Leiomyosarcoma of the rectum: A systematic review of recent literature

Leiomyosarcomas (LMSs) are rare tumors originating from the muscular layer. We performed a literature review of cases of confirmed rectal leiomyosarcomas (rLMSs) to clarify the history of such an infrequent tumor arising at such an uncommon location. In this research local recurrence was related to poorly differentiated rLMS and no other association between recurrence and any criteria was found. Concerning overall survival (OS), rLMS patients developing recurrence presented shorter longevity compared with the group without.

10] The development of LMSs from the muscular layer, usually covered by normal mucosa, often makes the diagnosis challenging regarding both its identification and localization by digital or endoscopic examinations.In fact, clinical, radiological, and endoscopic features are often nonspecific, preoperative biopsy is hampered by high false negative rate and LMSs are often misdiagnosed as benign leiomyomas or gastrointestinal stromal tumors (GISTs); thus, diagnosis is mostly achieved at final histology after surgery.
Colorectal LMSs (crLMSs), as well as all gastrointestinal LMSs, do not have their own specific classification and the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system of 1984, which identifies the prognosis identifying three classes based on differentiation, necrosis and number of mitosis, is still the most used. 11The latest ESMO guidelines for crLMSs propose radical tumor resection and pre/postoperative chemo-radiotherapy, although literature does not propose a unique approach with significant protocol variations among centers. 12The lack of standardized protocols leads to various surgical strategies ranging from local excision to radical resection with lymphadenectomy.
Owing to its propensity both to recur locally and to metastasize to liver and lung, 13,14 only roughly half of the patients affected by crLMS are alive 5 years postoperatively, being tumor size, patient age, and mitoses the main criteria related to poor survival. 2,15Also due to its rarity and the fact that colonic and rLMSs are usually

| Statistics
Statistical analysis was performed using MedCalc ® Statistical Software version 19.8 (MedCalc Software Ltd).As for univariate analysis, categorial variables were compared using the χ 2 test, whereas continuous data through the Student's t test; multivariate analysis was rendered with the logistic regression method.All the survival curves were created according to the Kaplan-Meier method and the Log-rank test was used to evaluate statistical significance.Multivariate analysis of survival was calculated through Cox regression (Cox proportional hazards model).A p value ≤ 0.05 was considered statistically significant.

| Analysis
At univariate analysis, local LMS recurrence was significantly related to poorly differentiated rLMS (higher grade cancer) (p = 0.0237) (Figure 2,

| Demographical features
rLMS confirms to be a relatively rare tumor, estimated to account for less than 0.1% of all rectal cancers. 3,4All reported cases are by small case series and one-case reports, and therefore a limited number of items may be discussed.Our analysis showed a mean age of 63 years (Table 2), with a wide range (SD: 19 years) at clinical presentation, consistently with previous reports. 33In our series, the male:female ratio was 1:1.38, whereas, in the literature, rLMS gender distribution appears less defined. 33,34

| Etiology
Consistently with literature on the subject, a possible association between rLMS and previous pelvic or perineal irradiation is suggested | 369 by literature, as 8 patients out of 31 (25.8%) had received pelvic radiotherapy at a mean interval of 20.5 years and roughly half of the cases had a personal history of cervical neoplasia (Table 2).
Gynecological malignancies are the main cause of irradiationrelated rLMS, followed by prostate cancer and anal cancer. 5,6,8,22,24,25,31,32In literature, patients are reported to develop radiation-associated soft-tissue sarcomas with a median time interval of about 10 years, 35 even though the risk remains significantly high for more than 40 years after radiotherapy. 36iteria to consider a malignancy to be radiation-induced are history of radiation, long latent period, histologically proven malignancy within the field of radiation, and different histology of the new tumor if radiation was given for malignancy. 37The radiation injury is supposed to be related to the effective dose, the course duration, and the individual sensitivity to radiation. 6Other risk factors for developing radiation-induced sarcoma include young age at initial treatment, genetic predisposition, and treatment-related agents, including high radiation dose and concomitant chemotherapy. 8Radiation causes the mutation of TP53 and RB1 genes which are important molecular events leading to the following development of radiation-induced sarcomas.Consecutive mutation of TP53 gene was identified in 58% of radiation-induced sarcomas and the biallelically co-inactivation with RB1 in some series is present in all sarcomas indicating that both genes played a major role in the formation of these malignancies. 38,39Radiation-induced sarcomas are often high-grade tumors, more aggressive than nonradiation-induced sarcomas and usually identified at advanced stages; for these reasons, their prognosis is worse compared with sporadic sarcomas regardless of histologic type. 8,31,35The lack of data about survival of the eight radiation-induced cases did not allow to carry out a statistical analysis of comparison with the remaining cases.

