Razakanaivo M, Nguyen NP, Thariat J, Molinie V, Vlastos AT, Verschraegen C, Vinh-Hung V. Overview of embryonal rhabdomyosarcoma of cervix in women over 40-year-old. World J Obstet Gynecol 2016; 5(1): 110-117 [DOI: 10.5317/wjog.v5.i1.110]
Corresponding Author of This Article
Vincent Vinh-Hung, MD, PhD, Radiation Oncology, University Hospital of Martinique, Hôpital Clarac, Bd Pasteur, Fort-de-France 97200, Martinique. anhxang@gmail.com
Research Domain of This Article
Obstetrics & Gynecology
Article-Type of This Article
Minireviews
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Malala Razakanaivo, Joseph Ravoahangy Andrianavalona University Hospital, Antananarivo 101, Madagascar
Nam P Nguyen, Radiation Oncology, Howard University Hospital, Washington, DC 20060, United States
Juliette Thariat, Antoine-Lacassagne Cancer Center, University Nice Sophia Antipolis, 06189 Nice Cedex, France
Juliette Thariat, Rare Cancer Network, Lausanne 1011, Switzerland
Vincent Molinie, Department of Pathology, University Hospital of Martinique, Fort-de-France 97200, Martinique
Anne-Therese Vlastos, Geneva Gynecology and Obstetrics, Place des Philosophes, 1205 Geneva, Switzerland
Claire Verschraegen, Division of Hematology Oncology, University of Vermont Cancer Center, Burlington, VT 05405, United States
Vincent Vinh-Hung, Radiation Oncology, University Hospital of Martinique, Fort-de-France 97200, Martinique
Vincent Vinh-Hung, Radiotherapy Department, UZ Brussel, Vrije Universiteit Brussel, 1090 Jette, Belgium
Nam P Nguyen, Juliette Thariat, Vincent Vinh-Hung, International Geriatric Radiotherapy Group (http://igrg.org/), Washington, DC 20060, United States
ORCID number: $[AuthorORCIDs]
Author contributions: Original concept and design were developed by Nguyen NP, Thariat J and Vinh-Hung V; literature search was performed by Razakanaivo M, Nguyen NP, Verschraegen C and Vinh-Hung V; data revisions were carried out by Nguyen NP, Thariat J, Verschraegen C and Vinh-Hung V; statistical analyses were performed by Vinh-Hung V; Razakanaivo M, Molinie V and Vlastos AT contributed to the writing of the manuscript; all authors approved the final version.
Conflict-of-interest statement: The authors have no conflicts of interests to report.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Vincent Vinh-Hung, MD, PhD, Radiation Oncology, University Hospital of Martinique, Hôpital Clarac, Bd Pasteur, Fort-de-France 97200, Martinique. anhxang@gmail.com
Telephone: +596-696-542019 Fax: +596-596-632254
Received: June 27, 2015 Peer-review started: June 30, 2015 First decision: August 16, 2015 Revised: November 11, 2015 Accepted: December 13, 2015 Article in press: December 14, 2015 Published online: February 10, 2016 Processing time: 218 Days and 6 Hours
Abstract
The literature on cervical embryonal rhabdomyosarcoma (RMS) is reviewed here to identify management guidelines for middle-aged women diagnosed with this rare type of gynecologic cancer. Specifically, the PubMed, Web of Science and Google Scholar databases, were searched to find published case series on cervical embryonal RMS reporting on four or more patients, of whom at least one was > 40-year-old. The χ2 test was used to assess heterogeneity. Five articles published between 1986 and 2013 were identified, reporting on a total of 47 patients, of whom 22 (46.8%) were older and 25 (53.2%) younger than 40-year-old. Although the two age groups did not differ significantly by stage of disease or radiotherapy treatment, the older age group received less chemotherapy (55% vs 90%, P = 0.008) and had more hysterectomy (86% vs 43%, P = 0.009). Follow-up data was missing for 18/47 (38.3%) patients. Among the 29 patients with follow-up data, survival was shorter in the older group, with 8/12 (67%) alive and 3 with disease at a median follow-up of 2.6 years, as compared with the younger group that had 15/17 (88%) alive and none with disease at a median follow-up of 3.5 years. The longest survivals among the older women were observed in those who received radiotherapy, including one case with a resected lung metastasis. A prospective multi-institutional collaboration and better follow-up are needed to determine the optimal management of cervical embryonal RMS. Long-term survival appears feasible if management is accompanied by chemotherapy and radiotherapy.
