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Background: Uterine adenosarcoma (UA) is an extremely rare sarcoma subtype. There has been limited evaluation of the immune microenvironment in these tumors. The objective of this study is to examine and describe the immune infiltrate and PD ‑1/PD ‑L1 expression in UA and to correlate these changes in the tumor micro ‑ environment with the overall survival status or the disease‑free survival status (DFSS), respectively. Methods: Patients (pts) treated at our center from 1982 to 2014 with UA were identified. Fifteen cases had tumor paraffin‑ embedded blocks available. Immunohistochemistry studies for CD3, CD8, FOXP3, CD163, PD‑1 and PD ‑L1 (clone 22C3) were performed. Image analysis was used to assess the density (cells/mm ), except in PD‑L1, where the percentage of membranous staining on tumor cells was noted. Results: Immune infiltrate analysis median (range) density in cells/mm varied broadly: CD3 178 (15–802); CD8 117 (11–661); FoxP3 4.8 (0.2–82); CD163 791 (264–1861); and PD1 5 (1–65). 3 cases had rare (1%) PD‑L1 tumor membra‑ nous labeling. The reports yielded that ten pts were alive, and 5 were dead. Pts who were alive had significant higher CD3 and CD8 median densities in tumors than those who were dead (p = 0.040). There was no correlation between DFSS and CD3 or CD8 median densities. Patients who had no local recurrence had significantly higher CD3 and CD8 median densities in tumors than those who had local recurrence (p = 0.040). Conclusions: In conclusion, this is the first report characterizing the presence of immune infiltrate and PD ‑1/PD ‑L1 expression in UA. CD3+ CD8+ T‑ cells density may be prognostic. The immune‑responsiveness of UA needs to be further investigated in a larger study. Keywords: Adenosarcoma, Microenvironment, Immune infiltrate, Immunotherapy, CD3+, CD8+ Background salpingo-oophorectomy [1–3]. Overall survival and rate Uterine adenosarcoma is a rare biphasic uterine sar- of recurrence are significantly influenced by the presence coma, composed of both benign, but atypical, glandu- of sarcomatous overgrowth (sarcomatous component of lar epithelial and malignant mesenchymal sarcomatous more than 25% of the tumor), as well as myometrial inva- components and most often occurring in adult women. sion [4–6]. Stage, resection status, age, lymphovascular Standard treatment of uterine adenosarcoma is sur- invasion, tumor size, mitosis number, and lymph nodes gical resection through hysterectomy and bilateral involvement are also prognostic [2, 4, 7]. Treatment options for patients with recurrent or metastatic disease are limited. Immunotherapy, particularly with blockade of the *Correspondence: firstname.lastname@example.org Department of Medical Oncology, Center for Sarcoma and Bone PD-1/PD-L1 pathway (programmed death-1/pro- Oncology, Dana‑Farber Cancer Institute, 450 Brookline Ave, grammed death ligand-1) has proven effective in Boston, MA 02215, USA numerous malignancies, such as malignant melanoma, Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://crea‑ tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo‑ main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Ali et al. Clin Sarcoma Res (2020) 10:5 Page 2 of 8 non-small cell lung cancer, renal cell carcinoma, and expression of PD-L1 (program death ligand). For the Hodgkin’s Lymphoma, though results are still limited evaluation of PD-L1 expression, an FDA approved assay for sarcomas . Immunotherapy trials in soft tissue Dako PharmDx anti-PD-L1 clone 22C3 antibody was and bone sarcomas, such as SARC 028, have occasion- used. This assay was chosen given it wide use and overall ally reported responses, particularly in one patient with consistency and comparability to most anti-PD-L1 anti- uterine leiomyosarcoma. Unfortunately, most sarcoma body clones, (PMID: 31409885, 27541827). Unstained patients do not respond to immunotherapy [9–11]. It slides were prepared and immunohistochemical studies is critically important to understand the tumor immu- were performed using an autostainer (Leica Biosystems, nologic microenvironment, which may help determine Bond III Autostainer, Buffalo Grove IL) with anti-CD3 which sarcomas could respond to immunotherapy. The (Rabbit polyclonal, 1:100, Dako), anti-CD8 (C8/144B, immune microenvironment of uterine adenosarcoma Thermo Scientific, 1:25), anti-FOXP3 (206D, Biolegend, previously poorly examined. Tumor infiltrating lym - 1:50), anti-CD163(10D6, Leica Biosystems, 1:100), anti- phocytes (TILs) and PD-1/PD-L1 expression have been PD-1 (EPR4877(2), Abcam, 1:250) and anti-PD-L1 (clone reported in soft tissue and bone sarcomas, including 22C3, Agilent Technologies, Carpinteria, CA) markers. some uterine leiomyosarcomas and undifferentiated uter - Image analysis on the entire tissue microarray core using ine sarcomas [12–15]. Pre-clinical data in other sarcoma Aperio analytic image software (Leica Biosystems) was suggest that tumor TILs or PD-1/PD-L1 expression may performed. Lymphocytic infiltrate of the above mark - represent an important prognostic factor in sarcomas ers together with histiocytic infiltrate were quantified as [12, 13]. Loss of tumor cell MHC expression may rep- density (Number/mm ). For PD-L1, the percentage of resent one possible resistance mechanisms to immuno- membranous staining on tumor cells was determined. therapy in sarcoma patients [16–18]. A 2nd mechanism The areas selected for the analysis were the ones mostly of resistant is the inhibitory effect of tumor infiltrating representative of the tumor. The clinical and pathologi - macrophages on the tumor immunologic micro-environ- cal characteristics of each of these uterine adenosarcoma ment . Undifferentiated pleomorphic sarcoma may patients were collected. have the most sensitive sarcoma tumor microenviron- The exact Wilcoxon rank sum test was used to compare ment to immunotherapy . These facts have led to the the continuous variables between patient characteristics’ increased interest in characterizing the immune micro- subgroups . The correlation between two continu - environment in uterine adenosarcoma, with the hope to ous factors was measured by Spearman correlation . better understand the microenvironment of these tumors Overall survival (OS) was defined as “from diagnosis to and to then improve treatment and outcomes. the time of death” or “to the time of last contact.” Dis- In this study, our objective was to examine the immune ease-free survival (DFS) was defined as “from time of sur - infiltrate in terms of T cells and macrophages, and PD-1/ gery to the time of recurrence or death,” whichever was PD-L1 expression in uterine adenosarcoma and relate it earlier, or “to the time of last contact.” Local recurrence- to the overall survival, disease-free survival, and clinical free survival (LRFS) was defined as “from the time of prognostic factors. surgery to the time of local recurrence or death,” which- ever was earlier, or “to the time of last contact.” Given the Materials and methods small numbers of events, the associations between the With the IRB’s approval, a search was conducted of the immune infiltrates and time-to-events outcomes were Tumor registry for patients with uterine or extra-uterine not assessed using time-to-event analysis approaches. adenosarcoma treated at a MD Anderson cancer treat- Instead, the exact Wilcoxon rank sum test was used ment center from August 1982 to December 2014. One to compare the immune infiltrate levels between the hundred and sixty-five uterine adenosarcoma patients patients who either experienced an event and who had were identified, though only fifteen cases had tumor par - not experienced an event by the time of the last follow- affin-embedded blocks available, the latter of which rep - up. Two-sided p-value < 0.05 was considered statistically resented the study population. Tissue was obtained from significant. All statistical analyses were performed in SAS hysterectomy or biopsy, and samples were treatment 9.4. naïve. A tissue microarray of the fifteen cases was created. Immunohistochemistry study was conducted to exam- Results ine for the presence of overall T cell lymphocytes (CD3), Clinical and pathological characteristics cytotoxic T-cells (CD8), regulatory T cells (FOXP3) and Clinical and pathological characteristics of the 15 histiocytes/macrophages (CD163). Additional immu- patients included in this study are described in Table 1, nohistochemistry was performed to examine for T and include age, tumor size, follow-up, sarcomatous cell expression of PD-1 (program death) and tumoral overgrowth, myometrial invasion, lymphovascular Ali et al. Clin Sarcoma Res (2020) 10:5 Page 3 of 8 Table 1 Patients pathologic characteristics the tumor was limited to the uterine