A case of Pseudomyxoma Peritonei of an unexpected origin.

A case of Pseudomyxoma Peritonei of an unexpected origin. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report A case of Pseudomyxoma Peritonei of an unexpected origin. Marie Csanyi-Bastien, France Blanchard, Aude Lamy, Jean-Christophe Sabourin This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-907797/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Dec, 2021 Read the published version in Diagnostic Pathology → Version 1 posted 15 You are reading this latest preprint version Abstract Background: Pseudomyxoma peritonei (PMP) is a complex and partially understood disease defined by mucin deposits in the peritoneal cavity, mostly of appendiceal origin caused by the rupture of a mucocele often containing Low or High grade Appendiceal Mucinous Neoplasm (LAMN/HAMN). Other origins include primary ovarian mucinous cystadenoma or cystadenocarcinoma almost always with an associated teratoma, but to our knowledge no case of ovarian teratomatous appendiceal-like mucocele with LAMN has been reported as a cause of PMP. Case presentation: A 25-year old female with infertility was diagnosed with an isolated left ovarian tumor in a context of PMP. Histological examination revealed an ovarian teratoma containing an appendiceal-like structure with mucocele and LAMN, without any associated lesion of the appendix on full histological analysis. Molecular characterization of the ovarian lesion showed co- KRAS and GNAS mutations, as described in PMP of appendiceal origin, while only KRAS mutations are reported in primary ovarian mucinous tumor. Conclusions: Detection of co- KRAS and GNAS mutations in our case of ovarian teratomatous appendiceal-like mucocele with LAMN shows that when PMP derives from a mucinous ovarian lesion (with histological proof of none-appendiceal involvement), it is probably of a digestive teratomatous origin, emphasizing the need to actively search for tetatomatous signs in a context of ovarian PMP. Pathology Laboratory Diagnostics Pseudomyxoma peritonei Ovarian pseudomyxoma peritonei Appendiceal pseudomyxoma peritonei Ovarian teratoma KRAS / GNAS mutations LAMN Figures Figure 1 Figure 2 Figure 3 Figure 4 Background: Pseudomyxoma Peritonei (PMP) is a rare neoplastic disease defined by the presence of mucinous material in the peritoneal cavity. Its complex physiopathology remains unclear. The majority of PMP are of appendiceal origin due to rupture of a mucocele associated with a low-grade appendiceal mucinous neoplasm (LAMN) or a high-grade appendiceal mucinous neoplasm (HAMN). However, in a few cases, tumors of other origins, especially ovarian, may be associated with PMP. Indeed, the description of authentic cases of PMP without appendiceal involvement but with associated ovarian tumor have confirmed its ovarian origin. Primary ovarian PMP are thought to develop from a broad spectrum of mucinous ovarian entities, from mucinous cystadenoma to borderline cystadenoma and cystadenocarcinoma, almost always in the context of an associated teratoma. Mucinous proliferation in teratoma is well described but to our knowledge, no teratomatous LAMN has been reported. We describe a case of PMP caused by a ruptured appendiceal-like mucocele associated with LAMN in an ovarian teratoma. Our investigations provide clinical, histological, immunohistochemical and molecular data. We also conducted a literature review about PMP origin, especially ovarian. Case Presentation: Clinical context : A 25-year-old woman, without previous medical history, presented for infertility lasting for more than one year. Clinical examination was normal but abdominal and pelvic tomodensitometry (TDM) revealed a cyst of the left ovary associated with abundant peritoneal ascites that could correspond to mucinous material. Pelvic magnetic resonance imaging (MRI) confirmed ascites and showed a heterogeneous mass of the left ovary measuring 8.4 x 6.8 cm with adipose, solid and cystic regions whose features were suggestive of a dermoid cyst. The right ovary and uterus seemed normal. No other lesion was seen in the rest of the body, notably in the digestive system. In this context, surgery was performed three months after the first consultation, consisting in a left oophorectomy with appendicectomy and omentectomy. No hyperthermic intraperitoneal chemotherapy (HIPEC) was undertaken. Intra-operative examination revealed mucinous material inside the peritoneal cavity and a normal digestive tract with a normal appendix. There was no complication of the surgery. Clinical and imaging surveillance was then decided. The 5-month follow-up available data revealed no clinical complaints. Without relapse, the patient was able to pursue her plan to have a child. Histopathological findings : Macroscopically, the left ovary was cystic measuring 9.5 x 7 x 7 cm and weighing 305 g. It was ruptured on 4 cm. Its cut section revealed a heterogeneous and viscous mass with hair. The appendix, measuring 6 cm in length, and the omentum were macroscopically normal. Histologically, the ovarian cyst corresponded to a mature pluritissular teratoma with intermingled skin and pilosebaceous annexes, serous and mucinous glands, respiratory epithelium, adipose tissue and smooth muscle ( Fig. 1 ) . The organoid areas with the aspect of a colon were composed of colonic mucosa, muscularis mucosae, and submucosa from the surface to the depth. A thick muscularis propria was also observed. In the colonic mucosa, some glands were elongated and layered