Core tip: The present review of adult cervical embryonal rhabdomyosarcoma case series summarizes 5 studies reporting on 47 female patients, 22 of whom were > 40-year-old. Women over 40 had worse disease-free survival but also received less chemotherapy administration. Although radiotherapy was not often used, the longest survival in the > 40 age group was observed among those who received radiotherapy, including a case with resected lung metastasis. The review argues for multimodality management in this rare disease.
Citation: Razakanaivo M, Nguyen NP, Thariat J, Molinie V, Vlastos AT, Verschraegen C, Vinh-Hung V. Overview of embryonal rhabdomyosarcoma of cervix in women over 40-year-old. World J Obstet Gynecol 2016; 5(1): 110-117
Rhabdomyosarcoma (RMS), a mesenchymal tumor with the potential to differentiate into skeletal muscle, is the most common soft tissue sarcoma in children[1,2]. It is a complex disease that can originate in any part of the body, from the head or neck to the limbs. The major histologic subtypes are the alveolar rhabdomyosarcoma (ARMS) and the embryonal rhabdomyosarcoma (ERMS). ARMS is frequently characterized by the translocation of t (2; 13) PAX3-FOXO1 and t (1; 13) PAX7-FOXO1, while ERMS typically has a loss of heterozygosity of the short arm of chromosome 11[1,2]. ERMS is further divided into two classifications for the sarcoma botryoid variant or spindle cell variant[2]. Considerable improvements in the survival of ERMS patients have been attributed to intensive chemotherapy[3]. While RMS is rare, cervical location is exceedingly rare in adults, but a well-known entity. Thus far, only 10 adult cases of women > 40-year-old have been reported in the literature[4]. The present review aims to define the presentation of cervical RMS in adult women. We examined how outcomes of women > 40-year-old compared with younger women diagnosed with ERMS.
LITERATURE ON ERMS
The PubMed and Web of Science databases were searched for publications on ERMS. The key word combinations used were “rhabdomyosarcoma and embryonal” or “sarcoma and botryoid*” and “cervical or cervix”. The search was expanded manually using Google Scholar. Articles selected were case series reporting on four or more patients with cervical ERMS, among whom at least one was 40-year-old or older. The cutoff age of 40-year-old was chosen because fertility might be less of a concern than in younger women. We also took into consideration a bimodal age distribution around 40 years[5,6]. We focused on ERMS because of its preponderance among cervical sarcomas, representing 64.0% of all cervical sarcomas[7].
Two classification systems most commonly used were the pre-treatment TNM-based staging classification (Table 1), and the Intergroup Rhabdomyosarcoma Study Group (IRSG) clinical grouping based on operative pathology (Table 2). Tumor-node-metastasis classification has 4 stages (1-4) varying on the site of primary tumor, tumor size (T), regional lymph node involvement (N) and presence or absence of distant metastases (M). The IRSG classifies tumors in four groups (I-IV). Group I tumors are localized and completely resectable; however, based on whether they are confined to an organ/muscle or infiltrate outside is further classified as groups IA or IB, respectively. Tumors in group II are subdivided into three subgroups (A-C). In these tumors, the microscopic disease remains at margins and/or regional nodes. Group III (A-B) tumors are characterized by an incomplete resection or biopsy with gross residual disease remaining. Group IV tumors have distant metastases present at onset.
Table 1 Intergroup Rhabdomyosarcoma Study Group pretreatment clinical staging system.
