1

1 Article

2 What lessons are there to be learned from a small single-center

3 series of twelve uterine sarcomas
4 Nicolae Serban Ioanid 1, Maria Gabriela Aniței 1,2*, Alexandra Nicoleta Ioanid 3, Nicolae Ioanid1, Cristina Terinte1
5 Răzvan Vieriu-Moțoc 1, Ionuț Huțanu 1,2, Bogdan Filip 1,2, Dan Ferariu1, Viorel Scripcariu 1,2

6 1
Iasi Regional Institute of Oncology 1; oncoiasi@iroiasi.ro
7 2
Medical School of the Grigore T. Popa University of Medicine and Pharmacy 2; dec_med@umfiasi.ro
8 3.
Cuza-Voda Clinical Hospital ; contact@spitalcuzavodaiasi.ro
9 * Correspondence: dr.mgabriela@gmail.com;

10 Abstract: Uterine sarcomas are a very rare type of uterine malignancy. Due to their scarcity and
11 their impressive variability, there is no standardized approach. We retrospectively analyzed data
12 from 12 cases of uterine sarcomas that were operated in a single center with a high volume tertiary
13 center for gynecologic malignancies. Eight cases were operated with curative intent, one was a
14 palliative resection and three were pelvic recurrences. We found a fairly equal distribution
15 between histological subtypes: three adenosarcomas (AS), two endometrial stromal sarcomas
16 (ESS), two leiomyosarcomas (LMS) and two undifferentiated sarcomas (US). Neither adnexal nor
17 parametrial involvement was observed in any patient that was operated with curative intent.
18 Recurrence surgery was performed in three patients with a median interval of 11 months after
19 index surgery. Two of them underwent radical surgery for vaginal stump and obturator fossa
20 recurrence respectively, while the other one underwent terminal colostomy for massive pelvic
21 Citation: Lastname, F.; Lastname, F.; recurrence. Uterine sarcomas are a rare and heterogeneous subgroup of uterine tumors, often
22 Lastname, F. Title. Diagnostics 2022, exhibiting extremely aggressive behavior and further studies are needed to establish a more
23 12, x. https://doi.org/10.3390/xxxxx standardized and tailored approach.

Academic Editor: Firstname

24 Keywords: Uterine sarcomas; Surgical radicality; Immunehistochemical staining; Uterine sarcoma
Lastname
25 recurrence
26 Received: date
Accepted: date
Published: date

27 Publisher’s Note: MDPI stays 1. Introduction

28 neutral with regard to jurisdictional Uterine sarcomas comprise approximately 1.5-3.5% of uterine malignancies, of
claims in published maps and
29 which the most common type are the leiomyosarcomas representing around 60% of
institutional affiliations.
30 uterine sarcomas1. They exhibit a high degree of variability as far as their biology and
31 therapeutic response are concerned.2

Copyright: © 2022 by the authors.

Submitted for possible open access
publication under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).

3 Diagnostics 2022, 12, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/diagnostics

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32 The latest classification of the World Health Organisation 3 divides them into five
33 groups: leiomyosarcoma (LMS), endometrial stromal sarcoma (ESS), undifferentiated
34 sarcoma (US), adenosarcoma (AS) and epithelioid myofibroblastic sarcoma (EMS).
35 Further subdivisions are described for LMS, which are divided into spindle and
36 epithelioid and myxoid subtype, and ESS that are sub-categorized as low-grade or high-
37 grade.
38 LMS has an incidence of approximately 1 case per 100,000. Cited risk factors
39 include: obesity, diabetes, black race, long-term tamoxifen therapy and TP53 mutations 4–
6
40 . Despite the fact that 60% of tumors are diagnosed at an early stage, their prognosis
41 remains poor with a 15-25% 5-year survival rate 3,7. Clinical manifestations of ULMS are
42 vague and nonspecific, including metrorrhagia, rapidly growing pelvic mass and pain in
43 the lower abdomen8. Magnetic resonance imaging suggests malignancy in around 80%
44 of cases9. Early-stage management of the disease includes total abdominal hysterectomy
45 and bilateral salpingo-oophorectomy, without lymphadenectomy nor omentectomy as
46 the risk of metastasis in these locations is negligible 9. Adjuvant chemotherapy and/or
47 radiotherapy is not recommended in localized cases, as its role is not yet established,
48 even in cases that associate high risk of recurrence and mortality10.
49 Concerning ESS, the standard of care is total abdominal hysterectomy and bilateral
50 salpingo- oophorectomy, with lymph node sparing 2 . Low-grade ESS has a more
51 favorable prognosis with episodes of recurrence, with a low response to conventional
52 chemotherapy. High grade uterine sarcomas are aggressive, with unfavorable outcomes.
53 Usually there is low response to conventional chemotherapy 11. Current studies are
54 focused on cabozatinib, an anti VEGFR agent.
55 Adenosarcomas generally have a good prognosis, usually exhibiting an indolent
56 natural history for which adjuvant therapies are usually not employed or have a limited
57 role2,12.
58 The rarity and complexity of uterine sarcomas is what makes them such a
59 challenge, with lots of questions still to be answered in the quest of the right
60 management.
61 We aim to retrospectively analyze the surgical management and the
62 histopathological features of uterine sarcomas in a single center high-volume regional
63 surgical oncology clinic.

