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Early Lymph Node Metastasis May Predict Poor Prognosis in Soft Tissue Sarcoma

Early Lymph Node Metastasis May Predict Poor Prognosis in Soft Tissue Sarcoma Hindawi International Journal of Surgical Oncology Volume 2019, Article ID 6708474, 5 pages https://doi.org/10.1155/2019/6708474 Research Article Early Lymph Node Metastasis May Predict Poor Prognosis in Soft Tissue Sarcoma 1 2 2 3 Makoto Emori , Hiroyuki Tsuchie , Hiroyuki Nagasawa, Tomoko Sonoda, 1 1 1 1 Arihiko Tsukamoto, Junya Shimizu, Yasutaka Murahashi, Emi Mizushima, 4 4 5 5 5 Kohichi Takada, Kazuyuki Murase, Kotoe Iesato, Keita Igarashi, Tsukasa Hori, 5 6 2 6 Masaki Yamamoto, Shintaro Sugita, Naohisa Miyakoshi , Tadashi Hasegawa, 2 1 Yoichi Shimada, and Toshihiko Yamashita Department of Orthopedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Hokkaido 060-8543, Japan Department of Orthopedic Surgery, Akita University School of Medicine, Akita, Akita 010-8543, Japan Department of Public Health, Sapporo Medical University School of Medicine, Sapporo, Hokkaido 060-8543, Japan Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido 060-8543, Japan Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Hokkaido 060-8543, Japan Department of Diagnostic Pathology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido 060-8543, Japan Correspondence should be addressed to Makoto Emori; emrmkt@yahoo.co.jp Received 24 March 2019; Revised 19 September 2019; Accepted 25 October 2019; Published 12 December 2019 Academic Editor: C. H. Yip Copyright © 2019 Makoto Emori et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Lymph node metastasis (LNM) is a relatively rare event in soft tissue sarcoma. An association between the timing of LNM detection and patient prognosis is presently unknown. Patients and Methods. We retrospectively analyzed the clinico- pathological features of 33 patients with LNM between 2001 and 2015. Analysis of the timing of LNM diagnosis was grouped according to patients presenting LNM in either <8 months (the median time from primary tumor diagnosis to LNM) or ≥8 months after primary tumor diagnosis. Results. A relationship between the primary tumor size and the timing of the LNM was not significantly found (Rs � 0.0088, p � 0.96). Sixteen patients had an LNM detection duration of<8 months, and 17 patients had a duration of≥8 months. *e 5-year survival for patients with an LNM detection duration of<8 months and≥8 months was 19% and 71%, respectively (p � 0.0016). *ere were 19 patients with pulmonary metastases. Among them, there were 13 patients with a duration of primary tumor diagnosis to LNM of <8 months and 6 with a duration of ≥8 months (p � 0.01). Conclusion. Early LNM (<8 months) may predict poor prognosis in soft tissue sarcoma. Lymph node metastasis (LNM) is a relatively rare event 1. Introduction in STS, except for lymphogenous histotypes such as rhab- Distant metastasis is common in patients with soft tissue domyosarcoma, epithelioid sarcoma, and clear cell sarcoma sarcoma (STS) of the extremities, occurring in about 25% of [6]. *e overall prevalence is 1.75–12% with an increasing patients [1, 2]. Pulmonary metastasis is the most common form frequency due to the implementation of FDG-PET for whole of metastatic disease. *e median survival after a diagnosis of body screening [7, 8]. Regional LNM is an important distant metastatic disease was approximately 12 months, with a prognostic factor in STS, suggesting that LNM represents a 5-year survival of about 10% [3]. However, several studies have component of disseminated disease [7, 9]. Unlike pulmonary suggested that surgical management of pulmonary metastasis metastasis, the precise role of lymphadenectomy remains to has achieved 5-year survival rates of 30% or more [4, 5]. be defined because LNM in patients with STS is rare, thereby 2 International Journal of Surgical Oncology limiting the feasibility of well-designed prospective studies performed for analyzing the relationship between the pul- to establish the role of lymphadenectomy. *ere are some monary metastases as a dependent variable and the timing of reports describing an association between the time from the LNM diagnosis as an independent variable. OS was esti- primary STS diagnosis to LNM and patient prognosis mated using the Kaplan–Meier method, with any differences [10, 11]. However, the precise duration, from primary di- in survival being determined using the log-rank test. A agnosis to detection of LNM, affecting overall survival (OS) probability of p< 0.05 was considered statistically signifi- is unknown. cant. Statistical analyses were performed with SPSS, version *e objective of this study was to analyze the clinico- 23 (IBM Corp., Armonk, NY, USA). pathological features and patterns of LNM, focusing on the time duration from the primary diagnosis to the detection of 4. Results LNM. 4.1. Clinicopathological