corpus. Ten patients had sarcomatous overgrowth (SO), and nine patients had Patient characteristics Median (min, max) myometrial invasion (MI). None of the fifteen patients Age of diagnosis 48 years (26, 61) had lymphovascular (LVI) invasion. None of the fifteen Tumor size 5.9 cm (2.5, 11) patients had lymph node involvement. Only four patients Follow‑up period 6.6 years (2.4, 10.8) had tumors that were negative for ER and PR (Table 1). n (%) At the last follow-up, 10 patients were alive and 5 patients were dead; 9 patients had no recurrence and 6 patients ER had disease recurrence, of the disease recurrences 5 Negative 4 (27) patients had local recurrence and one patient had distant Positive 11 (73) recurrence (Table 1). PR Negative 4 (27) Immune Infiltrates Positive 11 (73) The Immune infiltrate analysis median (range) den - Myometrial invasion sity in cells/mm varied broadly for CD3, CD8, FoxP3, Absent 6 (40) CD163, PD-1, and PD-L1. Table 2 shows the immune Present 9 (60) infiltrate minimum, median, maximum, mean, and Lymphovascular invasion standard deviation for each of these immune infil - Absent 15 (100) trates. For example, the median and range for CD3 Present 0 (0) was 178 (15–802), CD8 was 117 (11–661), FoxP3 was Sarcomatous overgrowth 4.8 (0.2–82), CD163 was 791 (264–1861), and for PD1 Absent 5 (33) was 5 (1–65) (Table 2). Three cases had rare (1%) PD-L1 Present 10 (67) tumor membranous labeling. Figure 1 shows examples Lymph node involvement of IHC staining for each of these immune infiltrates. No 15 (100) Figo stage overall I 14 (93) Correlation with OS, DFS, LRFS II/III/IV 1 (7) Patients who were alive with disease, alive with NED, or Vital status censored at last follow-up had a significantly higher CD3 Alive 10 (67) and CD8 median densities in their tumors than those Dead 5 (33) who were dead of disease (p = 0.040). (Table 3, Fig. 2). Disease‑free survival status There was no correlation between median FoxP3 and Disease‑free 9 (60) CD163 densities, or PD-1 expression and overall sur- Disease recurred 6 (40) vival status. There was no correlation between disease- Local recurrence‑free survival status free survival status and CD3 or CD8 median densities Local recurrence‑free 10 (67) (Table 4). There was no correlation between median Local recurrence 5 (33) FoxP3 and CD163 densities, or PD-1 expression and disease-free survival status. However, patients who were invasion, stage, and estrogen and progesterone receptor alive and had no local recurrence at the last follow-up status. The age distribution of adenosarcoma varied from had significantly higher CD3 and CD8 median densities 26 to 61 years with a mean age of diagnosis of 48 years. in their tumors than those who were alive and had local Fourteen patients at diagnosis had a FIGO stage I where recurrence (p = 0.040). (Table 5, Fig. 3). There was no Table 2 Immune infiltrate characteristics Factor n Min Median Max Mean SD CD3 15 15 178 802 248.8 226.2 CD8 15 11 117 661 151.5 162 FoxP3 15 0.2 4.8 82 12.2 21.6 CD163 15 264 791 1861 918.9 547.1 PD1 15 1 5 65 11.5 16.9 The exact Wilcoxon rank sum test was used to compare the continuous variables between patient characteristics’ subgroups Ali et al. Clin Sarcoma Res (2020) 10:5 Page 4 of 8 Fig. 1 Immune infiltrate immunohistochemistry labeling. Green boxes are examples of highlighted areas used for analysis. Examples are show for IHC staining for CD3, CD8, PD‑1, PD ‑L1, CD163, and FoxP3 Ali et al. Clin Sarcoma Res (2020) 10:5 Page 5 of 8 Table 3 Comparison of the immune infiltrate by overall Table 4 Comparison of the immune infiltrate by disease- survival statuses free survival statuses Factor Overall, Alive (n1 = 10), Dead (n2 = 5), p-value Factor Overall, No disease Disease p-value median median median median (n1 = 9), (n2 = 6), (min, max) (min, max) (min, max) (min, max) median median (min, max) (min, max) CD3 178 (15, 802) 297 (59, 802) 78 (15, 143) 0.040 CD3 178 (15, 802) 284 (59, 802) 98 (15, 376) 0.181 CD8 117 (11, 661) 165 (11, 661) 37 (15, 133) 0.040 CD8 117 (11, 661) 137 (11, 661) 54 (15, 250) 0.181 FoxP3 5 (0, 82) 7 (0, 82) 1 (0, 14) 0.322 FoxP3 5 (0, 82) 9 (0, 82) 2 (0, 14) 0.403 CD163 791 (264, 1861) 834 (399, 1861) 791 (264, 1807) 0.953 CD163 791 (264, 1861) 1090 (399, 1861) 685 (264, 1807) 0.607 PD1 5 (1, 65) 5 (1, 65) 5 (1, 23) 0.839 PD1 5 (1, 65) 4 (1, 65) 12 (1, 26) 0.664 The exact Wilcoxon rank sum test