64 2. Materials and Methods

65 Electronic records of patients operated for uterine neoplasms were gathered from
66 the electronic database of the institution. We included patients that were operated with
67 curative intent from January 1st 2016 until September 30 th 2022. We only included
68 patients with true uterine sarcomas, excluding the mixed Mullerian tumors. Data
69 regarding patient age, preoperative staging, surgery, and histological characteristics on
70 surgical specimen was gathered. All the data that was retrieved was organized in a

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71 retrospective anonymous database. Approval from the ethics committee of the Iasi
72 Regional Institute of Oncology was obtained in order to carry the research and publish
73 the results.

74 3. Results

75 3.1. Patient characteristics

76 The population size at time of surgery tends to be between the sixth and eighth decade
77 of life, with a median of 63 years of age.

78 3.2 Tumor characteristics and impact on the type of surgery performed

79 Uterine sarcomas tend to have a relatively big tumor size, ranging from 4.6 cm to 15.3
80 cm as estimated by pre-operative MRI while histological assessement ranged from 2 cm
81 to 26 cm. The median size did not differ by a lot between the two instances as seen in
82 table 2.

83 One of the patients had the tumor located in cervix uteri and, after multidisciplinary
84 case review, she underwent neoadjuvant chemotherapy followed by type B radical
85 hysterectomy with pelvic lymphadenectomy. For the other eight patients with tumors of
86 the corpus, half of them underwent type A radical hysterectomy, two type B radical
87 hysterectomies, two type C radical hysterectomies and one type C radical trachelectomy
88 for an adenosarcoma on a cervical stump on a patient that had previously undergone
89 subtotal hysterectomy for other pathology. Data regarding surgery is further
90 summarized in table 3.

91 3.3 Histopathological findings

92 3.3.1. Histological types
93 Final pathological exam revealed three adenosarcomas, one of which also exhibited an
94 endometrial stromal sarcoma component, two endometrial stromal sarcomas, two
95 leiomyosarcomas and two undifferentiated sarcomas. In three cases, pelvic
96 lymphadenectomy was performed, but only in one case was a metastatic lymph node
97 found, that being the case of the mixed adenosarcoma and endometrial stromal sarcoma
98 of the cervix uteri (patient 9 in table 3).
99 3.3.2. Immunehistochemistry findings
Preoperative Specimen histology Final staging
Patient nr. MRI Staging Surgery
biopsy

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Patient 1 ESS AS IB Type B HR + BSO + PL IC

Patient 2 ESS ESS IA Type A HR + BSO IB
Patient 3 C-LMS C-LMS IB Type A HR + BSO IB
Patient 4 N/A US IB Type A HR + BSO IB
Patient 5 ESS ESS IB Type A HR + BSO + PLN sampling IB
Patient 6 AS AS IB Type C TR IB
Patient 7 N/A US IV Type C HR + BSO IV
Patient 8 E-LMS E-LMS IIIA Type C HR + BSO IB
Patient 9 ESS AS+ESS component IIA1 Type B HR + BSO + PL II

100 Table 1. Summary of tumor characteristics and surgical procedures performed

101 * AS = adenosarcoma; ESS = endometrial stromal sarcoma; C-LMS = conventional leiomyosarcoma;
102 E-LMS = epithelioid leiomyosarcoma; US = undifferentiated sarcoma; HR = radical hysterectomy;
103 RT = radical trachelectomy; BSO = bilateral salpingo-oophorectomy; PLN = pelvic lymph node; PL
104 = pelvic lymphadenectomy; MRI = magnetic resonance imaging.