Characteristics. Patient de- mographics, primary diagnosis, tumor site, tumor size, tu- 2. Patients and Methods mor grade, surgical stage, treatment for the primary tumor, 2.1. Patients. We retrospectively reviewed the oncology/ type of surgery, and pulmonary metastasis are shown in reconstruction surgery database of our institutions. *irty- Table 1. Tumors were located in the upper extremities, the three patients with LNMs who were treated at two hospitals lower extremities, and the trunk (including the chest wall, (Sapporo Medical University Hospital and Akita University back wall, and buttocks) in 10, 17, and 6 patients, re- Hospital) between 2001 and 2015 (19 males and 14 females, spectively. *e most frequent histology was myxofi- with a median age of 61 years) were enrolled. *e time to brosarcoma, undifferentiated pleomorphic sarcoma, metastasis was defined as the period from the initial di- rhabdomyosarcoma, and epithelioid sarcoma. Twenty-seven agnosis of the primary tumor to the detection of LNM. *e patients (82%) underwent surgery (wide resection and surgical stage was classified according to the seventh edition intralesional). Two patients received carbon ion radiother- of the tumor-node-metastasis (TNM) classification of the apy. Four patients received no therapy. *ere were 19 pa- International Union Against Cancer at initial presentation. tients with pulmonary metastasis. *e 5-year OS rate of the *e histological grade was determined on the basis of the 33 patients with LNMs was 45.5% (Figure 1). French Federation of Cancer Centers (FNCLCC) grading system. *is classification is based on the mitotic index, 4.2. Association between the Primary Tumor Size and the extent of necrosis, and degree of histological differentiation Timing of LNM Diagnosis. *e average tumor size was of the tumor. *is study was approved by the Institutional 75 mm (range 17–183 mm). *e average time from the Review Board for Clinical Research at our universities. primary tumor diagnosis to LNM was 18.8 months (range Patients were reviewed at 3-month intervals until 3 years 0–144 months). *e median time from the primary tumor after the primary tumor diagnosis, then at 6-month intervals diagnosis to LNM was 8 months. We investigated if there until 5 years after the primary tumor diagnosis, and then at was a relationship between the primary tumor size and the 12-month intervals for the rest of the patient’s life. A timing of LNM using Spearman rank analysis; there was no computed tomography scan of the chest and a localized significant correlation found (Rs � 0.0088, p � 0.96). magnetic resonance imaging scan were performed every 3 months during the third year after primary tumor diagnosis and every 6 months thereafter. 4.3. Association between the Time of LNM Diagnosis and Pulmonary Metastasis. *ere were 16 patients with a du- ration from primary tumor diagnosis to detection of LNM of 2.2. Definition and Treatment Strategy of LNM. We defined <8 months (the median time from primary tumor diagnosis LNM as growing nodes and irregular borders, as detected on to LNM) and 17 with a duration of ≥8 months. Next, we CT or MRI (n � 6), or diagnosed as LNM after biopsy or investigated if there was an association between the timing of resection (n � 27). Patients with isolated LNMs were mainly LNM diagnosis and prognosis. *e 5-year OS of patients treated with surgery as the primary modality. Patients with a with a duration of primary tumor diagnosis to LNM of <8 surgically inaccessible location, extensive nodal disease, or months and those with a duration of ≥8 months was 19% systemic dissemination were treated primarily with che- and 71%, respectively (p � 0.0016) (Figure 2). *ere were 19 motherapy or radiotherapy. patients with pulmonary metastases. Among them, there were 13 patients with a duration of primary tumor diagnosis 3. Statistical Methods to LNM of <8 months and 6 with a duration of ≥8 months OS was defined as the time interval between the date of (p � 0.01). *e median time from primary tumor diagnosis initial patient presentation and either the date of death from to pulmonary metastasis was 6 months (range 0–72 any cause or the date of the last patient contact. Spearman months). All LNMs developed earlier than pulmonary rank correlation coefficients were used to determine any metastases, except for 1 patient. Fisher’s exact test and association between the primary tumor size and the timing Mann–Whitney test were used to compare the timing of the of LNM diagnosis. Fisher’s exact test and Mann–Whitney U LNM diagnosis and the clinicopathological factors. *e test were used to compare the timing of LNM diagnosis and following factors were evaluated: sex, tumor size, tumor the clinicopathological factors. Logistic regression was location (trunk or extremity), presence or absence of International Journal of Surgical Oncology 3 Table 1: Characteristics of the study patients. 