was used to compare the continuous variables between patient characteristics’ subgroups The exact Wilcoxon rank sum test was used to compare the continuous variables between patient characteristics’ subgroups correlation between median FoxP3 or CD163 density, or PD-1 expression and local recurrence-free survival. Discussion To our knowledge, this study is the first of its kind and it was conducted to characterize the immune infiltrate and Correlation with prognostic factors PD-1, PD-L1 analysis in uterine adenosarcoma. There was no correlation between presence or absence Our study showed that patients who were (1) alive with of myometrial invasion or sarcomatous overgrowth and disease, or (2) alive with no evidence of disease, had sig- median CD3 (p = 0.96, 0.31), CD8 (p = 0.86, 0.31), FoxP3 nificantly higher CD3 and CD8 median densities com - (p = 0.55, 0.082), CD163 density (p = 0.69, 0.86), or PD-1 pared to those patients who died of disease. Additionally, expression (p = 0.71, 0.49), respectively. There was insuf - patients who were alive with no local recurrence had sig- ficient patients with lymph-node involvement or lym - nificantly higher CD3 and CD8 median densities com - phovascular invasion or an advanced stage to correlate pared to those who had a local recurrence. High levels of with the immune infiltrate. Patients with tumors nega - CD8+ T-lymphocytes have been strongly associated with tive for ER and PR had significantly higher CD163 median prolonged overall survival and with favorable prognostic densities than tumors that were positive for ER and PR factors which, in turn, highlight the role of the immune (p = 0.040; p = 0.040). Otherwise there was no correlation system in endometrial cancer . Similar findings have between median CD3, CD8, FoxP3 densities and PD-1 been seen in ovarian cancers where the presence of CD3 expression and estrogen and progesterone receptor status. was found to be a strong prognostic factor of 10-year There was no correlation between the age of the patient at survival rates . The presence of CD8 was associated diagnosis and median CD3, CD8, FoxP3, CD163 densities, with improved 5 and 10-year survival . TILs have also or PD-1 expression. been have associated with improved outcomes in some soft tissue sarcoma subtypes  and the presence of Fig. 2 Box Plots for CD3 and CD8 Density by Overall Survival Status. Show shows a box plot comparing a CD3 density and b CD8 density to overall survival status (alive/dead) Ali et al. Clin Sarcoma Res (2020) 10:5 Page 6 of 8 Table 5 Comparison of the immune infiltrate by local recurrence-free statuses Factor Overall, median No recurrence (n1 = 10), Recurrence (n2 = 5), p-value (min, max) median (min, max) median (min, max) CD3 178 (15, 802) 297 (59, 802) 78 (15, 143) 0.040 CD8 117 (11, 661) 165 (11, 661) 37 (15, 133) 0.040 FoxP3 5 (0, 82) 7 (0, 82) 1 (0, 14) 0.322 CD163 791 (264, 1861) 834 (399, 1861) 791 (264, 1807) 0.953 PD1 5 (1, 65) 5 (1, 65) 5 (1, 23) 0.839 The exact Wilcoxon rank sum test was used to compare the continuous variables between patient characteristics’ subgroups Fig. 3 Box Plots for CD3 and CD8 Density by Local Recurrence‑Free Survival Status. Show shows a box plot comparing a CD3 density and b CD8 density to local recurrence‑free survival status (local recurrence yes/no) TILs may be a predictor of more favorable outcomes in 15% and disease control rate of 45%. However, results uterine adenosarcomas. in soft tissue sarcoma trials have been less promising. Existing evidence suggests that the presence of TIL The majority of soft tissue sarcomas do not respond to infiltrate in tumor tissue with an active PD-1/PDL1 immunotherapy. In fact, a trial examining immunother expression is essential for immune checkpoint inhibi - apy in uterine leiomyosarcomas showed no responses. tors. This evidence has been the basis for the FDA In the present study, PD1 and PD-L1 expression was not significant in uterine adenosarcomas. Therefore, approval of certain immune therapeutic agents in the treatment of specific tumors, such as non-small cell PD1-PDL1 expression may not be the best predictor lung cancer. The role of immunotherapy in gyneco of immunotherapy response in uterine adenosarco - - logical cancers has emphasized the concepts of active mas. The microenvironment of adenosarcoma in our immunotherapy through therapeutic vaccination, pas- cohort showed a