Microscopic disease remaining (at margins or in regional nodes)
IIA
Grossly resected tumors with microscopic residual tumor
IIB
Regional disease, completely resected, with nodes involved and/or tumor extension into an adjacent organ
IIC
Regional disease, with involved nodes, grossly resected, but with evidence of microscopic residual tumor
Group III
Incomplete resection or biopsy with gross residual disease remaining
IIIA
After biopsy
IIIB
After major surgical resection
Group IV
Distant metastases present at onset
Data extracted from the publications were cross-tabulated by age group, the source of publication, and clinical grouping. For the analyses, we considered a pooled survival analysis using established methods[8]. However, upon browsing the publications, we realized that firstly there were no randomized trials, and secondly data were too scarce to allow advanced analyses[9]; providing inferential statistical outcomes would be misleading. We restricted the analyses to ad-hoc descriptive statistics, using the χ2 test only to indicate heterogeneity of the data. If patients in a group received significantly more treatment than the other group, we would report the P value to indicate the heterogeneous treatment attribution. However, if survival outcome differed, we would not test the survival difference. We detailed each retrieved publication as a “vignette”, so as to preserve a direct link with the source. We designed, after the fact, the cross tabulation to go one step beyond the narrative, without overextending to the pretense of a pooled review or a meta-analysis[10].
Review of ERMS case studies
A total of five eligible publications out of 6180 links from the three internet databases were identified (Figure 1, flowchart according to Moher et al[11]).
(1) Montag et al[5]: 4 cases of cervical ERMS; 18-42-year-old. One cervical ERMS patient was 42-year-old; (2) Brand et al[12]: 5 cases of cervical ERMS; 0-48-year-old. One cervical ERMS patient was 48-year-old; (3) Ferguson et al[13]: 15 cases of RMS embryonal and non-embryonal, of which 8 were cervical; 17-58-year-old. Five cervical ERMS patients were over 40-year-old; (4) Kriseman et al[14]: 11 cases; 3-52-year-old. ERMS in 10 cases, undifferentiated RMS in 1 case. Two cervical ERMS patients were > 40-year-old; and (5) Li et al[15]: 25 cases of ERMS, of which 20 were cervical; 20-89-year-old. Thirteen cervical ERMS patients were > 40-year-old.
Three additional publications also reported adult case series; however, there were no patients > 40-year-old[16-18]. Hence, these three publications were not selected for the review.
There were 47 patients with cervical ERMS from the five eligible case studies, with a mean age of 36-year-old at presentation (median, 33 years; range, 1-89 years). Table 3 summarizes patient characteristics according to age group. Table 4 provides the distribution by age and the IRSG grouping.
Table 3 Case-series of cervical embryonal rhabdomyosarcomas reporting on > 4 patients, of whom at least one was > 40-year-old.
No FU: 10 (45.5%) Alive: 8/12 (66.7%), 3 WD, Median FU 2.6 yr Died: 4 (33.3%), at median 1.2 yr
Table 4 Intergroup Rhabdomyosarcoma Study Group clinical grouping of the 5 case-series of cervical embryonal rhabdomyosarcomas, overwhelming missing data.
IRSG clinicalstage
Women ≤40-year-oldn = 25n (%)
Women > 40-year-oldn = 22n (%)
NA
11 (44.0)
13 (59.1)
I
11 (44.0)
9 (40.9)
II
1 (4.0)
0 (0.0)
III
1 (4.0)
0 (0.0)
IV
1 (4.0)
0 (0.0)
Montag et al[5] reported 6 cases of ERMS, diagnostic period unspecified, 4 of which involved the cervix or the cervix and uterus, and 2 of which had involvement of only uterus[5]. Five patients had a history of vaginal bleeding starting at 6 wk to 16 mo before the diagnosis. The ages of patients with a cervical origin were 18-, 21-, 26-, and 42-year-old. One patient had a vaginal protrusion of the tumor. The 42-year-old patient had a history of vaginal polyp excision, which had occurred 4 mo earlier. She was treated with a total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), omental biopsy, and pelvic and paraaortic lymph node biopsies. There was no evidence of extra-uterine disease. The patient received external postoperative radiation therapy consisting of 4500 cGy to the whole pelvis and an additional 4000 cGy to the vaginal cuff with radium brachytherapy. Nine months later, the patient developed a metastasis in the right lung. No other site of recurrence could be documented. The patient underwent resection of the upper lobe of the right lung followed by intravenous chemotherapy with nine cycles of doxorubicin and dacarbazine, then nine other cycles combining vincristine, actinomycin-D and cyclophosphamide (VAC), duration unspecified. The patient was alive without evidence of disease 10 years after her initial surgery. The younger patients were treated with radical hysterectomy and bilateral pelvic lymph node dissection (PLND). The 3 younger cervical ERMS patients all received postoperative chemotherapy, and 2 of them also preoperative chemotherapy. They were alive without evidence of disease 17 mo, 7 years, and 8 years after their surgery, respectively. The authors insisted on the importance of initial staging, which included cystoscopy, radiological exams and scans, as the single most important factor affecting prognosis and survival. For non-metastatic locally advanced disease, chemotherapy and radiotherapy have been used to convert inoperable RMS into a resectable disease. The authors argued that surgery followed by adjuvant chemotherapy and, occasionally, radiotherapy for residual disease produced the highest survival rates. An interesting point was the aggressive management of oligometastases in the patient with the longest survival.