0.9 No. Follow-up period (months) Median 56 (1–216) 0.8 Age at diagnosis (y) Median 61 (3–89) 0.7 <50 7 0.6 ≥50 26 0.5 Gender 0.4 Male 19 Female 14 0.3 Tumor site 0.2 Upper extremity 10 0.1 Lower extremity 17 Trunk 6 0 50 100 150 200 250 Tumor location Months Superficial 4 Deep 29 Figure 1: 5-year OS rate of patients with lymph node metastases. Tumor size (cm) <5 8 ≥5 25 Histology 0.9 Myxofibrosarcoma 8 0.8 ≧8 months Undifferentiated pleomorphic sarcoma 6 0.7 Rhabdomyosarcoma 5 0.6 Epithelioid sarcoma 4 Dedifferentiated liposarcoma 3 0.5 Myxoid liposarcoma 2 0.4 Log-rank Pleomorphic liposarcoma 2 <8 months 0.3 p = 0.0016 Synovial sarcoma 1 0.2 Leiomyosarcoma 1 0.1 Malignant peripheral nerve sheath tumor 1 Tumor grade 0 50 100 150 200 250 1 2 Months 2 8 Figure 2: 5-year OS rate of patients with time of diagnosis for 3 23 lymph node metastases of <8 months and ≥8 months. Surgical stage IB 1 IIA 4 IIB 5 Table 2: Results of logistic regression analysis. III 19 95% CI for HR IV 4 Hazard ratio p value Lower Upper Treatment for the primary tumor Surgery: presence 1.114 0.0077 16.116 0.937 Surgery 27 Carbon ion 2 LNM: <8 months 6.381 1.031 39.506 0.046 None 4 Type of surgery Intralesional excision 2 significant variable (p � 0.046) (Table 2). *e 5-year OS of Marginal excision 5 patients with pulmonary metastasis and those with LNM Wide excision 20 alone was 17% and 80%, respectively (p � 0.00019). Pulmonary metastasis Absent 14 Present 19 4.4. Treatment for LNM. Surgery was the most common surgery, age, tumor grade, and stage. *e significant con- treatment modality for LNM. *e number of patients receiving LNM treatment with surgery, surgery + chemotherapy, sur- founding factor was presence or absence of surgery (p � 0.04). Next, logistic regression was performed for gery + radiation, chemotherapy, chemotherapy + radiation, and radiation was 3, 5, 3, 9, 4, and 2. Seven patients received no analyzing the relationship between the pulmonary metas- tases as a dependent variable and the timing of LNM di- treatment. Patient demographics are shown in Table 3. *e 5- year OS rate of patients receiving any treatment and those agnosis as an independent variable. Presence or absence of surgery was used as an independent variable to adjust for receiving no treatment was 50% and 29%, respectively (p � 0.14) (Figure 3). confounding factors. *e timing of LNM diagnosis was the Cumulative survival Cumulative survival 4 International Journal of Surgical Oncology Table 3: Characteristics of no-treatment patients for LNM. 0.9 No. 0.8 Age at diagnosis (y) Median 74 (61–79) 0.7 <50 0 Any treatment 0.6 ≥50 7 0.5 Gender 0.4 Male 4 Female 3 0.3 Log-rank p = 0.14 Tumor site 0.2 No treatment Upper extremity 1 0.1 Lower extremity 4 Trunk 2 0 50 100 150 200 250 Tumor location Months Superficial 0 Figure 3: 5-year OS rate of patients receiving any treatment and Deep 7 those receiving no treatment for lymph node metastasis. Tumor size (cm) <5 1 ≥5 6 as rhabdomyosarcoma, epithelioid sarcoma, and clear cell sarcoma may be a result of the small sample size of this Histology Myxofibrosarcoma 2 study, resulting in relatively good OS. Although myxofi- Undifferentiated pleomorphic sarcoma 1 brosarcoma has a high rate of local recurrence, the overall Epithelioid sarcoma 1 risk of distant metastases is relatively low compared to that Dedifferentiated liposarcoma 1 of other sarcoma subtypes; the 5-year local recurrence rate Myxoid liposarcoma 1 has been reported to be 18–31%, with corresponding OS Malignant peripheral nerve sheath tumor 1 rates of approximately 70% [12–14]. *e low risk of distant Tumor grade metastasis is a factor for the relatively good OS associated 1 0 with myxofibrosarcoma. 2 4 Some reports describe that the survival of patients with 3 3 LNM at diagnosis is similar to that of patients who later Surgical stage develop LNM [10, 11]. *erefore, we examined which time IB 0 duration from primary diagnosis to detection of LNM IIA 1 influenced OS. Of the 33 patients with LNM, there were 19 IIB 3 patients with pulmonary metastases. All LNMs developed III 2 earlier than the pulmonary metastases, except for 1 patient. IV 1 *ere were 13 patients with a duration from the primary Treatment for the primary tumor diagnosis to LNM detection of <8 months and 6 with a Surgery 5 Carbon ion 1 duration of≥8 months (p � 0.01). *e 5-year OS of patients None 1 with a duration from the primary diagnosis to LNM de- Type of surgery tection of<8 months and that of patients with a duration of Intralesional excision 1 ≥8 months were 19% and 71%, respectively (p � 0.0016). Marginal excision 1 *erefore, a short duration from primary diagnosis to LNM Wide excision 3 detection (<8 months) may predict a shorter survival, as well Pulmonary metastasis as possibly representing a component of disseminated Absent 4 disease. Present 3 In our study, it was demonstrated that any treatments for LNM did not result in a better survival than that of patients receiving no treatment. *e