105 h-caldesmon

106 Both LMSs were h-caldesmon positive. For the USs, one was h-caldesmon positive and
107 for the other one h-caldesmon staining was not performed, the same as for the
108 endometrial stromal sarcomas. Both AS were h-caldesmon positive.

109 CD10

110 Both the endometrial stromal sarcomas and both adenosarcomas reacted positive for
111 CD10. The mixed adenosarcoma and endometrial stromal sarcoma was also CD10
112 positive.

113 Of the US, one reacted positive and one negative, while for the LMS, the epithelioid one
114 reacted negative and for the conventional one CD10 was undetermined.

115 Cyclin D1

116 All of the ESS were cyclin D1 positive, including the mixed AS and ESS of cervical
117 origin. One of the ESS, corresponding to patient number 2 in Table 3 was diffusely
118 positive in more than 90% of tumor cells suggesting a t(10,17) translocation.

119 Both US were cyclin D1-negative, while for the one LMS that was stained for cyclin D1,
120 30% of its nuclei exhibited a positive reaction.

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121 CKAE1/AE3

122 All of the cases were negative for CKAE1/3 except for one case of US (patient 4 in table
123 3) which reacted positive in very rare tumor cells.

124 Desmin

125 Of all the cases studied, desmin was found to be intensely positive in only the
126 conventional LMS.

127 Smooth muscle actin (SMA)

128 The conventional LMS reacted positive while the epithelioid one was negative. Also, one
129 US was also positive, as well as one ESS and one AS.

130 Other stainings

131 Ki67 was determined for patients 1 (AS), 2 (ESS), 3 (C-LMS) and 5 (ESS) who reacted
132 positive in 40, 90, 30 and 80 per cent of tumor cells.

133 WT1 was determined in patient 1 (AS) and was positive.

134 Mutant p53 was determined in patient 4 (US) and was positive in 80-90% of cells. p16
135 was also intensely positive in this patient.

136 Miogenin staining for patients 7 (US) and 8 (E-LMS) were negative.

137 Surgery for recurrence and pathological findings

138 Three uterine sarcoma recurrences were operated in our clinic. The median time to
139 recurrence was 10 months (6-12 months). Two patients were operated before in our
140 clinic and are included in Table 3 as patients number 4 and 5.

141 Patient 4 (US) presented with an obturator lymph node metastasis detected on PET scan
142 12 months after index surgery and was successfully operated with clear margins.

143 Patient 5 (ESS) presented at 11 months with a massive pelvic recurrence that invaded the
144 sacrum, the rectum and the posterior wall of the urinary a bladder. The case was
145 deemed inoperable, and a terminal colostomy was performed.
146 The third case was referred to our clinic at 11 months after index total hysterectomy
147 with bilateral salpingo-oophorectomy for adenosarcoma of the uterus. No adjuvant

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148 treatment was administered. At 6 months after index surgery, she was diagnosed with a
149 1.7 cm vaginal stump recurrence, she underwent two cycles of chemotherapy and was
150 successfully operated at 10 months from index surgery with a clear margin subtotal
151 colpectomy. Interestingly, preoperative biopsy of the recurrence revealed an
152 endometrial stromal sarcoma, later confirmed by the resected specimen pathology exam.

153 Data are summarized in Table 2.

Time
between
index
surgery
and
Site of recurrence Surgery Specimen histology exam Comments
diagnosis
of
recurrenc
e
(months)
Lymph node of the right Right obturator 12 Lymph node metastasis of Patient 4 in Table 1. The
obturator fossa and right external undifferentiated sarcoma recurrence was diagnosed
iliac on control PET-scan
lymphadenectomy
Patient 5 in table 1.
Pelvic Palliative terminal 10 No biopsy was taken Massive (16 cm) pelvic
colostomy recurrence invading the
sacrum, rectum and
posterior bladder wall

Vaginal stump Subtotal 6 R0 resection of vaginal stump Reclassified at our

colpectomy recurrence of high grade endometrial institution as high grade
stromal sarcoma ESS, from AS

154 Table 2. Data from surgery for uterine sarcoma recurrence

155 4. Discussion
156 As it pertains to the tumor size, our study identified that tumors measured around
157 eight and a half centimeters. However, we mentioned that one of the nine patients had
158 the tumor located in cervix area and the multidisciplinary decision was to initiate

