Undifferentiated Pleomorphic Sarcoma of the Extremity and Trunk: A Retrospective Cohort Study of 166 Cases in a Large Institution

Abstract

Background：An imperative need for better management strategies to improve the survival in patients with Undifferentiated Pleomorphic Sarcoma (UPS).

Methods: The retrospective analysis of clinicopathological data of 166 UPS patients, who have undergone surgical treatment in our hospital, was carried out from January 2005 to January 2018. Cox regression model and Kaplan-Meier method were employed to identify the relevant factors affecting the rate of local recurrence (LR), distant metastasis (DM), and overall survival (OS) via univariate and multivariate analysis. The P-values > 0.05 were found to be statistically considerable.

Results: At the end of follow-up, the rate of LR, DM and OS in 166 UPS patients was 22.9% (38/166), 32.5%（54/166）and 75.3% (125/166) with a median follow-up time of 55 months. The existing study reveals that the UPS in trunk and R1/R2 resection margin are the prognostic markers of poor survival rate. Women are more susceptible to LR, and R1/R2 resection margin is significantly correlated with a high rate of LR. Old Patients (> 60 years), the UPS in trunk and R1/R2 resection margin are susceptible to DM.

Conclusion: R0 resection margin was an only independent favorable prognostic factor, which was correlated with LRFS, DMFS, and OS.

Introduction

Soft tissue sarcoma (STS) is a type of malignant tumor that develops from mesenchymal tissue, which is estimated to be 1–2% of all malignant tumors, and contains more than 50 histological subtypes[1, 2]. Undifferentiated Pleomorphic Sarcoma (UPS) is one of the most common subtypes of STS, previously known as Malignant Fibrous Histiocytoma (MFH)[1, 3, 4]. In 1964, Stout and O'Brien extensively studied the features of MFH and for the first time, it was considered a new type of sarcoma[5]. In 1978, Weiss and Enzinger et al.[6] revealed that the underlined malignancy had variable morphologic characteristics and often revealed transitions from an area of extremely arranged storiform pattern to a less differentiated area with a pleomorphic appearance. In 2002, the World Health Organization (WHO) reconsidered the definition of MFH, and pointed out that it should be a diagnosis of exclusion. In this view, the term ‘malignant fibrous histiocytoma’ was exchanged by the undifferentiated pleomorphic sarcoma[7]. UPS should be labeled as such after the exclusion of particular lines of differentiation[8–10], along with the key element which is composed of several types of pleomorphic sarcoma cells with heterogeneity[7]. The mixed growth mode normally consists of tissue cells while fibroblasts are the leading histological characteristic of UPS, which mainly manifests the function of fibroblasts, however, its important source is tissue cells[7]. As the most common histological subtype in STS[11], once a clear direction of differentiation can be ruled out, the diagnosis must be considered first in the STSs.

The deep-seated, aggressive and enlarged progressively without pain, always represents the clinical manifestations of UPS, and 60–70% occurs in the extremity[3]. Related reports suggest that the recurrence rate of UPS is greater than 31%[12]. Compared with other STSs, the 5-year survival rate is lower in UPS, around 50–70%[9, 13–15], and some studies revealed that the 5-years OS rate could reach 72%[16]. Surgical treatment is largely followed in the UPS[15, 17], which can achieve significantly local control for primary UPS. 40% of patients with these tumors develop pulmonary metastases[14], which was with 8–12 months of median survival[18].

The current mainstay of treatment for STS is wide resection, and the effectiveness of adjuvant radiotherapy and adjuvant chemotherapy is unclear[17, 19–21]. This research work mainly focuses on the analysis of clinical and pathological features of UPS to confirm the prognostic factors correlated with the overall survival, metastatic survival and local survival. We aimed to provide a more effective surgical approach by statistically evaluating the prognosis in 166 UPS patients in trunk and extremity.