| Diagnosis and work-up
Although its rectal location, and therefore it is easily reachable by any diagnostic tool including digital examination, rLMS diagnosis is difficult to be achieved preoperatively.As LMSs arise within the muscular layer, rectal mucosa is usually normal and rLMS are often F I G U R E 2 Grading and recurrence.difficult to identify and correctly localize by digital or endoscopic examinations, unless they grow toward the rectal lumen.Moreover, interestingly enough, in roughly one out of three cases, digital examination is not even reported, which is unusual for rectal tumors.
Endoscopic biopsy may be a challenging task to carry out but is crucial for establishing the subsequent operative setting 40 and sometimes it may underestimate tumor malignancy grade. 41In our series, excluding the four cases of endoscopic resection, a preoperative histological diagnosis was not reported in 10/28 (35,7%) cases (Table 3), endoscopy was not decisive in one case 23 and in two cases may not allow for a conclusive histologic report on the first attempt. 5,26At preoperative imaging usually performed for any rectal tumor, rLMS presents as a nonspecific mass.In our review, colonoscopy, CT scan, and MRI were reportedly performed in only 19 (61.3%), 18 (58.1%),and 10 (32.3%) patients, respectively (Table 2), which are unusually low number for rectal tumors.[44] Differently from colonic LMSs, where preoperative biopsy and accurate radiological diagnosis/staging are sometimes not reported due to the emergency setting of surgery (obstruction, bleeding, or perforation), [45][46][47] rLMSs are all reported in elective setting, and therefore any effort should be made for the best preoperative work up.rLMSs patients should be meticulously studied and all available diagnostic tools and techniques, starting from a systematic digital exploration to imaging and EUSs, are needed, especially in the case of an inconclusive preoperative histology.In this setting, multidisciplinary management involving surgeons, radiologists, gastroenterologists, and oncologists is mandatory. 41

| Pathology
The definitive diagnosis is mainly based on immunohistochemistry. 41 Until the discovery of the oncogenic role of KIT in GISTs, in 1998, many smooth muscle neoplasms, including LMSs, were misdiagnosed. 16This is the reason why our analysis included cases of pathologist-confirmed rLMSs from 1998, although in some cases the details of pathology and immunohistochemistry were not reported (Table 3).Pathological examination is the only tool for differentiating LMSs from benign leiomyomas other than GISTs, as they often have similar symptoms and morphology at imaging.
Macroscopically, rLMSs are usually larger with firm consistency and tight adherence to the surrounding tissues.Since they can spread outside the lumen of the rectum, the preoperative bioptical histological analysis may be different and therefore inconclusive. 26 histopathologic examination, typical LMS consists of sheets of densely packed spindle cells with abundant fibrillar eosinophilic cytoplasm.Foci of necrosis, hemorrhage, and cystic degeneration can also be present. 6,30,31At immunohistochemical examination, LMSs express various smooth muscle cell markers: actin, desmin, hcaldesmon, HHF35 and, more recently, transgelin but they usually test negative for CD34 and CD117 (which are, conversely, typically positive in GIST). 18,48,49he absence of specific symptoms may be supposed to be responsible of such a low rate of an early rLMS identification, as suggested by several series showing a correct preoperative diagnosis in 29%-30% of cases. 33,50Clinical symptoms heavily depend on the direction of tumor growth.][10] As formerly reported by several series, rectal bleeding, abdominal pain, and defecation troubles resulting from the presence of a rectal encumbrance were the predominant symptoms also in our series (Table 2), being only five patients asymptomatic at diagnosis. 7,18,25,28