with moderate proliferating epithelial cells with minimal atypia, near to mucin pools stained with Alcian blue. The colonic epithelial cells were immunohistochemistry stained with CK20 and CDX2, and showed heterogeneous staining for CK7. These cells were negative for estrogen and progesterone receptors ( Fig. 2 ) . The ovarian surface was covered with hyperplastic mesothelial cells and presented acellular mucinous pools, also found in the omentum. The left fallopian tube was normal. The appendix examined in totality was histologically normal besides mucin deposits on the surface of the serosa. It did not present any mucocele or LAMN/HAMN. All together, these data suggested a diagnosis of acellular PMP (according to Carr classification [ 1 ] ) caused by a ruptured appendiceal-like mucocele associated with LAMN, in a left ovarian teratoma. Molecular features : Next generation sequencing of the LAMN of the teratomatous mucocele revealed an activating mutation of KRAS gene c.35G > A corresponding to the p.(Gly12Asp) substitution ( Fig. 3 ) . Complementary molecular analysis by SNaPshot showed an associated mutation of GNAS c.602G > A resulting in p.(Arg201His). No mutation was found by these two techniques on the other tissues of the ovarian teratoma (squamous, respiratory, adipose or smooth muscle elements) or in the normal appendix and ovarian parenchyma ( Fig. 4 ) . Discussion: PMP is an anatomo-clinical entity defined either by mucinous ascites or mucinous deposits in the peritoneal cavity. It is a rare disease whose incidence is approximately 1 to 2 cases per million people per year and which affects more commonly women [ 2 ] . Its clinical manifestations are abdominal distention, pain and transit disorder. PMP is caused by the peritoneal localization of mucin, almost exclusively in the context of a tumor, by two possible mechanisms: tumor rupture in the peritoneal cavity causing the spread of mucinous material containing a variable amount of tumor cells, or metastatic diffusion to the peritoneum of a mucinous adenocarcinoma. Most of the tumors (90%) are of appendiceal origin from LAMN or HAMN associated with a mucocele [ 2 ] . Other tumors correspond to mucinous adenocarcinomas of colonic [ 3 ] , gastric [ 4 ] , pancreatic [ 5 , 6 ] , urachian [ 7 ] , pulmonary [ 8 ] , endocervical [ 9 ] or mammary [ 10 ] origin, or to rare mucinous ovarian tumors, cystadenomas or cystadenocarcinomas [ 9 ] . Some authors reported non-neoplastic intra-peritoneal mucinous deposits caused by alternative processes as mucin retention due to a stercolith or a diverticule, or mucinous metaplasia of fallopian tubes [ 11 , 12 , 13 ] , but such situations are very rare and questionable. Physiopathologically, the mucin deposits, more or less associated with tumor cells, lead by the redistribution phenomenon [ 14 ] and epithelio-mesenchymal transition [ 15 ] to the spread of mucin into the whole peritoneal cavity. Hematogenic and lymphatic routes of dissemination seem to be infrequent in this complex pathology, still partially understood. However, its clinical evolution leads to consider PMP as a neoplastic condition with variable behaviors, either indolent or aggressive. Curative treatment of PMP relies on maximal cytoreduction surgery completed by HIPEC, performed by experienced staff in a reference center [ 16 , 17 ] . This surgical act is indeed associated with numerous potential complications, leading to high morbidity (16 to 65%) and mortality (0 to 18%). Nevertheless, extended survey is possible (59% at 5 years) [ 18 ] . Several histological classifications have been established for PMP. In 2017, Carr et al. proposed a PMP classification divided in four categories: mucin without epithelial cells; PMP with low-grade histological features; PMP with high-grade histological features; and PMP with signet ring cells [ 1 ] . Recently, the 2019 WHO (World Health Organization) classification adopted a three-tiered system of classification to unify and simplify denomination of the disease. Grade 1 (or low grade appendiceal mucinous neoplasm) is defined by acellular or hypocellular mucinous deposits, with pushing tumor margins, and low grade epithelial cell cytology. Grade 2 (or high grade appendiceal mucinous neoplasm) is characterized by mucinous deposits with numerous epithelial cells often arranged in clusters with marked atypia. Grade 3 (or high grade with signet-ring cells) is represented by neoplasms containing true signet-ring cells defined as intracytoplasmic mucin vacuole indenting the nucleus (degenerating cells floating within mucin pools should not be considered as true signet-ring cells) [ 19 ] . The primitive ovarian origin of PMP has been debated for a long time. First descriptions of PMP were from appendiceal or intestinal origins. Thus, when a female patient presented with a clinical situation of PMP with both mucinous lesions of the appendix and the ovaries, she was considered to present either a PMP of appendiceal origin with secondary localization of the ovaries or an appendiceal PMP with a concomitant borderline mucinous ovarian tumor [ 20 – 22 ] . In order to elucidate the origin of PMP in cases of both appendiceal and ovarian mucinous lesions, some authors tried to define morphological criteria comparing the aspects of mucinous tumor of the ovaries with and without PMP and appendiceal tumor. For Ronett et al., the secondary ovarian localization of a primitive digestive tumor was retained when (i) the ovarian tumor was only superficial; (ii) ovaries