Materials And Methods

Results

The overall survival (OS) rate of 166 UPS patients was 75.3% (125/166) until the end of follow-up, while the 3- and 5-year OS rates were 81.7% and 76.4%, respectively. In our study, univariate analysis reveals that prognostic factors i.e., older (> 60 years), local recurrence at diagnosis, tumor size (> 5cm), AJCC stage (III) and R1/R2 were considerably associated with the poor OS rate (P-value < 0.05) (Table 4; Fig. 3I,3J,3K, 3L). The effective results of the univariate analysis were incorporated into the cox multivariate analysis which confirms the two independent factors i.e., trunk (P = 0.026, HR = 4.964) and R1/R2 (P = 0.001, HR = 10.182) which correlated with a poorer OS, as presented in Table 4.

In the analysis of prognostic factors affecting the overall survival of soft tissue sarcoma, chemotherapy has always been the focus of controversy. In this study, in 54 patients with metastases, whether chemotherapy or not was significantly related to overall prognosis.

Discussion

UPS, called malignant fibrous histiocytoma (MFH) previously, which was recognized as the most common STS in adults, accounting for 50% of diagnoses. However, the pathological diagnosis of UPS shown no evidence of true histiocytic differentiation, meaning it encompasses the morphologic manifestations of a variety of poorly differentiated tumors rather than being a single entity.[14] So the diagnosis and treatment of UPS are still highly challenging because of the confused pathological classification. MRI is commonly used as a non-invasive effective diagnostic tool for STS. Characteristics of UPS in the MRI are mostly presented as the irregular, lobular, or oval-shaped tumors with a large scale, sometimes necrosis and liquefaction can be found in the center of mass.

R1/R2 resection margins identified as predictors of poor outcomes. Herein, the R0 resection margin was an only independent favorable prognostic factor that was correlated with LRFS, DMFS, and OS. The resection margin was found to be the prognostic factor that was effectively correlated with the duration of survival. Peiper et al.[12] proposed that positive microscopic margins were correlated with an elevated local recurrence rate (RR = 4.8, P-value < 0.01). Özkurt et al.[23] studied 14 cases of confirmed bone UPS and it was found that the 5-year survival rate of patients with wide resection and border resection were 81.9% and 33.3% (P-value < 0.05), which reveals that surgical excision with wide margins and adjuvant chemotherapy provided adequate control of the disease and longer survival. Just like some article says that surgery striving for negative margins, with radiotherapy, is the treatment of choice.[10, 14, 22]

With respect to tumor size, winchester et al.[24] evaluated the prognostic factors of 319 UPS patients and revealed that tumor size (greater than 5 cm) and deep subcutaneous fat infiltration were significant factors that affect the local recurrence rate. In the existing study, compared with those with tumor sizes ≤ 5cm and > 5cm, the 5-year LR, DM and OS rates decreased by 11.3%, 18.4% and 16.7%, respectively. (Table 2) The extensive analysis of the data of more cases may contribute to better resolve the underlined problem.

The metastasis predominantly occurs in the lungs[10, 25] relative to regional lymph nodes[26]. Winchester et al.[13] suggested that the main factors that affect the distant metastasis of UPS were the tumor site, tumor size larger than 2cm, invasion beyond subcutaneous fat, and lymphovascular invasion. In the existing study, cox multivariate survival analysis found that > 60 years were at a higher risk of metastasis than the younger patients, and the chances of metastasis were lower in the R0 resection margin, as presented in Table 3. Furthermore, in multivariate analysis, the tumor site was an independent predictor correlated with DMFS, as depicted in Fig. 3F. Our findings of increased metastatic disease for the UPS in trunk is likely due to trunk tumors being more possibility and visible to hematogenous metastasis in the early stages of disease.

In the analysis of OS, the Cox multivariate survival analysis revealed that tumor site (P = 0.026), tumor size (P = 0.048), AJCC stage (P = 0.048), and resection quality (P = 0.001) were independent factors that affect postsurgical survival in UPS patients (all P-value < 0.05), as represented in Table 4. According to our cohort, for the patients having tumors of the trunk, the tumor size ≥ 5 cm and R1/R2, a more significant and effective approach should be adopted. Winchester et al.[24] found that age, immunosuppression, tumor size larger than 2 cm, and lymphovascular invasion were independent risk factors affecting overall prognosis. Simultaneously, the existing study revealed that patients with severe subcutaneous fatty infiltration of tumors had a bad prognosis rate. In the AJCC staging system, tumor size and tumor depth were significantly associated with the prognosis.