| Surgery
A wide variety of operations has been reported for rLMS, ranging from endoscopic to pelvic exenteration. 18,25,31The main issue concerning surgery is whether endoscopic local resection or radical surgery associated with lymphadenectomy should be preferred.Also owing to the fact that diagnosis was rarely achieved preoperatively, histology did not play a major role in surgical management strategy in most cases.Historically, tumor size, already known to be related with tumor metastatic potential, led the surgeon in the choice between radical surgery or local excision and the latter was generally preferred in the case of low-risk tumors (less than 2.0 cm in maximum diameter). 51,52However, already in 1984, Walsh et al. retrospective analysis showed that local excision of smooth muscle neoplasms of the rectum were associated with a high local recurrence rate, despite the fact that long-term survival was similar to the one reported after radical surgery and lymphadenectomy. 3The supposed rLMS higher recurrence rate after local excision compared with radical surgery has later been debated.Walsh et al.'s results were confirmed by another review, 53 showing a significantly higher rate of local recurrence compared with radical resection (55% vs. 24%), whereas, in a more recent series, 34  T A B L E 5 Overall and disease-free survival in patients with recurrence and not.Abbreviations: CI, confidence interval; DFS, disease-free survival; OS, overall survival; SE, standard error.
F I G U R E 3 Overall survival and local recurrence.
Since LMS history is typically associated with early hematogenous metastases, while spread to lymph nodes is rare. 2,30The real benefit of lymphadenectomy associated with rLMS removal is questionable.In our review, lymph node involvement was not statistically related to local recurrence (p = 0.2207) although this conclusion may be influenced by the fact that in most cases (74.2%) lymph node involvement was not reported (Table 3).Whereas it is difficult to draw any conclusion concerning the entity of surgical resection and lymphadenectomy, conversely, it is out of debate that tumor-infiltrated surgical margins (R1 or R2) should be avoided, and that re-excision is recommended in such cases, whenever feasible. 55

| Approach
Also owing to its rarity, rLMS management is far from standardized, and the choice of surgical approach may be supposed to depend on several factors including clinical setting at symptoms' onset (emergency), diagnostic work-up eventually carried out, macroscopic and histopathologic findings 7 and technical expertise of the team. 23,28In our review, no cases were managed in an emergency setting.
Moreover, the lack of data more frequently used to assess the results of surgery (length of hospitalization, postoperative complications) did not allow extrapolating which approach may be preferred.
Unfortunately, surgical approach and technique was not reported in 11 out of 31 reported cases.Although the technique of an open procedure was actually described in detail in only eight cases (40% of the 20 reported surgical resections), we may deduce that a traditional approach was used whenever not reported otherwise (Table 2).In only two cases, a mini-invasive approach was reported, robotic 23 and laparoscopic 28 in one case each, respectively.Although one anecdotal case obviously does not set a rule, the fact that the latter case was associated with a late-onset urethral injury and the patient was discharged 42 days after the operation, at some level confirms the difficulty of the procedure.