were of a quite normal size; (iii) a unilateral ovarian tumor had a digestive phenotype in a context of anteriority of such a digestive tumor; (iv) a bilateral ovarian tumor had a digestive phenotype without any known antecedent; (v) an appendiceal tumor was ruptured with an intact associated ovarian tumor [ 22 ] . Stewart et al. observed that secondary ovarian tumor was made by scalloped glands layered by sub epithelial clefts while primary ovarian tumor did not share these features but was instead associated with an abundant stroma reaction and histiocytic infiltration [ 23 ] . Immunohistochemistry has also been used to distinguish between primary and secondary ovarian origin. Ferraira et al. showed that CK20 and MUC2 were more often expressed by mucinous ovarian tumors associated with PMP than by mucinous ovarian tumors without PMP, supporting the hypothesis of a secondary ovarian localization of a primitive digestive tumor [ 24 ] . However, Saluja et al. reported a case of PMP associated with an ovarian borderline mucinous tumor without any digestive tumor [ 24 ] . In this case, the appendix was normal on full microscopic examination, and the ovarian tumor expressed both CK7 and CK20, with MUC2. Finally, studies revealed that the immunohistochemical profile of the tumor did not allow to distinguish between PMP of primary ovarian or digestive origin, both of them being positive for CK20 and CDX2 with variable staining for CK7 [ 25 ] . O’Connell et al. investigated the mucin composition of PMP, which is principally made of MUC2 and MUC5AC and revealed that while MUC2 was more abundant in PMP, but also in appendiceal mucinous tumors and normal digestive tissue, MUC5AC was predominant in mucinous ovarian primitive tumors, suggesting that mucin composition could help to distinguish the origin of PMP [ 26 , 27 ] . However, only a few studies on mucin composition are available. However, some cases of authentic PMP with an ovarian origin have been described. These cases were associated with various mucinous tumors of the ovary, as benign mucinous adenomas, borderline mucinous tumors and adenocarcinomas [ 28 – 31 ] . Many of these primary ovarian PMP, in which an appendiceal origin was formally excluded, mucinous ovarian tumors were associated with teratoma, suggesting for some authors that primary ovarian origin of a PMP was only possible in a context of a mucinous ovarian tumor arising from an ovarian teratoma [ 32 ] . It should be noted that ovarian teratomas associated with mucinous tumors causing PMP did not show particularities from other teratomas without mucinous associated lesion. The unique and original feature of our case is that the primary ovarian tumor responsible for the PMP was not a classic mucinous tumor of the ovary associated with a teratoma but a teratomatous appendiceal-like mucocele with LAMN. To our knowledge, such teratomatous involvement has never been described. Molecular sequencing of PMP revealed frequent KRAS and GNAS mutations as in mucinous tumors of the appendix. These mutations are frequent in LAMN and HAMN and slightly rarer in mucinous appendiceal adenocarcinomas, which harbor frequent TP53 mutations as in HAMN but not LAMN [ 33 ] . KRAS mutations occur in exon 2. GNAS mutations are located at codon 201 in c.601 or c.602. Mutations in codon 601 are frequently c.601C > T, resulting in p.(R201C), and those in codon 602 are often c.602G > A resulting in p.(R201H) [ 34 ] . While the former is more common in LAMN, the latter is more common in HAMN. Molecular data on primary mucinous ovarian carcinomas without the context of PMP showed frequent mutations in KRAS , without GNAS mutation [ 34 ] . Choi et al. studied molecular alterations in primary ovarian mucinous tumor associated with teratoma and PMP. They revealed KRAS and GNAS associated mutations [ 35 ] . These results, as ours, could indicate that ovarian mucinous tumors associated with teratomas and responsible for PMP are in fact of a teratomatous digestive origin. Molecular data on PMP of other origins than appendiceal and ovarian are not available, those cases being very rare. Conclusions: PMP is a rare neoplastic disease, deriving in most cases from a mucinous appendiceal tumor from LAMN, HAMN or adenocarcinoma, all associated with KRAS and GNAS associated mutations. Mucinous tumors of other origins, mostly adenocarcinomas, can also cause PMP, among them mucinous ovarian tumors, almost always in a context of concomitant ovarian teratoma. In the literature, molecular data show that KRAS and GNAS co-mutations are also present in primary ovarian PMP associated with teratoma. By reporting here the presence of KRAS and GNAS mutations in this extremely rare case of primary ovarian PMP derived from the rupture of a teratomatous appendiceal-like mucocele with LAMN arising in an ovarian teratoma, our results suggest the teratomatous digestive origin of the mucinous ovarian tumors causing PMP. This finding emphasizes the need to actively search for teratomatous signs in a context of primary ovarian PMP. Abbreviations HAMN: High-grade Appendiceal Mucinous Neoplasm HIPEC: Hyperthermic IntraPEritoneal Chemotherapy LAMN: Low-grade Appendiceal Mucinous Neoplasm MRI: Magnetic Resonance Imaging PMP: PseudoMyxoma Peritonei TDM: TomoDensitoMetry WHO: World Health Organization Declarations Ethics approval and consent to participate: The ethics committee of Rouen University Hospital has approved this study. Consent for publication: Consent for publication was obtained according