In the AJCC staging guidelines, tumor size is an important criteria for the judgment of soft tissue staging. Univariate analysis revealed that the size of the tumor was not considerably associated with LRFS and DMFS, but was closely associated with OS (P = 0.012), as shown in Fig. 2K. In multivariate analysis, tumor size (≥ 5cm) was not an independent prognostic factor affecting LRFS, DMFS, and OS (all P > 0.05). Furthermore, in 2009, Lehnhardt et al.[16] also shown that tumor size ≥ 5 cm was considerably associated with the OS, which was in line with Chen and Al-Agha[25, 27]. Peiper et al.[12] found that tumor size (RR = 6.0, P༜0.01) was a significant factor that affects the DFS of UPS patients. Larger tumors suggest a higher ability to divide and proliferate, a wider range of invasion, a higher degree of malignancy, and more complicated surgical methods, so the first visit to the professional sarcoma center is critical.

In the existing study, Univariate K-M analysis revealed that the local recurrence at diagnosis was a significant factor that affects the local recurrence rate, distant metastasis rate, and OS rate (P-value < 0.05). But in multivariate analysis, the presentation of tumor was not an independent prognostic factor affecting local recurrence rate, distant metastasis rate, and OS rate, with P values ​​of 0.076, 0.091, and 0.162, respectively. Lehnhardt et al.[16] shown that a considerable variation was found between the group presenting with primary tumors (5-year survival: 84%, P-value < 0.05) and recurrent tumors (5-year survival: 62%, P-value < 0.05), which is correlated with our existing research work. The prognosis for patients with UPS of the extremities depends predominantly on adequate wide resection of the primary tumor, which is same to the idea that complete surgical resection was the most important UPS treatment strategy for UPS[17]. In short, the local recurrence at diagnosis and then R0 resection in the first therapy may play a crucial role in patient prognosis.

The value of adjuvant radiotherapy and chemotherapy in the diagnosis and treatment of soft tissue sarcoma has been mixed. Radiotherapy is mostly considered to be an effective mean to control local tumor recurrence, but in this study, it was not found that radiotherapy has any significance in the control of UPS. Trials from Gronchi suggested an overall survival benefit with five cycles of adjuvant full-dose epirubicin plus ifosfamide in localised high-risk soft-tissue sarcoma of the extremities or trunk wall[28, 29]. Adjuvant chemotherapy was associated with improved LRFS only in patients >/= 30 years[30]. Pazopanib and immune checkpoint inhibitors are a new attempt in UPS treatment[31–33]. Undifferentiated pleomorphic sarcoma is an immunologically active subtype of soft tissue sarcoma, which is particularly amenable to immune checkpoint inhibitors[33]. Immunohistochemical biomarkers significantly contribute to predicting the rate of recurrence, metastasis, and OS rate. A significant predictive index for evaluating the effect of VEGFR receptor inhibitors in the treatment of advanced soft tissue sarcoma, TP53 plays a significant role in the diagnosis and treatment of UPS[34].

As a retrospective study, although this study has given us a crucial hint, there are some shortcomings in the existing study. Firstly, the statistics on chemotherapy and radiotherapy are not sufficient due to the low incidence rate of the underlined disease, limited samples, and a large time span and the significant evaluation of the adjuvant therapy is also very difficult. Nevertheless, the accumulation and analysis of more comprehensive medical data for UPS can objectively reflect the characteristics and outcome of the disease that needs to be improved.