potential benefit of lympha- 5. Discussion denectomy remains to be defined. Lymphadenectomy has been shown to improve long-term survival [15, 16], while *e current study revealed that (1) most LNMs occur earlier than pulmonary metastases and (2) survival from LNM radical lymphadenectomy does not confer a substantial survival benefit [9, 10]. *is study suggests that early LNM depends on the time duration from primary STS diagnosis to (<8 months of duration from the primary tumor diagnosis) detection of LNM, and an early diagnosis of LNM (<8 may have less impact to decide on an aggressive treatment months) may predict poor prognosis. for LNM. *e 5-year survival for patients with LNM from STS is reported to be 12.8% to 34.1% [7, 9, 10]. In our study, the 5- We acknowledge several limitations of this study: First, there were a limited number of patients with LNM. Second, year OS was 45.5%. *e most common subtype of LNM was myxofibrosarcoma and undifferentiated pleomorphic sar- our study was limited by the fact that imaging assessment (CTor MRI) was used to examine the regional lesions at 3- to coma. *e low prevalence of lymphogenous histotypes such Cumulative survival International Journal of Surgical Oncology 5 [7] A. Daigeler, C. Kuhnen, R. Moritz et al., “Lymph node me- 6-month intervals. *erefore, we cannot detect all LNMs tastases in soft tissue sarcomas-a single center analysis of 1,597 unless the patient presents with lymph node swelling. *ird, patients,” Langenbeck’s Archives of Surgery, vol. 394, no. 2, we used a retrospective study design and not a single in- pp. 321–329, 2009. stitutional study design. Fourth, several different histologic [8] T. Yanagawa, K. Saito, and K. Takagishi, “Risk factors for tumors were included. Fifth, treatment was not performed in lymphatic metastasis of malignant bone and soft-tissue tu- a randomized, controlled fashion. mors: a retrospective cohort study of 242 patients,” Medicine, vol. 93, no. 27, p. e225, 2014. 6. Conclusion [9] E. Z. Keung, Y.-J. Chiang, R. K. Voss et al., “Defining the incidence and clinical significance of lymph node metastasis *is study demonstrated that early LNM (<8 months from in soft tissue sarcoma,” European Journal of Surgical Oncology, the primary diagnosis) may predict poor prognosis. vol. 44, no. 1, pp. 170–177, 2018. [10] C. Sawamura, S. Matsumoto, T. Shimoji, K. Ae, and A. Okawa, Data Availability “Lymphadenectomy and histologic subtype affect overall survival of soft tissue sarcoma patients with nodal metastases,” *e datasets generated and/or analyzed during the current Clinical Orthopaedics and Related Research, vol. 471, no. 3, study are available from the corresponding author on rea- pp. 926–931, 2013. sonable request. [11] W. B. Al-Refaie, R. H. I. Andtbacka, J. Ensor et al., “Lym- phadenectomy for isolated lymph node metastasis from ex- tremity soft-tissue sarcomas,” Cancer, vol. 112, no. 8, Ethical Approval pp. 1821–1826, 2008. [12] A. Gronchi, S. Lo Vullo, C. Colombo et al., “Extremity soft *is study was approved by the Institutional Review Board tissue sarcoma in a series of patients treated at a single in- for Clinical Research at Sapporo Medical University Hos- stitution: local control directly impacts survival,” Annals of pital and Akita University Hospital. Surgery, vol. 251, no. 3, pp. 506–511, 2010. [13] K. E. Haglund, C. P. Raut, A. F. Nascimento, Q. Wang, Conflicts of Interest S. George, and E. H. Baldini, “Recurrence patterns and sur- vival for patients with intermediate- and high-grade myx- *e authors declare that they have no conflicts of interest. ofibrosarcoma,” International Journal of Radiation Oncology∗Biology∗Physics, vol. 82, no. 1, pp. 361–367, 2012. Acknowledgments [14] R. Sanfilippo, R. Miceli, F. Grosso et al., “Myxofibrosarcoma: prognostic factors and survival in a series of patients treated at *is work was partly supported by the grant from JSPS a single institution,” Annals of Surgical Oncology, vol. 18, no. 3, KAKENHI (17K10974 to M. Emori). pp. 720–725, 2011. [15] Y. Fong, D. G. Coit, J. M. Woodruff, and M. F. Brennan, References “Lymph node metastasis from soft tissue sarcoma in adults analysis of data from a prospective database of 1772 sarcoma [1] C. S. Trovik, H. C. F. Bauer, T. A. Alvegard ˚ et al., “Surgical patients,” Annals of Surgery, vol. 217, no. 1, pp. 72–77, 1993. margins, local recurrence and metastasis in soft tissue sar- [16] S. Riad, A. M. Griffin, B. Liberman et al., “Lymph node comas: 559 surgically-treated patients from the Scandinavian metastasis in soft tissue sarcoma in an extremity,” Clinical sarcoma group register,” European Journal of Cancer, vol. 36, Orthopaedics and Related Research, vol. 426, pp. 129–134, no. 6, pp. 710–716, 2000. [2] P. W. Pisters, D. H. Leung, J. Woodruff, W. Shi, and M. F. Brennan, “Analysis of prognostic factors in 1,041 pa- tients with localized soft tissue sarcomas of the extremities,” Journal of Clinical