to the policies of the institutional review board of Rouen University Hospital and the French Ministry of Scientific Research. Availability of data and materials: Concerning clinical and sample collection, approval was obtained according to the agreement of the tumor biobank of Rouen University Hospital (tissue sample collection n° DC2008-689). Competing interests: The authors declare no conflict of interest regarding this work. Source of funding: This work was not funded by any grant. Authors’ contributions: MCB and JCS performed histological examination of the left ovary and appendix. FB and AL realized molecular analyses. MCB and JCS were major contributors in writing the manuscript. All authors read and approved the final manuscript. Acknowledgements: The authors are indebted to Nikki Sabourin-Gibbs (Rouen University Hospital) for assistance with language editing. References Carr NJ, Bibeau F, Bradley RF, Dartigues P, feakins RM, Geisinger KR, Gui X, Isaac S, Milione M, Misdraji J, Pai RK, Rodriguez-Justo M, Sobin LH, van Velthuysen MF, Yantiss RK. The histopathological classification, diagnosis and differential diagnosis of mucinous appendiceal adenocarcinomas and pseudomyxoma peritonei. Histopathology. 2017;6. Van den Heuvel MG, Lemmens VE, Verhoeven RH, de Hingh IH. The incidence of mucinous appendiceal malignancies: a population-based study. Int J Colorectal Dis. 2013;28:1307–10. de Bree E, Witkamp A, Van De Vijver M, Zoetmulde F. Unusual origins of pseudomyxoma peritonei. J Surg Oncol. 2000;75. Ikejiri K, Anai H, Kitamura K, Yakabe S, Saku M, Yoshida K. Pseudomyxoma peritonei concomitant with early gastric cancer: report of a case. Surg Today 1996;26. Chejfec G, Rieker WJ, Jablokow VR, Gould VE. Pseudomyxoma peritonei associated with colloid carcinoma of the pancreas. Gastroenterology 1986;90. Mizuta Y, Akazawa Y, Shiozawa K, et al. Pseudomyxoma peritonei accompanied by intraductal papillary mucinous neoplasm of the pancreas. Pancreatology 2005;5. Agrawal AK, Bobin´ski P, Grzebieniak Z, et al. Pseudomyxoma peritonei originating from urachus: case report and review of the literature. Curr Oncol. 2014;21. Kurita M, Komatsu H, Hata Y, et al. Pseudomyxoma peritonei due to adenocarcinoma of the lung: case report. J Gastroenterol 1994;29. Dario Baratti S, Kusamura M, Milione, et al. Pseudomyxoma peritonei of extra-appendiceal origin: a comparative study. Ann Surg Oncol 2016;23. Hawes D, Robinson R, Wira R. Pseudomyxoma peritonei from metastatic colloid carcinoma of the breast. Gastrointest Radiol 1991;16. Lamps LW, Gray GF Jr, Dilday BR, Washington MK. The coexistence of low grade mucinous neoplasms of the appendix and appendiceal diverticula: a possible role in the pathogenesis of pseudomyxoma peritonei. Mod Pathol. 2000;13. Dupre MP, Jadavji I, Matshes E, Urbanski SJ. Diverticular disease of the vermiform appendix: a diagnostic clue to underlying appendiceal neoplasm. Hum Pathol 2008;39. Minguillon C, Friedmann W, Vogel M, Wessel J, Lichtenegger W. Mucinous metaplasia of fallopian tube mucous membrane as a cause of peusomyxoma peritonei. Zentralbl Pathol. 1992;138. Sugarbaker PH. Pseudomyxoma peritonei: a cancer whose biology is characterized by a redistribution phenomenon. Ann Surg 1994;219. Bibi R, Pranesh N, Saunders MP, Wilson MS. O’dwyer ST, Stern. PL. et al. A specific cadherin phenotype may characterise the disseminating yet non-metastatic behaviour of pseudomyxome peritonei. Br J Cancer 2006;95. Sugarbaker PH. Cytoreductive surgery and peri-operative intraperitoneal chemotherapy as a curative approach to pseudomyxoma peritonei syndrome. Eur J Surg Oncol.2001; 27. Dartigues P, Isaac S, Villeneuve L, et al. Mise au point sur le pseumdomyxome peritonéal. Aspects anatomo-apthologiques, et implications thérapeutiques. Ann Pathol. 2014;34. Chua TC, Moran BJ, Sugarbaker PH, et al. Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin Oncol 2012;30. Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, Washington KM, Carneiro F, Cree IA. & WHO Classification of Tumours Editorial Board (2020). The 2019 WHO classification of tumours of the digestive system. Histopathology, 76;2. Young RH, Gilks CB, Scully RE. Mucinous tumors of the appendix associated with mucinous tumors of the ovary and pseudomyxoma peritonei: A clinicopathologic analysis of 22 cases supporting an origin in the appendix. Am J Surg Pathol 1991;15. Prayson RA, Hart WR, Petras RE. Pseudomyxoma peritonei: A clinicopathologic study of 19 cases with emphasis on site of origin and nature of associated ovarian tumors. Am J Surg Pathol 1994;18. Ronnett BM, Kurman RJ, ZAHN, CM, et al. Pseudomyxoma peritonei in women: a clinicopathologic analysis of 30 cases with emphasis on site of origin, prognosis and relationship to ovarian mucinous tumors of low malignant potential. Hum pathol 1995;26. Stewart CJ, Ardakani NM, Doherty DA, Young RH. An evaluation of the morphologic features of low-grade mucinous neoplasms of the appendix metastatic in the ovary, and comparison with primary ovarian mucinous tumors. Int J Gynecol Pathol. 2014;33. Ferreira CR, Carvalho JP, Soares FA, Siquiera SA, Carvalho FM. Mucinous ovarian tumors associated with pseudomyxoma peritonei of adenomucinosis type: immunohistochemical evidence that they are secondary tumors. Int J Gynecol Cancer 2008;18. Saluja M, Kenwright DN, Keating JP. Pseudomyxome peritonei arising from a mucinous borderline ovarian tumor: case report and literature review. Aust N Z J Obstet Gynaecol. 