Brand et al[12] reported 4 cases of ERMS of the uterine cervix diagnosed between 1960 and 1986. Patients were 17-mo-old, 2 were 17-year-old, and 1 was 48-year-old. The patients had a history of vaginal bleeding for 1 to 8 mo prior to the diagnosis of ERMS. The patient over 40 was treated with TAH-BSO. She received eight cycles of cyclophosphamide over a 3-mo period. Vaginal ERMS recurrence was diagnosed 2 mo later, for which she received whole pelvis external radiation (5400 cGy) and intravaginal radium therapy (3500 cGy). She was alive without evidence of malignancy 22 years after the initial treatment. Among the ≤ 40-year-old patients, the 17-mo-old infant presented with pulmonary, bone and brain metastases (Group IV, definition in Table 2). She received vincristine, dactinomycin and doxorubicin over 3 years and was reported to be alive and free of disease 8 years after the diagnosis of ERMS. The two other ≤ 40-year-old patients, who were both 17-year-old, presented with Group IA disease (definition in Table 2, localized disease), and received both TAH-BSO. One received postoperative radiotherapy and was diagnosed with bone metastasis at 1 mo after the radiotherapy; she died with metastatic disease 1 year after the initial diagnosis of ERMS. The other 17-year-old received adjuvant chemotherapy with dactinomycin and vincristine; she was alive and free of disease at 1 year after the initial diagnosis of ERMS. In the series, the outcome of the 48-year-old patient was comparable to that of the younger patients. Brand and colleagues stressed the importance of neo-adjuvant chemotherapy to conserve the function of the bladder, rectum, vagina, and ovaries when feasible. The author considered the role of radiotherapy unclear and did not recommend it for the Group I patients.
Ferguson et al[13] reported 8 cases of cervical ERMS treated between January 1963 and December 2003. Five patients were > 40-year-old at diagnosis (range, 46-58 years). All women older than 40 years presented with early-stage disease. The primary therapy for these women was surgery with TAH/BSO/PLND, except for 1 patient who had no BSO. Four of the women received adjuvant therapy, 2 with radiation alone and 2 in combination with chemotherapy. Three patients were alive without evidence of disease at 7, 27, and 37 mo after the diagnosis. Two patients who did not receive chemotherapy died of the disease. Among the 3 younger patients (age at diagnosis: 17-, 22-, and 32-year-old), 2 had a recurrence of the disease. Time to progression was 7 and 9 mo, and these 2 patients died of disease at 5 and 8 mo after recurrence, respectively. The authors stated that survival in women with gynecologic ERMS was not as favorable as compared to the pediatric population but emphasized that ERMS in adults is responsive to chemotherapy. They argued that adequate initial treatment should be multidisciplinary with surgery, radiation, and combination chemotherapy to offer the best chance of survival.