Oncology, vol. 14, no. 5, pp. 1679–1689, [3] K. G. Billingsley, M. E. Burt, E. Jara et al., “Pulmonary me- tastases from soft tissue sarcoma: analysis of patterns of diseases and postmetastasis survival,” Annals of Surgery, vol. 229, no. 5, pp. 602–610, 1999. [4] S. Schur, K. Hoetzenecker, W. Lamm et al., “Pulmonary metastasectomy for soft tissue sarcoma—report from a dual institution experience at the Medical University of Vienna,” European Journal of Cancer, vol. 50, no. 13, pp. 2289–2297, [5] D. Jablons, S. M. Steinberg, J. Roth, S. Pittaluga, S. A. Rosenberg, and H. I. Pass, “Metastasectomy for soft tissue sarcoma: further evidence for efficacy and prognostic indicators,” 4e Journal of 4oracic and Cardiovascular Surgery, vol. 97, no. 5, pp. 695–705, 1989. [6] G. K. Zagars, M. T. Ballo, P. W. T. Pisters et al., “Prognostic factors for patients with localized soft-tissue sarcoma treated with conservation surgery and radiation therapy: an analysis of 1225 patients,” Cancer, vol. 97, no. 10, pp. 2530–2543, 2003. 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Early Lymph Node Metastasis May Predict Poor Prognosis in Soft Tissue Sarcoma

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Hindawi Publishing Corporation
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Copyright © 2019 Makoto Emori et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi International Journal of Surgical Oncology Volume 2019, Article ID 6708474, 5 pages https://doi.org/10.1155/2019/6708474 Research Article Early Lymph Node Metastasis May Predict Poor Prognosis in Soft Tissue Sarcoma 1 2 2 3 Makoto Emori , Hiroyuki Tsuchie , Hiroyuki Nagasawa, Tomoko Sonoda, 1 1 1 1 Arihiko Tsukamoto, Junya Shimizu, Yasutaka Murahashi, Emi Mizushima, 4 4 5 5 5 Kohichi Takada, Kazuyuki Murase, Kotoe Iesato, Keita Igarashi, Tsukasa Hori, 5 6 2 6 Masaki Yamamoto, Shintaro Sugita, Naohisa Miyakoshi , Tadashi Hasegawa, 2 1 Yoichi Shimada, and Toshihiko Yamashita Department of Orthopedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Hokkaido 060-8543, Japan Department of Orthopedic Surgery, Akita University School of Medicine, Akita, Akita 010-8543, Japan Department of Public Health, Sapporo Medical University School of Medicine, Sapporo, Hokkaido 060-8543, Japan Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido 060-8543, Japan Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Hokkaido 060-8543, Japan Department of Diagnostic Pathology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido 060-8543, Japan Correspondence should be addressed to Makoto Emori; emrmkt@yahoo.co.jp Received 24 March 2019; Revised 19 September 2019; Accepted 25 October 2019; Published 12 December 2019 Academic Editor: C. H. Yip Copyright © 2019 Makoto Emori et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Lymph node metastasis (LNM) is a relatively rare event in soft tissue sarcoma. An association between the timing of LNM detection and patient prognosis is presently unknown. Patients and Methods. We retrospectively analyzed the clinico- pathological features of 33 patients with LNM between 2001 and 2015. Analysis of the timing of LNM diagnosis was grouped according to patients presenting LNM in either <8 months (the median time from primary tumor diagnosis to LNM) or ≥8 months after primary tumor diagnosis. Results. A relationship between the primary tumor size and the timing of the LNM was not significantly found (Rs � 0.0088, p � 0.96). Sixteen patients had an LNM detection duration of<8 months, and 17 patients had a duration of≥8 months. *e 5-year survival for patients with an LNM detection duration of<8 months and≥8 months was 19% and 71%, respectively (p � 0.0016). *ere were 19 patients with pulmonary metastases. Among them, there were 13 patients with a duration of primary tumor diagnosis to LNM of <8 months and 6 with a duration of ≥8 months (p � 0.01). Conclusion. Early LNM (<8 months) may predict poor prognosis in soft tissue sarcoma. Lymph node metastasis (LNM) is a relatively rare event 1. Introduction in STS, except for lymphogenous histotypes such as rhab- Distant metastasis is common in patients with soft tissue domyosarcoma, epithelioid sarcoma, and clear cell sarcoma sarcoma (STS) of the extremities, occurring in about 25% of [6]. *e overall prevalence is 1.75–12% with an increasing patients [1, 2]. Pulmonary metastasis is the most common form frequency due to the implementation of FDG-PET for whole of metastatic disease. *e median survival after a diagnosis of body screening [7, 8]. Regional LNM is an important distant metastatic disease was approximately 12 months, with a prognostic factor in STS, suggesting that LNM represents a 5-year survival of about 10% [3]. However, several studies have component of disseminated disease [7, 9]. Unlike pulmonary suggested that surgical management of pulmonary metastasis metastasis, the precise role of lymphadenectomy remains to has achieved 5-year survival