2010;50. O’Connell JT, Hacker CM, Barsky SH. MUC2 is a molecular marker for pseudomyxome peritonei. Mod Pathol. 2002;15. O’Connell JT, Tomlinson JS, Roberts AA, McGonigle KT, Barsky SH. Pseudomyxoma peritonei is a disease of MUC2-expressing goblet cells. Am J Pathol. 2002;161. Ronnett BM, Seidman JD. Mucinous tumors arising in ovarian mature cystic teraromas: relationship to the clinical syndrome of pseudomyxome peritonei. Am J Surg Pathol. 2003;27. McKenney JK, Soslow RA, Longacre TA. Ovarian mature teratomas with mucinous epithelial neoplasms: morphologic heterogeneity and association with pseudomyxome peritonei. Am J Surg Pathol 2008;32. Pranesh N, Menasce LP, Wilson MS, O’Dwyer ST. Pseudomyxoma peritonei: unusual origin from an ovarian mature cystic teratoma. J Clin Pathol 2005;58. Marquette S, Amant F, Vergote I, Moerman P. Pseudomyxoma peritonei associated with a mucinous ovarian tumor arising from a mature cystic teratoma. A case report. Int J Gynecol Pathol; 2006;25. Hwang JH, So MD, Modi KA, Lee G, Lee JK, Lee NW, Kim KW. I; Borderline-like mucinous tumor arising in mature cystic teratoma of the ovary associated with pseudomyxome peritonei. Int J Gynecol Pathol. 2009;28. Nishikawa G, Sekine S, Ogawa R, et al. Frequent GNAS mutations in low-grade appendiceal mucinous neoplasms. B. J. Cancer 2013;108. Nummela P, SaarinenL, Thiel A, et al. Genomic profile of pseudomyxome peritonei analyzed using next-generation sequencing and immunohistochemistry. Int J Cancer 2015;136. Choi YJ, Lee SH, Kim MS, et al. Whole-exome sequencing identified the genetic origin of a mucinous neoplasm in a mature cystic teratoma. Pathology 2016;48. Cite Share Download PDF Status: Published Journal Publication published 01 Dec, 2021 Read the published version in Diagnostic Pathology → Version 1 posted Review # 2 received at journal 20 Oct, 2021 Editorial decision: Minor Revision 20 Oct, 2021 Review # 1 received at journal 19 Oct, 2021 Reviewer # 5 agreed at journal 11 Oct, 2021 Review # 4 received at journal 11 Oct, 2021 Review # 3 received at journal 11 Oct, 2021 Reviewer # 4 agreed at journal 10 Oct, 2021 Reviewer # 3 agreed at journal 06 Oct, 2021 Reviewer # 2 agreed at journal 05 Oct, 2021 Reviewer # 1 agreed at journal 05 Oct, 2021 Reviewers invited by journal 30 Sep, 2021 First submitted to journal 29 Sep, 2021 Editor assigned by journal 29 Sep, 2021 Submission checks completed at journal 29 Sep, 2021 Editor invited by journal 29 Sep, 2021 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-907797","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":55460873,"identity":"5752ad47-1cad-4422-a54e-2a93403301e3","order_by":0,"name":"Marie Csanyi-Bastien","email":"","orcid":"https://orcid.org/0000-0002-6311-4393","institution":"CHU Rouen: Centre Hospitalier Universitaire de Rouen","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Marie","middleName":"","lastName":"Csanyi-Bastien","suffix":""},{"id":55460874,"identity":"faae8616-9f83-4d2f-a309-3b3820fbf249","order_by":1,"name":"France Blanchard","email":"","orcid":"","institution":"CHU Rouen: Centre Hospitalier Universitaire de Rouen","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"France","middleName":"","lastName":"Blanchard","suffix":""},{"id":55460875,"identity":"234ad77c-25de-4686-8478-7b2680f9f1d3","order_by":2,"name":"Aude Lamy","email":"","orcid":"","institution":"CHU Rouen: Centre Hospitalier Universitaire de Rouen","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Aude","middleName":"","lastName":"Lamy","suffix":""},{"id":55460876,"identity":"b82a25cc-1bfa-4478-bc51-a287603b83da","order_by":3,"name":"Jean-Christophe Sabourin","email":"data:image/png;base64,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","orcid":"","institution":"CHU Rouen: Centre Hospitalier Universitaire de Rouen","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jean-Christophe","middleName":"","lastName":"Sabourin","suffix":""}],"badges":[],"createdAt":"2021-09-15 10:14:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-907797/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-907797/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13000-021-01179-z","type":"published","date":"2021-12-01T12:48:45+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":14264556,"identity":"7aa399e1-a755-4823-9f4b-92d5ff2048a5","added_by":"auto","created_at":"2021-10-05 15:13:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1195461,"visible":true,"origin":"","legend":"Title: Immunohistochemical profile of the colonic epithelium with LAMN inside the ovarian teratoma.\nLegend: The epithelial cells are strongly stained by CK20 (a) and CDX2 (b) antibodies. They are heterogeneously stained by CK7 (c) antibody. They present no staining by estrogen (d) and progesterone (e) receptors.\n","description":"","filename":"fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-907797/v1/1baf9d5a94cd9424b7b83985.png"},{"id":14265012,"identity":"86607dac-f477-4634-842c-3fc324adf98d","added_by":"auto","created_at":"2021-10-05 15:16:20","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":692196,"visible":true,"origin":"","legend":"Title: List of mutations found in the teratomatous LAMN.\nLegend: Among the mutations revealed in the LAMN lesion, there was a c.35G\u003eA mutation in KRAS gene corresponding to a p.(Gly12Asp) protein effect (highlighted line).\n","description":"","filename":"fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-907797/v1/ba28818e813db48d6526d53e.png"},{"id":14264554,"identity":"e0128818-f00a-4397-8ecd-75f1d38c2af6","added_by":"auto","created_at":"2021-10-05 15:13:20","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":482699,"visible":true,"origin":"","legend":"Title: List of mutations found in the teratomatous LAMN.