| Prognosis
The literature reports a poor prognosis after rLMS.Yeh et al., analyzing 40 patients with rLMS treated with surgical resection, documented a 5-year OS and DFS of 75% and 46%, respectively.
Among the studied criteria, high mitotic rate, large tumor size, and high tumor grade were found to be consistently associated with worse survival and higher risk of metastasis in several series. 33,53,55,56 our analysis, local recurrence was statistically related only to high tumor grade (p = 0.0237 at univariate analysis) (Table 4, Figure 2), but such a finding was not confirmed at multivariate analysis (p = 0.9979) although the overall model was statistically fit (p = 0.0067).
Unfortunately, the very limited sample did not allow for further analyses.Differently from retroperitoneal sarcomas, which seem to be more amenable to adjuvant or neoadjuvant radiotherapy 57,58 and are presently under clinical trials, 59 data concerning adjuvant radiotherapy in rLMS are extremely scanty and conflicting. 60,61In our review, only three patients underwent adjuvant radiotherapy with apparently poor results (Table 4).
[64] Unfortunately, no results of CT are available for rLMS.The small number of our review (only 11 patients underwent adjuvant chemotherapy), other than the bias of retrospective analysis, does not allow for any conclusion on the subject (p = 0.1025) (Table 4).
Finally, uncommonness of this disease makes us conclude that OS is related only with local or regional recurrence (p = 0.0291) with a similar result also for DFS despite a statistical significance was almost reached (Table 5, Figure 3).
4.9 | Parallelism with small bowel LMSs, colon LMSs, and GISTSs Small bowel tumors are extremely rare, representing less than 5% of gastrointestinal malignancies with an incidence of approximately 22.7 per million.The most frequent small bowel tumors are carcinoids (44.3%) while leiomyosarcomas (sbLMSs) account for 1.2%. 65,66As for rLMS, literature on the subject mostly relies on individual case reports or case series.sbLMS have a peak incidence toward the sixth decade with a preponderance for male sex. 67e symptoms are usually absent and when present are nonspecific (abdominal pain, anemia, melaena); consequently, they are associated with late diagnosis and poor prognosis. 68reover, whenever symptoms eventually prompt further investigations, diagnosis remains difficult to achieve as gastroscopy and colonoscopy are often inconclusive.So, third-level exams are often needed, such as CT colonography and magnetic resonance enterography (MRE) are the most used exams. 69,70Wireless capsule endoscopy (WRE) is often added, and it has proven to be accurate, especially for smaller lesions. 71,72vertheless, the preoperative differentiation between benign and malignant lesions is challenging and only histopathology may allow for the definitive diagnosis.
The treatment of choice for smLMSs remains surgical resection 68 and often, when needed, liver metastasectomy should be considered. 73e few available data do not allow defining the best surgical approach.Although adjuvant therapies are reported in the treatment of LMSs of the uterus, 74 smLMSs appear to have a low response rate. 75Similarly to rLMSs, there is no clear evidence on the effect of chemotherapy.The size of the tumor and the degree of histological differentiation represent the main prognostic factor, and, although the reported survival is longer than for adenocarcinomas of the same district, the overall prognosis remains poor as the 5-year survival ranges from 10% to 48%. 67,76 in other sites, defining colic prevalence is difficult given the overall rarity of these tumors, but the colon is estimated to be the location in approximately 38% of gastrointestinal LMSs, 2 with a peak age between 50 and 60 years. 77,78Similarly to rLMSs, colic leiomyosarcomas' (cLMS) symptoms are also nonspecific.In a review of the literature, Wang analyzed 41 cases of cLMSs identifying in one-third of cases abdominal pain as the main symptom, followed by rectal bleeding, bloody stool, occlusion, anemia, lower gastrointestinal bleeding, alternating constipation, with only one case totally asymptomatic. 77Similarly to rLMSs, the diagnosis is difficult.
Imaging examinations are not specific, and since mucosa is often normal at colonoscopy, correct biopsy sampling can be difficult or can underestimate the grade of the neoplasm. 40though historically considered to have a favorable prognosis when discovered, 1,79 cLMSs have later been associated with high degree of recurrence in liver, lung, and peritoneum, and with low survival rates. 13,77,80,81The size of the tumor 2,80 and the mitotic activity 13 are considered the main prognostic factor.Wang in 2020 confirmed a minor survival for those with tumors >8 cm and for individuals >60 years but the unavailability of data did not allow to establish certain relationships with mitotic activity. 77Data on the type of surgery are scarce but radical resection with lymphadenectomy, as far for rLMSs, remain the recommended management.
3][84] The stomach represents the most frequent location while, as for LMSs, colorectal GISTs are rare and represents only from 5% to 15% of colorectal tumors. 85aditionally included in stromal tumors together with leiomyomas and LMSs, GISTs' immunohistochemical profile is different as GISTs practically always express the CD-117 antigen or the transmembrane KIT receptor tyrosine kinase, which is the product of the KIT proto-oncogene. 16,86Unlike LMSs, which arise from smooth muscle cells, GISTs arise from the interstitial cells of Cajal (ICC).Located in the muscular layer of the intestinal wall, ICC represent a sort of gastrointestinal pacemaker and help to regulate peristalsis acting as a link between the autonomic system of the intestine and the smooth muscle. 87Similarly to LMSs, the clinical presentation of GISTs is highly dependent on the site of onset with symptoms ranging from simple intestinal bleeding, to vague abdominal pain, to intestinal obstruction and acute abdominal perforation.
Unlike LMSs, where the choice between radical surgery with lymphadenectomy and local excision is still debated, the surgical management of GIST is far more standardized: the main treatment for localized GISTs >2 cm is surgical resection without lymphadenectomy and minimally invasive surgery is accepted as long as it meets all oncological criteria [88][89][90] while there is no consensus regarding the management of smallest lesions.
The essential difference of GISTs lies in the possibility of exploiting small tyrosine kinase inhibitors (TKIs), such as imatinib, which inhibit tumor growth by blocking KIT and PDGFRA signaling.
TKIs are used to treat GISTs in the adjuvant setting to reduce the risk of recurrence and, in the neoadjuvant setting, to reduce tumor burden in locally advanced disease before resection.
Sphincter-sparing surgery and esophagus-sparing surgery should be considered for rectal and gastroesophageal junction GISTs, respectively.Several case reports have demonstrated that the use of preoperative imatinib enables organ-sparing surgery and improves surgical outcomes in patients with rectal GISTs (rGIST). 91 for the other sites, complete resection with negative margins and avoiding tumor rupture are the fundamental principles that can be followed also for rGISTs.The main challenges are for the lower rGISTs, the resection of whom is technically demanding and hampered by significative morbidity and mortality, especially when the sphincters and pelvic floor muscles or organs are involved.In these cases, the European ESMO guidelines suggest a neoadjuvant therapy with Imatinib for 6-12 months to down-size and down-stage the tumor and to eventually obtain a feasible surgical resection (RO-R1). 88In particular, if abdominoperineal resection is necessary to achieve a negative margin resection, then preoperative imatinib should be considered.
[109] Imatinib therapy appears to be the standard first-line treatment for locally advanced, inoperable, and metastatic patients, and for metastatic patients who have had all lesions surgically removed. 88All GISTs have the potential to develop metastases and their biological behavior is variable.Among the main prognostic factors are the mitotic index, size as well as the site (the stomach has a better prognosis than the colon and rectum) and rupture of the tumor. 85,88,110A nomogram proposed by Gold in 2009 include and consider all these factors. 111As far as the rectum is concerned, the potential rate of progressive disease is highly variable ranging from 0% for GIST <2 cm and low mitotic rate to 72% for GIST >10 cm and high mitotic rate. 85