Conclusion

The existing study determines that the UPS in trunk and R1/R2 resection margin are prognostic markers of poor over survival. R1/R2 resection margin significantly correlated with high local recurrence rate and women are more susceptible to LR. The UPS in trunk and R1/R2 resection margin are significantly correlated with distant metastasis and old patients (> 60 years) are more susceptible to distant metastasis. Therefore, an extensive study on the molecular mechanism is needed to explore the targeted therapy and feasibility of immune checkpoint inhibitors.[17, 35–37]

Abbreviations

Soft tissue sarcoma (STS)

Undifferentiated Pleomorphic Sarcoma (UPS)

Malignant Fibrous Histiocytoma (MFH)

World Health Organization (WHO)

American Joint Committee on Cancer (AJCC)

Declarations

Ethics approval and consent to participate:

The study was established, according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital. Written informed consent was obtained from individual or guardian participants.

Consent for publication:

Not applicable.

Availability of data and material:

All data generated or analysed during this study are included in this published article.

Competing interests:

The authors declare that they have no competing interests.

Fund：

(1) CAMS Innovation Fund for Medical Sciences (CIFMS) (no. 2017-I2M-1-005)

(2) Beijing Hope Run Special Fund of Cancer Foundation of China (no. LC2016L01)

(3) Capital Characterized Clinical Application Research Fund of Beijing Municipal Science and Technology Commission of China (Z171100001017210)

(4) Clinical Research Special Fund of Wu Jieping Medical Foundation（320.6750.14298）

Authors' contributions:

All authors were involved in the preparation of this manuscript. Conception and design：SGZ and SJY；Analysis and interpretation: SGZ and SJY；Data collection: SGZ, CYJ and HML；Writing the article: SGZ；Critical revision of the article: ZGZ, LBX, SFX, XXZ,TL and SGY. All authors read and approved the final manuscript.

Acknowledgements:

We appreciated all the authors and UPS patients in this article.