\nLegend: Among the mutations revealed in the LAMN lesion, there was a c.35G\u003eA mutation in KRAS gene corresponding to a p.(Gly12Asp) protein effect (highlighted line).\n","description":"","filename":"fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-907797/v1/a49bd704e2afe118c467cd99.png"},{"id":14264553,"identity":"c5e40ca1-4290-4a3c-b598-e2bc9d050c37","added_by":"auto","created_at":"2021-10-05 15:13:20","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":95140,"visible":true,"origin":"","legend":"Title: Mutational status of GNAS gene in teratomatous LAMN, ovarian teratoma and appendix by SNaPshot analysis.\nLegend: In the teratomatous LAMN there was a c.602C\u003eT (reverse) corresponding to a c.602G\u003eA (forward) mutation in GNAS (a) while in the other tissues of the teratoma (b) and in the normal appendix (c) there was no mutation detected in GNAS.\n","description":"","filename":"fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-907797/v1/03b07e0cb5424738e866f72e.png"},{"id":16609447,"identity":"9ad07819-dc89-440d-b2e9-7717eac94948","added_by":"auto","created_at":"2021-12-20 12:48:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2471146,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-907797/v1/20aaaf50-e0b1-4325-a3e0-8c344369de7f.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eA case of Pseudomyxoma Peritonei of an unexpected origin.\u003c/p\u003e","fulltext":[{"header":"Background:","content":"\u003cp\u003ePseudomyxoma Peritonei (PMP) is a rare neoplastic disease defined by the presence of mucinous material in the peritoneal cavity. Its complex physiopathology remains unclear. The majority of PMP are of appendiceal origin due to rupture of a mucocele associated with a low-grade appendiceal mucinous neoplasm (LAMN) or a high-grade appendiceal mucinous neoplasm (HAMN). However, in a few cases, tumors of other origins, especially ovarian, may be associated with PMP. Indeed, the description of authentic cases of PMP without appendiceal involvement but with associated ovarian tumor have confirmed its ovarian origin. Primary ovarian PMP are thought to develop from a broad spectrum of mucinous ovarian entities, from mucinous cystadenoma to borderline cystadenoma and cystadenocarcinoma, almost always in the context of an associated teratoma. Mucinous proliferation in teratoma is well described but to our knowledge, no teratomatous LAMN has been reported. We describe a case of PMP caused by a ruptured appendiceal-like mucocele associated with LAMN in an ovarian teratoma. Our investigations provide clinical, histological, immunohistochemical and molecular data. We also conducted a literature review about PMP origin, especially ovarian.\u003c/p\u003e"},{"header":"Case Presentation:","content":"\u003cp\u003e \u003cem\u003eClinical context\u003c/em\u003e:\u003c/p\u003e \u003cp\u003eA 25-year-old woman, without previous medical history, presented for infertility lasting for more than one year. Clinical examination was normal but abdominal and pelvic tomodensitometry (TDM) revealed a cyst of the left ovary associated with abundant peritoneal ascites that could correspond to mucinous material. Pelvic magnetic resonance imaging (MRI) confirmed ascites and showed a heterogeneous mass of the left ovary measuring 8.4 x 6.8 cm with adipose, solid and cystic regions whose features were suggestive of a dermoid cyst. The right ovary and uterus seemed normal. No other lesion was seen in the rest of the body, notably in the digestive system. In this context, surgery was performed three months after the first consultation, consisting in a left oophorectomy with appendicectomy and omentectomy. No hyperthermic intraperitoneal chemotherapy (HIPEC) was undertaken. Intra-operative examination revealed mucinous material inside the peritoneal cavity and a normal digestive tract with a normal appendix. There was no complication of the surgery. Clinical and imaging surveillance was then decided. The 5-month follow-up available data revealed no clinical complaints. Without relapse, the patient was able to pursue her plan to have a child.\u003c/p\u003e \u003cp\u003e \u003cem\u003eHistopathological findings\u003c/em\u003e:\u003c/p\u003e \u003cp\u003eMacroscopically, the left ovary was cystic measuring 9.5 x 7 x 7 cm and weighing 305 g. It was ruptured on 4 cm. Its cut section revealed a heterogeneous and viscous mass with hair. The appendix, measuring 6 cm in length, and the omentum were macroscopically normal. Histologically, the ovarian cyst corresponded to a mature pluritissular teratoma with intermingled skin and pilosebaceous annexes, serous and mucinous glands, respiratory epithelium, adipose tissue and smooth muscle \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. The organoid areas with the aspect of a colon were composed of colonic mucosa, muscularis mucosae, and submucosa from the surface to the depth. A thick muscularis propria was also observed. In the colonic mucosa, some glands were elongated and layered with moderate proliferating epithelial cells with minimal atypia, near to mucin pools stained with Alcian blue. The colonic epithelial cells were immunohistochemistry stained with CK20 and CDX2, and showed heterogeneous staining for CK7. These cells were negative for estrogen and progesterone receptors \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. The ovarian surface was covered with hyperplastic mesothelial cells and presented acellular mucinous pools, also found in the omentum. The left fallopian tube was normal. The appendix examined in totality was histologically normal besides mucin deposits on the surface of the serosa. It did not present any mucocele or LAMN/HAMN. All together, these data suggested a diagnosis of acellular PMP (according to Carr classification \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e) caused by a ruptured appendiceal-like mucocele associated with LAMN, in a left ovarian teratoma.