| CONCLUSION
articles reporting a detailed description of the surgical act, eight patients underwent open surgery by laparotomy, three transanal, one robotic, and one laparoscopic resection.Two patients underwent adjuvant chemotherapy, two adjuvant radiotherapy and one underwent both chemo-and radio-therapy in the postoperative setting.Information on adjuvant radiotherapy and chemotherapy was missing for 16 patients (51.6%).Eight (25.8%) patients received pelvic radiotherapy several years before rLMS occurrence (average 20.5 years; SD 9.51).Tables Abbreviations: APR, abdominoperineal resection; AR, anterior resection; CT, chemotherapy; DoD, died of disease; HG, high grade; LE, local excision; LG, low grade; NR, not reported; PE, pelvic exenteration; POL, polypectomy; RT, radiotherapy; SR, segmentary resection; TP, total proctocolectomy.
the type of surgery was not reported to significantly affect the local recurrence rate.Those results were consistent with our findings (p = 0.3026).Unfortunately, available literature does not allow defining accurately the impact of local resection versus radical extirpation, including extended surgical resections such as abdominoperineal resection, since bulging, advanced tumors infiltrating the surrounding tissues were seemingly more often treated by radical excision.Small numbers and retrospective nature of reviews could affect these results, too.Considering extended resections, interestingly, in 1999, Grann et al. proposed a sphincter-preserving surgery followed by brachytherapy and/or external beam radiation as an alternative to abdominoperineal resection in eight patients with locally advanced tumors of 5 cm or less.The rate of local recurrence was 25% (two patients) after 53 months of follow-up.54 rLMSs are rare tumors with only recently well-defined histological features.Submucosal harboring makes preoperative diagnosis difficult to be achieved.Preoperative diagnosis by histology is preferable, but difficult.Previous irradiation is present in roughly ¼ of patients and should be recorded in personal history whenever a bulging rectal mass with normal mucosa is found.All efforts should be made in the preoperative work-up.Small, low-graded neoplasms could be managed by transanal resection or endoscopic removal while advanced grading and suspicion of preoperative lymph node involvement would require more invasive surgery.Despite few data in the literature, the laparoscopic or robotic approach could be considered safe and feasible in an elective setting in high-volume centers while the open approach should remain the preferred one in emergency cases.Further studies are needed to

1
Leiomyosarcomas of the rectum: Reported cases since 1998.

Table 4
Demographic and clinico-pathological data.
T A B L E 2 (Continued) a In 17 patients distance from anal verge was not reported.bIn three patients dimension was not reported.cCalculated on 27 surgical procedures (4 polypectomies were excluded).TA B L E 3 Histology and immunohistochemistry.