References

1. Singer S, Demetri GD, Baldini EH, Fletcher CD: Management of soft-tissue sarcomas: an overview and update. Lancet Oncol 2000, 1:75–85.
2. Penel N, Coindre JM, Giraud A, Terrier P, Ranchere-Vince D, Collin F, Guellec SLE, Bazille C, Lae M, de Pinieux G et al: Presentation and outcome of frequent and rare sarcoma histologic subtypes: A study of 10,262 patients with localized visceral/soft tissue sarcoma managed in reference centers. Cancer 2018, 124(6):1179–1187.
3. Delisca GO, Mesko NW, Alamanda VK, Archer KR, Song Y, Halpern JL, Schwartz HS, Holt GE: MFH and high-grade undifferentiated pleomorphic sarcoma-what's in a name? J Surg Oncol 2015, 111(2):173–177.
4. Matushansky I, Charytonowicz E, Mills J, Siddiqi S, Hricik T, Cordon-Cardo C: MFH classification: differentiating undifferentiated pleomorphic sarcoma in the 21st Century. Expert Rev Anticancer Ther 2009, 9(8):1135–1144.
5. O'Brien JE, Stout AP: Malignant Fibrous Xanthomas. Cancer 1964, 17:1445–1455.
6. Weiss SW, Enzinger FM: Malignant fibrous histiocytoma: an analysis of 200 cases. Cancer 1978, 41(6):2250–2266.
7. Fletcher CD: The evolving classification of soft tissue tumours - an update based on the new 2013 WHO classification. Histopathology 2014, 64(1):2–11.
8. Jo VY, Fletcher CD: WHO classification of soft tissue tumours: an update based on the 2013 (4th) edition. Pathology 2014, 46(2):95–104.
9. Lewin J, Garg S, Lau BY, Dickson BC, Traub F, Gokgoz N, Griffin AM, Ferguson PC, Andrulis IL, Sim HW et al: Identifying actionable variants using next generation sequencing in patients with a historical diagnosis of undifferentiated pleomorphic sarcoma. Int J Cancer 2018, 142(1):57–65.
10. Chamale JB, Bruno M, Mandojana F, Jose L, Armando L, Alejandro D: Malignant fibrous histiocytoma in the right portion of the mandible with metastasis in pancreas. Int J Surg Case Rep 2017, 41:71–75.
11. Boccalatte LA, Gomez NL, Yanzon A, Mazzaro EL, Cayol F, Figari MF: Head and Neck Tumors: Management of Primary Undifferentiated Pleomorphic Sarcoma. Iran J Otorhinolaryngol 2019, 31(107):335–342.
12. Peiper M, Zurakowski D, Knoefel WT, Izbicki JR: Malignant fibrous histiocytoma of the extremities and trunk: an institutional review. Surgery 2004, 135(1):59–66.
13. Beck AH, West RB, van de Rijn M: Gene expression profiling for the investigation of soft tissue sarcoma pathogenesis and the identification of diagnostic, prognostic, and predictive biomarkers. Virchows Arch 2010, 456(2):141–151.
14. Vodanovich DA, Spelman T, May D, Slavin J, Choong PFM: Predicting the prognosis of undifferentiated pleomorphic soft tissue sarcoma: a 20-year experience of 266 cases. ANZ J Surg 2019, 89(9):1045–1050.
15. Malik AT, Baek J, Alexander JH, Voskuil RT, Khan SN, Scharschmidt TJ: Malignant fibrous histiocytoma of bone: A survival analysis from the National Cancer Database. J Surg Oncol 2020, 121(7):1097–1103.
16. Lehnhardt M, Daigeler A, Homann HH, Schwaiberger V, Goertz O, Kuhnen C, Steinau HU: MFH revisited: outcome after surgical treatment of undifferentiated pleomorphic or not otherwise specified (NOS) sarcomas of the extremities -- an analysis of 140 patients. Langenbecks Arch Surg 2009, 394(2):313–320.
17. Lee K, Song JS, Kim JE, Kim W, Song SY, Lee MH, Chung HW, Cho KJ, Lee JS, Ahn JH: The clinical outcomes of undifferentiated pleomorphic sarcoma (UPS): A single-centre experience of two decades with the assessment of PD-L1 expressions. Eur J Surg Oncol 2020, 46(7):1287–1293.
18. Weitz J, Antonescu CR, Brennan MF: Localized extremity soft tissue sarcoma: improved knowledge with unchanged survival over time. J Clin Oncol 2003, 21(14):2719–2725.
19. Ibanez MA, Rismiller K, Knackstedt T: Prognostic factors, treatment, and survival in cutaneous pleomorphic sarcoma. J Am Acad Dermatol 2020, 83(2):388–396.
20. Gronchi A, Palmerini E, Quagliuolo V, Martin Broto J, Lopez Pousa A, Grignani G, Brunello A, Blay JY, Tendero O, Diaz Beveridge R et al: Neoadjuvant Chemotherapy in High-Risk Soft Tissue Sarcomas: Final Results of a Randomized Trial From Italian (ISG), Spanish (GEIS), French (FSG), and Polish (PSG) Sarcoma Groups. J Clin Oncol 2020, 38(19):2178–2186.