Kriseman et al[14] reported 11 cases of cervical ERMS between 1980 and 2010. Vaginal bleeding or discharge was present in all 11 patients, and 4 patients also had a protruding vaginal mass as a presenting symptom. Two patients had no staging information available. The other 9 had disease classified as IRSG group I, for whom the authors also provided International Federation of Gynecology and Obstetrics (FIGO) staging information intended for carcinoma rather than sarcoma[19,20]. All patients received surgery at some point during the treatment. Two patients were > 40-year-old at diagnosis (49 and 52 years). The 49-year-old patient had FIGO stage IB1 disease (tumor ≤ 4 cm). She was treated with TAH-BSO and received adjuvant chemotherapy (cyclophosphamide, doxorubicin, vincristine, and dacarbazine) and radiation beginning 6 mo after the diagnosis (4600 cGy delivered over 31 d). Six years later, this patient was diagnosed with an unresectable high-grade adenocarcinoma of the right parotid which metastasized to the lungs and caused her death. The 52-year-old patient had FIGO stage IB2 disease (tumor > 4 cm). She was treated by cone biopsy and did not receive adjuvant therapy. The patient was in complete remission 19 mo after the end of the treatment. The 9 younger patients presented with stage IB1 disease (2 cases), stage IB2 disease (3 cases), stage IIA disease (tumor involving upper 2/3 of the vagina, without parametrial invasion; 1 case), and stage unknown (2 cases). Eight patients were treated by cone biopsy, and 1 had a TAH. Neo-adjuvant chemotherapy was given in 2/9 cases. Post-operative chemotherapy was given in 6/9 cases. Five patients were alive without evidence of disease at 4, 6, 23, 35, and 121 mo after completion of therapy. One patient was alive with the disease following a local recurrence, 1 died of the disease, 1 died of unknown cause, and 1 died of complications related to neutropenic fever. The authors stressed the importance of multimodal therapy, even at an early stage. They found no differences in treatment or survival among women > 19-year-old and younger patients.
Li et al[15] reported 20 cases of cervical ERMS. Eleven patients were > 40-year-old. A cervical polyp was the most common clinical presentation. The diagnosis was made by biopsy (1 case), polypectomy (8 cases), and hysterectomy (2 cases). Therapeutic modalities were not available for all patients. Of the 3 patients with follow-up, 1 was alive without evidence of disease 3 years later; this case had received chemotherapy. One patient was alive with the disease at 5 mo after treatment. One patient died with pulmonary nodules at 5 mo after the treatment. Seven patients < 40-year-old were diagnosed by biopsy (2 cases) and polypectomy (5 cases). Follow-up data was available for 3 cases. These patients were alive without evidence of disease at 3.5, 6, and 8 years after chemotherapy. Li et al[15] compared the microscopic diagnosis of cervical ERMS in adults but reported no particular age-related morphological pattern. Their series’ age distribution showed a bimodal pattern with a peak at 40-49 years, but the authors did not comment. The authors discussed the importance of considering ERMS in the differential diagnosis of uterine corpus or cervical spindle cell tumors, regardless of the patient’s age.
Synthetic overview
Both adult and pediatric patients with cervical ERMS presented with vaginal bleeding and sometimes tumor protruding out of the vagina. However, in adults, symptoms can last up to 16 mo[5]; in contrast, in pediatric series, the vaginal bleeding and spotting lasted for 1 wk or less[18].
Histologically, ERMS tumors are characterized by myxoid stroma or edematous hypocellular spindle cell proliferation with cellular condensation beneath epithelial surfaces (cambium layer)[5,12,13,15]. Pathological diagnosis is based on the demonstration of skeletal muscle differentiation, morphologically, and with the use of immunohistochemistry for the coexpression of desmin and myogenin[5,13,15]. Ki-67 expression is usually elevated, and estrogen and progesterone receptors are absent[15]. ERMS differs from ARMS in that the stroma in ERMS is variably loose and shows dense cellularity within a myxoid matrix, whereas ARMS cells tend to cluster into nests that may be separated by fibrous septa[2].
Genetic alterations have yet to be clinically explored in cervical ERMS. In pathology series, there are frequent allelic losses, most notably in the chromosomal region 11p15.5[2]. Loss of heterozygosity on the short arm of chromosome 11 suggests inactivation of tumor suppressor genes[21]. Diverse gene fusions have been reported in subsets of ERMS[22,23], fusion-positive PAX3/7-FOXO1 in 7 of 31 ERMS, and hyperploidy associated with gains of chromosomes 2, 8 and 12[24]. While a discussion of genetic lesions is beyond the purpose of the present review, the lesions may potentially explain heterogeneity of cases and the increased risk for multiple primary cancers that have been reported by several authors[14,16,18]. FOXO1 translocation status will be used as a risk stratification criterion in future pediatric RMS studies[3].
