroblasts growing in long, sweeping fascicles, arrayed about a thin-walled, dilated vasculature, with perivascular edema. Although myxoid change may be seen in fibromatosis, the “abrupt” transition into myxoid nodules that typifies LGFMS is not seen, nor are arcades of curvilinear vessels. Desmoid-type fibromatoses often show aberrant nuclear accumulation of β-catenin protein, reflecting mutations in either CTNNB1 or APC.23,24 In contrast, cytoplasmic expression of β-catenin in LGFMS is wholly nonspecific and is not associated with CTNNB1 or APC aberrations. Other entities in the differential diagnosis of abdominal, pelvic or retroperitoneal LGFMS include gastrointestinal stromal tumors, peripheral nerve sheath tumors such as perineurioma, smooth muscle neoplasms, solitary fibrous tumor, dedifferentiated liposarcoma and inflammatory myofibroblastic tumor Table 2 . Table 2 Key Histologic and Immunophenotypic Features of Low-Grade Fibromyxoid Sarcoma and Its Mimics Tumor  Key Histologic Features   MUC4   Most Useful Immunohistochemical Marker(s) or Molecular Studies   Low-grade fibromyxoid sarcoma  Alternating myxoid and hyalinized zones; m ild to focal moderate cytologic atypia ; collagen rosettes  +  MUC4 (IHC), FUS rearrangement (FISH)  Desmoid-type fibromatosis  Long sweeping fascicles ; infiltrative growth pattern ; lacks cytologic atypia  −  β-Catenin (nuclear) (IHC)  Gastrointestinal stromal tumor, spindled type  Fascicles of spindled cells with pale eosinophilic and fibrillary cytoplasm  −  KIT, DOG1 (IHC)  Smooth muscle tumor  Brightly eosinophilic cytoplasm; b lunt-ended nuclei  −  Smooth muscle actin, desmin (IHC)  Peripheral nerve sheath tumor  Hyperchromatic and wavy nuclei; nuclear palisading  −  Schwannoma/neurofibroma: S100, SOX10 (IHC); p erineurioma: EMA, claudin, GLUT-1 (IHC)  Dedifferentiated liposarcoma  High-grade sarcoma juxtaposed to well- differentiated liposarcoma  No data  MDM2 amplification (FISH)  Inflammatory myofibroblastic tumor  Spindled to stellate shaped cells; myxoid or hyalinized background; inflammatory cells  −  Smooth muscle actin, ALK (IHC)  Solitary fibrous tumor  Uniform ovoid to spindled cells; branching and hyalinized blood vessels  −  STAT6 (IHC)  Tumor  Key Histologic Features   MUC4   Most Useful Immunohistochemical Marker(s) or Molecular Studies   Low-grade fibromyxoid sarcoma  Alternating myxoid and hyalinized zones; m ild to focal moderate cytologic atypia ; collagen rosettes  +  MUC4 (IHC), FUS rearrangement (FISH)  Desmoid-type fibromatosis  Long sweeping fascicles ; infiltrative growth pattern ; lacks cytologic atypia  −  β-Catenin (nuclear) (IHC)  Gastrointestinal stromal tumor, spindled type  Fascicles of spindled cells with pale eosinophilic and fibrillary cytoplasm  −  KIT, DOG1 (IHC)  Smooth muscle tumor  Brightly eosinophilic cytoplasm; b lunt-ended nuclei  −  Smooth muscle actin, desmin (IHC)  Peripheral nerve sheath tumor  Hyperchromatic and wavy nuclei; nuclear palisading  −  Schwannoma/neurofibroma: S100, SOX10 (IHC); p erineurioma: EMA, claudin, GLUT-1 (IHC)  Dedifferentiated liposarcoma  High-grade sarcoma juxtaposed to well- differentiated liposarcoma  No data  MDM2 amplification (FISH)  Inflammatory myofibroblastic tumor  Spindled to stellate shaped cells; myxoid or hyalinized background; inflammatory cells  −  Smooth muscle actin, ALK (IHC)  Solitary fibrous tumor  Uniform ovoid to spindled cells; branching and hyalinized blood vessels  −  STAT6 (IHC)  EMA, epithelial membrane antigen; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry. View Large In conclusion, we report the clinicopathologic features of 13 cases of abdominopelvic and retroperitoneal LGFMS. The morphological features of LGFMS at these sites are comparable to their counterparts arising in the extremities. However, due to the relative rarity of this entity at these locations compared to other spindle cell neoplasms, the diagnosis can be challenging. These tumors appear to exhibit similar recurrence rates to their somatic counterparts with risk for late distant metastasis. However, prognosis is predicated on accurate diagnosis, and misclassification may lead to undertreatment and increased adverse events. Pathologists should be aware that LGFMS may arise within the abdomen, pelvis, and retroperitoneum, and when confronted with a spindle cell neoplasm in these sites, careful morphological examination and targeted immunohistochemical panel, including MUC4, will aid in appropriate classification and treatment. Acknowledgments: The authors thank Brian P. Rubin and Renee Slaw, Department of Pathology and Laboratory Medicine, Cleveland Clinic, for arranging MUC4 staining of these cases. References 1. Goldblum JR, Folpe AL, Weiss SW, eds. Enzinger and Weiss’s Soft Tissue Tumors . 6th ed. Philadelphia PA: Elsevier Saunders; 2013: 324- 332. 2. Folpe AL, Lane KL, Paull Get al.   Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes: a clinicopathologic study of 73 cases supporting their identity and assessing the impact of high-grade areas. Am J Surg Pathol . 2000; 24: 1353- 1360. Google Scholar CrossRef Search ADS PubMed  3. Harish K, Ashok AC, Alva NK. Low grade fibromyxoid sarcoma of the falciform ligament: a case report. BMC Surg . 2003; 3: 7. Google Scholar CrossRef Search ADS PubMed  4. Koishi A, Gomibuchi H, Inoue Jet al.   Hyalinizing spindle cell tumor with giant rosettes of the omentum. J Obstet Gynaecol Res . 2003; 29: 388- 391. Google Scholar CrossRef Search ADS PubMed  5. 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American Journal of Clinical Pathology – Oxford University Press

Published: Feb 1, 2018

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