\u003c/p\u003e \u003cp\u003e \u003cem\u003eMolecular features\u003c/em\u003e:\u003c/p\u003e \u003cp\u003eNext generation sequencing of the LAMN of the teratomatous mucocele revealed an activating mutation of \u003cem\u003eKRAS\u003c/em\u003e gene c.35G\u0026thinsp;\u0026gt;\u0026thinsp;A corresponding to the p.(Gly12Asp) substitution \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. Complementary molecular analysis by SNaPshot showed an associated mutation of \u003cem\u003eGNAS\u003c/em\u003e c.602G\u0026thinsp;\u0026gt;\u0026thinsp;A resulting in p.(Arg201His). No mutation was found by these two techniques on the other tissues of the ovarian teratoma (squamous, respiratory, adipose or smooth muscle elements) or in the normal appendix and ovarian parenchyma \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e "},{"header":"Discussion:","content":"\u003cp\u003ePMP is an anatomo-clinical entity defined either by mucinous ascites or mucinous deposits in the peritoneal cavity. It is a rare disease whose incidence is approximately 1 to 2 cases per million people per year and which affects more commonly women \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Its clinical manifestations are abdominal distention, pain and transit disorder.\u003c/p\u003e \u003cp\u003ePMP is caused by the peritoneal localization of mucin, almost exclusively in the context of a tumor, by two possible mechanisms: tumor rupture in the peritoneal cavity causing the spread of mucinous material containing a variable amount of tumor cells, or metastatic diffusion to the peritoneum of a mucinous adenocarcinoma. Most of the tumors (90%) are of appendiceal origin from LAMN or HAMN associated with a mucocele \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Other tumors correspond to mucinous adenocarcinomas of colonic \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e, gastric \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e, pancreatic \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e, urachian \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e, pulmonary \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e, endocervical \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e or mammary \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e origin, or to rare mucinous ovarian tumors, cystadenomas or cystadenocarcinomas \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Some authors reported non-neoplastic intra-peritoneal mucinous deposits caused by alternative processes as mucin retention due to a stercolith or a diverticule, or mucinous metaplasia of fallopian tubes \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e, but such situations are very rare and questionable.\u003c/p\u003e \u003cp\u003ePhysiopathologically, the mucin deposits, more or less associated with tumor cells, lead by the redistribution phenomenon \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e and epithelio-mesenchymal transition \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e to the spread of mucin into the whole peritoneal cavity. Hematogenic and lymphatic routes of dissemination seem to be infrequent in this complex pathology, still partially understood. However, its clinical evolution leads to consider PMP as a neoplastic condition with variable behaviors, either indolent or aggressive.\u003c/p\u003e \u003cp\u003eCurative treatment of PMP relies on maximal cytoreduction surgery completed by HIPEC, performed by experienced staff in a reference center \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. This surgical act is indeed associated with numerous potential complications, leading to high morbidity (16 to 65%) and mortality (0 to 18%). Nevertheless, extended survey is possible (59% at 5 years) \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSeveral histological classifications have been established for PMP. In 2017, Carr et al. proposed a PMP classification divided in four categories: mucin without epithelial cells; PMP with low-grade histological features; PMP with high-grade histological features; and PMP with signet ring cells \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Recently, the 2019 WHO (World Health Organization) classification adopted a three-tiered system of classification to unify and simplify denomination of the disease. Grade 1 (or low grade appendiceal mucinous neoplasm) is defined by acellular or hypocellular mucinous deposits, with pushing tumor margins, and low grade epithelial cell cytology. Grade 2 (or high grade appendiceal mucinous neoplasm) is characterized by mucinous deposits with numerous epithelial cells often arranged in clusters with marked atypia. Grade 3 (or high grade with signet-ring cells) is represented by neoplasms containing true signet-ring cells defined as intracytoplasmic mucin vacuole indenting the nucleus (degenerating cells floating within mucin pools should not be considered as