Staging did not seem to differ across different age groups; however, diagnostic work-up was missing in half of the cases reviewed (Table 4). The case series spanned across a long time period, from as early as 1960, whereas current imaging procedures differ considerably. Patients who had a negative positron emission tomography (PET) following induction chemotherapy and radiotherapy had a better local relapse-free survival than RMS patients who had a positive PET (94% vs 75%, P = 0.02)[25]. PET might replace conventional staging imaging studies[3,26,27]. None of the case series reported the use of PET.
There were substantial differences in the management between the two age groups in the pooled data, though this could not be ascertained within each paper (Table 3). Data on hysterectomy was more often missing in older women than in younger women [36% (8/22 patients) vs 16% (4/25 patients)]. Among documented cases, hysterectomy rates were higher in older women [86% (12/14 patients) vs 43% (9/21 patients)]. In older women, chemotherapy was used less often (55% vs 90%), but radiotherapy more often (36% vs 21%). These differences may be due to the desire to preserve fertility in younger patients.
Chemotherapy and radiotherapy data were missing more frequently for the older than the younger patients (50% vs 22%). Among those with available information, the most commonly used chemotherapy regimens in 20 patients > 40-year-old included VAC (13 patients, 65.0%), VA (2 patients, 10.0%), and vincristine, doxorubicin and cyclophosphamide (VDC) (2 patients, 10.0%). One patient received VDC plus dacarbazine and cyclophosphamide. Two patients received a non-VAC regimen (etoposide alone[13] or cisplatin and doxorubicin combination[14]). Overall, 85% of the chemotherapy regimens followed a pediatric protocol, regardless of age group[28-30].
The death rate was twice as high in patients > 40-year-old than in the younger age group. Older patients who survived had more residual disease than the younger patients. The poorer outcome might be explained by lower chemotherapy administration rate (Table 3). The follow-up data was missing across all age groups, but was especially high in the older group (45% vs 32%), precluding reliable comparison. In the most recent publications, the frequency of surgery appeared to decrease, and radiotherapy was infrequently given, even in women over 40 (Table 3). The median time of death or the last follow-up among younger patients who received radiotherapy was 1 year, which raises the question whether or not these patients had been selected because of more advanced disease. The longest survivals were observed among those who received external beam radiotherapy and brachytherapy. The reported survival times in that subset ranged between extremes, from 1.4 and 2 years[13] through 6[14], 10[5], to 22 years in a patient who received early salvage radiotherapy and brachytherapy[12].
The limitations of our study have been a small sample size and a retrospective approach; nevertheless, EMRS is sensitive to chemotherapy and radiotherapy. Since ovarian preservation is less of a concern in women who are over 40 years old, radiotherapy could be applied in those who have metastatic pelvic and/or paraaortic lymph nodes or residual disease following surgery. In patients whose tumors are locally unresectable, chemoradiation may be given either preoperatively or to the patient who is not a surgical candidate because of associated co-morbidity. In patients who present with distant metastases, induction chemotherapy and reassessment for loco-regional treatment after chemotherapy may be an option, depending on the response to chemotherapy. In the era of modern radiotherapy techniques such as stereotactic body radiotherapy and image-guided radiotherapy, long-term remission may be feasible even when the patient has distant metastases[31]. Because of the rarity of the disease, the feasibility of prospective studies is questionable. An international registry for rare tumors could be used as a depository and a resource on treatment data and long-term follow-up.
CONCLUSION
ERMS is an exceedingly rare disease among middle-aged women. An international registry could help determine the optimal treatment of patients at various disease stages. Long-term survival is possible with multimodality treatments, as the tumor is chemo- and radio-sensitive. A multidisciplinary team approach is essential for optimal therapy. In the future, genomics might provide new therapeutic opportunities.
ACKNOWLEDGMENTS
The authors would like to thank Dayleen De Riggs and Kristen L. Young for their help in the preparation of this manuscript.
Footnotes
P- Reviewer: Sonoda K S- Editor: Kong JX L- Editor: A E- Editor: Wu HL
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