rates of 30% or more [4, 5]. be defined because LNM in patients with STS is rare, thereby 2 International Journal of Surgical Oncology limiting the feasibility of well-designed prospective studies performed for analyzing the relationship between the pul- to establish the role of lymphadenectomy. *ere are some monary metastases as a dependent variable and the timing of reports describing an association between the time from the LNM diagnosis as an independent variable. OS was esti- primary STS diagnosis to LNM and patient prognosis mated using the Kaplan–Meier method, with any differences [10, 11]. However, the precise duration, from primary di- in survival being determined using the log-rank test. A agnosis to detection of LNM, affecting overall survival (OS) probability of p< 0.05 was considered statistically signifi- is unknown. cant. Statistical analyses were performed with SPSS, version *e objective of this study was to analyze the clinico- 23 (IBM Corp., Armonk, NY, USA). pathological features and patterns of LNM, focusing on the time duration from the primary diagnosis to the detection of 4. Results LNM. 4.1. Clinicopathological Characteristics. Patient de- mographics, primary diagnosis, tumor site, tumor size, tu- 2. Patients and Methods mor grade, surgical stage, treatment for the primary tumor, 2.1. Patients. We retrospectively reviewed the oncology/ type of surgery, and pulmonary metastasis are shown in reconstruction surgery database of our institutions. *irty- Table 1. Tumors were located in the upper extremities, the three patients with LNMs who were treated at two hospitals lower extremities, and the trunk (including the chest wall, (Sapporo Medical University Hospital and Akita University back wall, and buttocks) in 10, 17, and 6 patients, re- Hospital) between 2001 and 2015 (19 males and 14 females, spectively. *e most frequent histology was myxofi- with a median age of 61 years) were enrolled. *e time to brosarcoma, undifferentiated pleomorphic sarcoma, metastasis was defined as the period from the initial di- rhabdomyosarcoma, and epithelioid sarcoma. Twenty-seven agnosis of the primary tumor to the detection of LNM. *e patients (82%) underwent surgery (wide resection and surgical stage was classified according to the seventh edition intralesional). Two patients received carbon ion radiother- of the tumor-node-metastasis (TNM) classification of the apy. Four patients received no therapy. *ere were 19 pa- International Union Against Cancer at initial presentation. tients with pulmonary metastasis. *e 5-year OS rate of the *e histological grade was determined on the basis of the 33 patients with LNMs was 45.5% (Figure 1). French Federation of Cancer Centers (FNCLCC) grading system. *is classification is based on the mitotic index, 4.2. Association between the Primary Tumor Size and the extent of necrosis, and degree of histological differentiation Timing of LNM Diagnosis. *e average tumor size was of the tumor. *is study was approved by the Institutional 75 mm (range 17–183 mm). *e average time from the Review Board for Clinical Research at our universities. primary tumor diagnosis to LNM was 18.8 months (range Patients were reviewed at 3-month intervals until 3 years 0–144 months). *e median time from the primary tumor after the primary tumor diagnosis, then at 6-month intervals diagnosis to LNM was 8 months. We investigated if there until 5 years after the primary tumor diagnosis, and then at was a relationship between the primary tumor size and the 12-month intervals for the rest of the patient’s life. A timing of LNM using Spearman rank analysis; there was no computed tomography scan of the chest and a localized significant correlation found (Rs � 0.0088, p � 0.96). magnetic resonance imaging scan were performed every 3 months during the third year after primary tumor diagnosis and every 6 months thereafter. 4.3. Association between the Time of LNM Diagnosis and Pulmonary Metastasis. *ere were 16 patients with a du- ration from primary tumor diagnosis to detection of LNM of 2.2. Definition and Treatment Strategy of LNM. We defined <8 months (the median time from primary tumor diagnosis LNM as growing nodes and irregular borders, as detected on to LNM) and 17 with a duration of ≥8 months. Next, we CT or MRI (n � 6), or diagnosed as LNM after biopsy or investigated if there was an association between the timing of resection (n � 27). Patients with isolated LNMs were mainly LNM diagnosis and prognosis. *e 5-year OS of patients treated with surgery as the primary modality. Patients with a with a duration of primary tumor diagnosis to LNM of <8 surgically inaccessible location, extensive nodal disease, or months and those with a duration of ≥8 months was 19% systemic dissemination were treated primarily with che- and 71%, respectively (p � 0.0016) (Figure 2). *ere were 19 motherapy or radiotherapy. patients with pulmonary metastases. Among them, there were 