21. Goertz O, Pieper A, Lohe LV, Stricker I, Dadras M, Behr B, Lehnhardt M, Harati K: The Impact of Surgical Margins and Adjuvant Radiotherapy in Patients with Undifferentiated Pleomorphic Sarcomas of the Extremities: A Single-Institutional Analysis of 192 Patients. Cancers (Basel) 2020, 12(2).
22. Kamat NV, Million L, Yao DH, Donaldson SS, Mohler DG, van de Rijn M, Avedian RS, Kapp DS, Ganjoo KN: The Outcome of Patients With Localized Undifferentiated Pleomorphic Sarcoma of the Lower Extremity Treated at Stanford University. Am J Clin Oncol 2019, 42(2):166–171.
23. Ozkurt B, Basarir K, Yildiz YH, Kalem M, Saglik Y: Primary malignant fibrous histiocytoma of long bones: long-term follow-up. Eklem Hastalik Cerrahisi 2016, 27(2):94–99.
24. Winchester D, Lehman J, Tello T, Chimato N, Hocker T, Kim S, Chang J, Markey J, Yom SS, Ryan W et al: Undifferentiated pleomorphic sarcoma: Factors predictive of adverse outcomes. J Am Acad Dermatol 2018, 79(5):853–859.
25. Chen S, Huang W, Luo P, Cai W, Yang L, Sun Z, Zheng B, Yan W, Wang C: Undifferentiated Pleomorphic Sarcoma: Long-Term Follow-Up from a Large Institution. Cancer Manag Res 2019, 11:10001–10009.
26. Senel FC, Bektas D, Caylan R, Onder E, Gunhan O: Malignant fibrous histiocytoma of the mandible. Dentomaxillofac Radiol 2006, 35(2):125–128.
27. Al-Agha OM, Igbokwe AA: Malignant fibrous histiocytoma: between the past and the present. Arch Pathol Lab Med 2008, 132(6):1030–1035.
28. Gronchi A, Ferrari S, Quagliuolo V, Broto JM, Pousa AL, Grignani G, Basso U, Blay JY, Tendero O, Beveridge RD et al: Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol 2017, 18(6):812–822.
29. Gronchi A, Stacchiotti S, Verderio P, Ferrari S, Martin Broto J, Lopez-Pousa A, Llombart-Bosch A, Dei Tos AP, Collini P, Jurado JC et al: Short, full-dose adjuvant chemotherapy (CT) in high-risk adult soft tissue sarcomas (STS): long-term follow-up of a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. Ann Oncol 2016, 27(12):2283–2288.
30. Kasper B, Ouali M, van Glabbeke M, Blay JY, Bramwell VH, Woll PJ, Hohenberger P, Schoffski P: Prognostic factors in adolescents and young adults (AYA) with high risk soft tissue sarcoma (STS) treated by adjuvant chemotherapy: a study based on pooled European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62771 and 62931. Eur J Cancer 2013, 49(2):449–456.
31. Kim HJ, Kim Y, Lee SJ, Lee J, Park SH: Pazopanib monotherapy in the treatment of pretreated, metastatic uterine sarcoma: a single-center retrospective study. J Gynecol Oncol 2018, 29(1):e3.
32. Guram K, Nunez M, Einck J, Mell LK, Cohen E, Sanders PD, Miyauchi S, Weihe E, Kurzrock R, Boles S et al: Radiation Therapy Combined With Checkpoint Blockade Immunotherapy for Metastatic Undifferentiated Pleomorphic Sarcoma of the Maxillary Sinus With a Complete Response. Front Oncol 2018, 8:435.
33. Arora S, Rastogi S, Shamim SA, Barwad A, Sethi M: Good and sustained response to pembrolizumab and pazopanib in advanced undifferentiated pleomorphic sarcoma: a case report. Clin Sarcoma Res 2020, 10:10.
34. Movva S, Wen W, Chen W, Millis SZ, Gatalica Z, Reddy S, von Mehren M, Van Tine BA: Multi-platform profiling of over 2000 sarcomas: identification of biomarkers and novel therapeutic targets. Oncotarget 2015, 6(14):12234–12247.
35. Monga V, Skubitz KM, Maliske S, Mott SL, Dietz H, Hirbe AC, Van Tine BA, Oppelt P, Okuno S, Robinson S et al: A Retrospective Analysis of the Efficacy of Immunotherapy in Metastatic Soft-Tissue Sarcomas. Cancers (Basel) 2020, 12(7).
36. Miyake M, Oda Y, Nishimura N, Morizawa Y, Ohnishi S, Hatakeyama K, Fujii T, Hori S, Gotoh D, Nakai Y et al: Integrative assessment of clinicopathological parameters and the expression of PD-L1, PD-L2 and PD-1 in tumor cells of retroperitoneal sarcoma. Oncol Lett 2020, 20(5):190.
37. Keung EZ, Burgess M, Salazar R, Parra ER, Rodrigues-Canales J, Bolejack V, Van Tine BA, Schuetze SM, Attia S, Riedel RF et al: Correlative Analyses of the SARC028 Trial Reveal an Association Between Sarcoma-Associated Immune Infiltrate and Response to Pembrolizumab. Clin Cancer Res 2020, 26(6):1258–1266.