higher density of CD8+ lymphocytes in tumor tissue in the absence of remarkable existence sive immunotherapy through adoptive cellular therapy of PDL-1 expression by the tumor cells. The dissocia using components of the immune system as antibod- - ies and lymphocytes, and the use of immune check- tion in the expression of CD8 and and PD1/PD-L1 axis point inhibitors which is by far the most promising suggests that adenosarcoma is a less favorable target for PD1/PD-L1 checkpoint inhibitors  and may use an yet . Monoclonal antibodies against cytotoxic T lymphocytes-associated antigen 4 (CTLA-4) and PD1 alternate immune escape mechanism. Further inves and PD-L1 are currently employed in many clinical set - tigations are required to identify immunologic thera- tings. Several reported and ongoing trials have looked peutic targets that may affect uterine adenosarcoma or into the role of checkpoint inhibitors in ovarian, cer- other soft tissue sarcomas [8, 10, 28]. The most accepted prognostic factors in the lit vical and endometrial cancers. In a trial of 20 patients - involving the use of nivolumab , an anti-PD-1 anti- erature for local adenosarcoma include the extent body in ovarian cancer has shown a response rate of of myometrial invasion, sarcomatous overgrowth, Ali et al. Clin Sarcoma Res (2020) 10:5 Page 7 of 8 Acknowledgements lymphovascular invasion, lymph node metastasis, and No further acknowledgements. age. Sarcomatous overgrowth and myometrial inva- Some of the data included in this report was previously presented at CTOS sion are both associated with a more aggressive dis- (Connective Tissue Oncology Society) Annual Meeting in 2017, in Hawaii, Presentation: The Immune Microenvironment of Uterine Adenosarcomas, ease course, shorter relapse time, and decreased overall Abstract #2794392 survival . Our study did not associate the immune infiltrate median densities and the PD-1 expression Disclaimers There are not disclaimers to report. with these factors. However, tumors with higher CD3 and CD8 median densities were significant determi - Authors’ contributions nants of overall survival. There was an association of MJN and AMRA contributed to writing of this manuscript. MJN, CHL, and HL contributed to the statistically analysis. AMRA, J‑ WT, AL and W‑LW contributed increased macrophage infiltrate in patients with estro - the pathologic analysis and immune infiltrates. MJN, VR, AC, W ‑LW contributed gen and progesterone receptor negative tumors. The to the overall study design planning, and obtaining funding, with MJN as the significance of this finding is uncertain, even though an main contributor. All authors read and approved and the final manuscript. increased macrophage infiltrate has also been reported Funding in triple negative breast cancer. WWWW Foundation, Inc. (QuadW ), Amschwand Sarcoma Cancer Foundation. In our study, characterization of immune infiltrate was Availability of data and materials limited to biopsies prior to treatment. Further analysis of All data is available upon request. the immune infiltrate densities following or during treat - ment with radiation and systemic chemotherapy may be Ethics approval and consent to participate Ethics approval was received from the institution review board. informative. Evaluation of HLA expression was not pos- sible given the limited available tissue and is a further Consent for publication limitation of this study. Thus, the major limitation to our There are no conflicts of interests to report. All authors consented to publication. study is the small patient sample size, and small amount of tumor tissue, due to lack of availability of tumor blocks Competing interests given the referral nature of our practice and the rarity of The authors declare that they have no competing interests. disease. Consequently, these results should be validated Author details in a larger multi-center study. Despite these limitations, Department of Translational Molecular Pathology, The University of Texas MD we were still able to identify that CD8 density may cor- Anderson Cancer Center, 2130 Holcombe Blvd, Life Science Plaza (LSP11.5010), Houston, TX 77030, USA. Department of Biostatistics, The University of Texas relate with disease status. 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Clinical Sarcoma Research – Springer Journals
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