13 patients with a duration of primary tumor diagnosis 3. Statistical Methods to LNM of <8 months and 6 with a duration of ≥8 months OS was defined as the time interval between the date of (p � 0.01). *e median time from primary tumor diagnosis initial patient presentation and either the date of death from to pulmonary metastasis was 6 months (range 0–72 any cause or the date of the last patient contact. Spearman months). All LNMs developed earlier than pulmonary rank correlation coefficients were used to determine any metastases, except for 1 patient. Fisher’s exact test and association between the primary tumor size and the timing Mann–Whitney test were used to compare the timing of the of LNM diagnosis. Fisher’s exact test and Mann–Whitney U LNM diagnosis and the clinicopathological factors. *e test were used to compare the timing of LNM diagnosis and following factors were evaluated: sex, tumor size, tumor the clinicopathological factors. Logistic regression was location (trunk or extremity), presence or absence of International Journal of Surgical Oncology 3 Table 1: Characteristics of the study patients. 0.9 No. Follow-up period (months) Median 56 (1–216) 0.8 Age at diagnosis (y) Median 61 (3–89) 0.7 <50 7 0.6 ≥50 26 0.5 Gender 0.4 Male 19 Female 14 0.3 Tumor site 0.2 Upper extremity 10 0.1 Lower extremity 17 Trunk 6 0 50 100 150 200 250 Tumor location Months Superficial 4 Deep 29 Figure 1: 5-year OS rate of patients with lymph node metastases. Tumor size (cm) <5 8 ≥5 25 Histology 0.9 Myxofibrosarcoma 8 0.8 ≧8 months Undifferentiated pleomorphic sarcoma 6 0.7 Rhabdomyosarcoma 5 0.6 Epithelioid sarcoma 4 Dedifferentiated liposarcoma 3 0.5 Myxoid liposarcoma 2 0.4 Log-rank Pleomorphic liposarcoma 2 <8 months 0.3 p = 0.0016 Synovial sarcoma 1 0.2 Leiomyosarcoma 1 0.1 Malignant peripheral nerve sheath tumor 1 Tumor grade 0 50 100 150 200 250 1 2 Months 2 8 Figure 2: 5-year OS rate of patients with time of diagnosis for 3 23 lymph node metastases of <8 months and ≥8 months. Surgical stage IB 1 IIA 4 IIB 5 Table 2: Results of logistic regression analysis. III 19 95% CI for HR IV 4 Hazard ratio p value Lower Upper Treatment for the primary tumor Surgery: presence 1.114 0.0077 16.116 0.937 Surgery 27 Carbon ion 2 LNM: <8 months 6.381 1.031 39.506 0.046 None 4 Type of surgery Intralesional excision 2 significant variable (p � 0.046) (Table 2). *e 5-year OS of Marginal excision 5 patients with pulmonary metastasis and those with LNM Wide excision 20 alone was 17% and 80%, respectively (p � 0.00019). Pulmonary metastasis Absent 14 Present 19 4.4. Treatment for LNM. Surgery was the most common surgery, age, tumor grade, and stage. *e significant con- treatment modality for LNM. *e number of patients receiving LNM treatment with surgery, surgery + chemotherapy, sur- founding factor was presence or absence of surgery (p � 0.04). Next, logistic regression was performed for gery + radiation, chemotherapy, chemotherapy + radiation, and radiation was 3, 5, 3, 9, 4, and 2. Seven patients received no analyzing the relationship between the pulmonary metas- tases as a dependent variable and the timing of LNM di- treatment. Patient demographics are shown in Table 3. *e 5- year OS rate of patients receiving any treatment and those agnosis as an independent variable. Presence or absence of surgery was used as an independent variable to adjust for receiving no treatment was 50% and 29%, respectively (p � 0.14) (Figure 3). confounding factors. *e timing of LNM diagnosis was the Cumulative survival Cumulative survival 4 International Journal of Surgical Oncology Table 3: Characteristics of no-treatment patients for LNM. 0.9 No. 0.8 Age at diagnosis (y) Median 74 (61–79) 0.7 <50 0 Any treatment 0.6 ≥50 7 0.5 Gender 0.4 Male 4 Female 3 0.3 Log-rank p = 0.14 Tumor site 0.2 No treatment Upper extremity 1 0.1 Lower extremity 4 Trunk 2 0 50 100 150 200 250 Tumor location Months Superficial 0 Figure 3: 5-year OS rate of patients receiving any treatment and Deep 7 those receiving no treatment for lymph node metastasis. Tumor size (cm) <5 1 ≥5 6 as rhabdomyosarcoma, epithelioid sarcoma, and clear cell sarcoma may be a result of the small sample size of this Histology Myxofibrosarcoma 2 study, resulting in relatively good OS. Although myxofi- Undifferentiated pleomorphic sarcoma 1 brosarcoma has a high rate of local recurrence, the overall Epithelioid sarcoma 1 risk of distant metastases is relatively low compared to that Dedifferentiated liposarcoma 1 of other sarcoma subtypes; the 5-year local recurrence rate Myxoid liposarcoma 1 has been reported to be 18–31%, with corresponding OS Malignant peripheral nerve sheath tumor 1 rates of approximately 70% [12–14]. *e low risk of distant Tumor grade metastasis is a factor for the relatively good OS associated 1 0 with myxofibrosarcoma. 