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159 neoadjuvant chemotherapy, to which the primary tumor has responded shrinking to
160 approximately 2 cm. If we were to exclude this patient and consider only body uterine
161 masses, the tumors would have median size of 10.7 cm.
162 As far as radicality of surgery is concerned, we observed parametrial invasion in
163 only one patient. However, it is worth mentioning that in this case we talk about a
164 palliative resection for a stage IV undifferentiated sarcoma of the body of the uterus. In
165 all the other eight cases that were otherwise treated with curative intent, no parametrial
166 involvement was observed, not even for the cervix uteri sarcoma. Data on parametrial
167 involvement for uterine sarcomas is very scarce. The largest series concerning this issue
168 is by Tse et al.13 who found that 9% (18 of 199) of high-grade uterine leiomyosarcomas
169 expressed parametrial involvement. Parametrial involvement was a predictor of three-
170 year survival in univariate analysis but failed to do so in multivariate analysis. Bai et al. 14
171 finds that two out of twenty low-grade endometrial stromal sarcomas expressed
172 parametrial involvement. Micci et al. 15found that the GREB1-NCOA2 fusion gene was
173 expressed in a uterine sarcoma that bilaterally invaded the parametrium and further
174 developed lung metastasis. Whether parametrial involvement is correlated with tumor
175 location as in epithelial tumors of the corpus versus cervix or is rather a feature of tumor
176 aggressiveness remains to be studied. Answering this question would allow for a more
177 tailored surgical approach and open the way to the standardization of surgical
178 radicality, which should be key in further research evaluating the impact of surgery.
179 The recurrences that were operated on occurred rather early, less than one year
180 after index surgery. In patient number 4, given the relatively short time to recurrence
181 and its location in the obturator fossa, one could retrospectively hypothesize that at the
182 time of index surgery sentinel lymph node mapping as the one performed for
183 endometrial cancer followed by ultrastaging may have shown micrometastasis in that
184 node. Interestingly, that patient was the only one exhibiting positive reaction to
185 CKAE1/AE3, which are the cytokeratin antibodies employed in staining for lymph node
186 micrometastasis of endometrial cancer 16. However, data on sentinel lymph node
187 mapping for sarcomas is very scarce and anecdotal but it could represent an interesting
188 research endeavor with its ultrastaging purpose. In patient number 5, one can notice the
189 presence of histological risk factors such as its high grade, the mitotic index of 50 and a
190 Ki67 of 80%. The third recurrence that was operated on occurred at 6 months after index
191 operation in a different institution and the final histology was changed from
192 adenosarcoma, which is considered a low-grade tumor that typically does not require
193 any adjuvant therapy for stage I disease 12, to high-grade endometrial stromal sarcoma
194 that has a significantly worse impact on survival17.
195 The almost equal distribution among histological subtypes is somewhat discordant
196 with the data from literature that states that leiomyosarcomas are the most frequent 1,6.
197 Apart from the fact that this series is very small in size, this result may also be due to it
198 being a surgical series and not data that is obtained from regional or national cancer

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199 registries. Patients that are referred to surgical management tend to have earlier stage
200 disease which could also be a direct effect of tumor biology.

201 5. Conclusions
202 True uterine sarcomas represent a small group of rare and polymorphous tumors,
203 with a potential of extremely aggressive behavior. Management of these patients should
204 be carried out in tertiary centers to accurately classify the tumor and correctly tailor the
205 surgical and adjuvant approach. Certain immunohistochemical features may be the key
206 towards this goal, as well as the implementation of prospective uterine sarcoma
207 registries.
208
209 Author Contributions:
210 Conceptualization, NSI, MGA, NI. Methodology, NSI, MGA. Validation, MGA, NI, VS. Formal
211 analysis, NSI. Resources, NSI, MGA, NI, CT, RVM, IH, BF, DF, VS. Data curation, NSI. Writing –
212 original draft preparation, NSI, ANI. Writing – review and editing, NSI, MGA, ANI. Visualization
213 – NSI, MGA. Supervision – MGA, VS. Project administration – MGA, VS.
214 Funding: This research received no external funding.
215 Institutional Review Board Statement: The study was conducted in accordance with the
216 Declaration of Helsinki, and approved by the or Ethics Committee of the Iasi Regional Institute of
217 Oncology.
218 Informed Consent Statement: Informed consent was obtained from all subjects involved in the
219 study.
220 Data Availability Statement: In this section, please provide details regarding where data
221 supporting reported results can be found, including links to publicly archived datasets analyzed
222 or generated during the study. Please refer to suggested Data Availability Statements in section
223 “MDPI Research Data Policies” at https://www.mdpi.com/ethics. If the study did not report any
224 data, you might add “Not applicable” here.
225 Conflicts of Interest: The authors declare no conflict of interest.

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