2 4 Some reports describe that the survival of patients with 3 3 LNM at diagnosis is similar to that of patients who later Surgical stage develop LNM [10, 11]. *erefore, we examined which time IB 0 duration from primary diagnosis to detection of LNM IIA 1 influenced OS. Of the 33 patients with LNM, there were 19 IIB 3 patients with pulmonary metastases. All LNMs developed III 2 earlier than the pulmonary metastases, except for 1 patient. IV 1 *ere were 13 patients with a duration from the primary Treatment for the primary tumor diagnosis to LNM detection of <8 months and 6 with a Surgery 5 Carbon ion 1 duration of≥8 months (p � 0.01). *e 5-year OS of patients None 1 with a duration from the primary diagnosis to LNM de- Type of surgery tection of<8 months and that of patients with a duration of Intralesional excision 1 ≥8 months were 19% and 71%, respectively (p � 0.0016). Marginal excision 1 *erefore, a short duration from primary diagnosis to LNM Wide excision 3 detection (<8 months) may predict a shorter survival, as well Pulmonary metastasis as possibly representing a component of disseminated Absent 4 disease. Present 3 In our study, it was demonstrated that any treatments for LNM did not result in a better survival than that of patients receiving no treatment. *e potential benefit of lympha- 5. Discussion denectomy remains to be defined. Lymphadenectomy has been shown to improve long-term survival [15, 16], while *e current study revealed that (1) most LNMs occur earlier than pulmonary metastases and (2) survival from LNM radical lymphadenectomy does not confer a substantial survival benefit [9, 10]. *is study suggests that early LNM depends on the time duration from primary STS diagnosis to (<8 months of duration from the primary tumor diagnosis) detection of LNM, and an early diagnosis of LNM (<8 may have less impact to decide on an aggressive treatment months) may predict poor prognosis. for LNM. *e 5-year survival for patients with LNM from STS is reported to be 12.8% to 34.1% [7, 9, 10]. In our study, the 5- We acknowledge several limitations of this study: First, there were a limited number of patients with LNM. Second, year OS was 45.5%. *e most common subtype of LNM was myxofibrosarcoma and undifferentiated pleomorphic sar- our study was limited by the fact that imaging assessment (CTor MRI) was used to examine the regional lesions at 3- to coma. *e low prevalence of lymphogenous histotypes such Cumulative survival International Journal of Surgical Oncology 5 [7] A. Daigeler, C. Kuhnen, R. Moritz et al., “Lymph node me- 6-month intervals. *erefore, we cannot detect all LNMs tastases in soft tissue sarcomas-a single center analysis of 1,597 unless the patient presents with lymph node swelling. *ird, patients,” Langenbeck’s Archives of Surgery, vol. 394, no. 2, we used a retrospective study design and not a single in- pp. 321–329, 2009. stitutional study design. Fourth, several different histologic [8] T. Yanagawa, K. Saito, and K. Takagishi, “Risk factors for tumors were included. Fifth, treatment was not performed in lymphatic metastasis of malignant bone and soft-tissue tu- a randomized, controlled fashion. mors: a retrospective cohort study of 242 patients,” Medicine, vol. 93, no. 27, p. e225, 2014. 6. Conclusion [9] E. Z. Keung, Y.-J. Chiang, R. K. Voss et al., “Defining the incidence and clinical significance of lymph node metastasis *is study demonstrated that early LNM (<8 months from in soft tissue sarcoma,” European Journal of Surgical Oncology, the primary diagnosis) may predict poor prognosis. vol. 44, no. 1, pp. 170–177, 2018. [10] C. Sawamura, S. Matsumoto, T. Shimoji, K. Ae, and A. Okawa, Data Availability “Lymphadenectomy and histologic subtype affect overall survival of soft tissue sarcoma patients with nodal metastases,” *e datasets generated and/or analyzed during the current Clinical Orthopaedics and Related Research, vol. 471, no. 3, study are available from the corresponding author on rea- pp. 926–931, 2013. sonable request. [11] W. B. Al-Refaie, R. H. I. Andtbacka, J. Ensor et al., “Lym- phadenectomy for isolated lymph node metastasis from ex- tremity soft-tissue sarcomas,” Cancer, vol. 112, no. 8, Ethical Approval pp. 1821–1826, 2008. [12] A. Gronchi, S. Lo Vullo, C. Colombo et al., “Extremity soft *is study was approved by the Institutional Review Board tissue sarcoma in a series of patients treated at a single in- for Clinical Research at Sapporo Medical University Hos- stitution: local control directly impacts survival,” Annals of pital and Akita University Hospital. Surgery, vol. 251, no. 3, pp. 506–511, 2010. [13] K. E. Haglund, C. P. Raut, A. F. Nascimento, Q. Wang, Conflicts of Interest S. George, and E. H. Baldini, “Recurrence patterns and sur- vival for patients with intermediate- and high-grade myx- *e authors declare that they have no conflicts of interest. ofibrosarcoma,” International Journal of Radiation Oncology∗Biology∗Physics, vol. 82, no. 1, pp. 361–367, 2012. Acknowledgments [14] R. 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