true signet-ring cells) \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe primitive ovarian origin of PMP has been debated for a long time. First descriptions of PMP were from appendiceal or intestinal origins. Thus, when a female patient presented with a clinical situation of PMP with both mucinous lesions of the appendix and the ovaries, she was considered to present either a PMP of appendiceal origin with secondary localization of the ovaries or an appendiceal PMP with a concomitant borderline mucinous ovarian tumor \u003csup\u003e[\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. In order to elucidate the origin of PMP in cases of both appendiceal and ovarian mucinous lesions, some authors tried to define morphological criteria comparing the aspects of mucinous tumor of the ovaries with and without PMP and appendiceal tumor.\u003c/p\u003e \u003cp\u003eFor Ronett et al., the secondary ovarian localization of a primitive digestive tumor was retained when (i) the ovarian tumor was only superficial; (ii) ovaries were of a quite normal size; (iii) a unilateral ovarian tumor had a digestive phenotype in a context of anteriority of such a digestive tumor; (iv) a bilateral ovarian tumor had a digestive phenotype without any known antecedent; (v) an appendiceal tumor was ruptured with an intact associated ovarian tumor \u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eStewart et al. observed that secondary ovarian tumor was made by scalloped glands layered by sub epithelial clefts while primary ovarian tumor did not share these features but was instead associated with an abundant stroma reaction and histiocytic infiltration \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eImmunohistochemistry has also been used to distinguish between primary and secondary ovarian origin. Ferraira et al. showed that CK20 and MUC2 were more often expressed by mucinous ovarian tumors associated with PMP than by mucinous ovarian tumors without PMP, supporting the hypothesis of a secondary ovarian localization of a primitive digestive tumor \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. However, Saluja et al. reported a case of PMP associated with an ovarian borderline mucinous tumor without any digestive tumor \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. In this case, the appendix was normal on full microscopic examination, and the ovarian tumor expressed both CK7 and CK20, with MUC2. Finally, studies revealed that the immunohistochemical profile of the tumor did not allow to distinguish between PMP of primary ovarian or digestive origin, both of them being positive for CK20 and CDX2 with variable staining for CK7 \u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eO\u0026rsquo;Connell et al. investigated the mucin composition of PMP, which is principally made of MUC2 and MUC5AC and revealed that while MUC2 was more abundant in PMP, but also in appendiceal mucinous tumors and normal digestive tissue, MUC5AC was predominant in mucinous ovarian primitive tumors, suggesting that mucin composition could help to distinguish the origin of PMP \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. However, only a few studies on mucin composition are available.\u003c/p\u003e \u003cp\u003eHowever, some cases of authentic PMP with an ovarian origin have been described. These cases were associated with various mucinous tumors of the ovary, as benign mucinous adenomas, borderline mucinous tumors and adenocarcinomas \u003csup\u003e[\u003cspan additionalcitationids=\"CR29 CR30\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. Many of these primary ovarian PMP, in which an appendiceal origin was formally excluded, mucinous ovarian tumors were associated with teratoma, suggesting for some authors that primary ovarian origin of a PMP was only possible in a context of a mucinous ovarian tumor arising from an ovarian teratoma \u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e. It should be noted that ovarian teratomas associated with mucinous tumors causing PMP did not show particularities from other teratomas without mucinous associated lesion.\u003c/p\u003e \u003cp\u003eThe unique and original feature of our case is that the primary ovarian tumor responsible for the PMP was not a classic mucinous tumor of the ovary associated with a teratoma but a teratomatous appendiceal-like mucocele with LAMN. To our knowledge, such teratomatous involvement has never been described.\u003c/p\u003e \u003cp\u003eMolecular sequencing of PMP revealed frequent \u003cem\u003eKRAS\u003c/em\u003e and \u003cem\u003eGNAS\u003c/em\u003e mutations as in mucinous tumors of the appendix. These mutations are frequent in LAMN and HAMN and slightly rarer in mucinous appendiceal adenocarcinomas, which harbor frequent \u003cem\u003eTP53\u003c/em\u003e mutations as in HAMN but not LAMN \u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. \u003cem\u003eKRAS\u003c/em\u003e mutations occur in exon 2. \u003cem\u003eGNAS\u003c/em\u003e mutations are located at codon 201 in c.601 or c.602. Mutations in codon 601 are frequently c.601C\u0026thinsp;\u0026gt;\u0026thinsp;T, resulting in p.(R201C), and those in codon 602 are often c.602G\u0026thinsp;\u0026gt;\u0026thinsp;A resulting in p.(R201H) \u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e. While the former is more common in LAMN, the latter is more common in HAMN. Molecular data on primary mucinous ovarian carcinomas without the context of PMP showed frequent mutations in \u003cem\u003eKRAS\u003c/em\u003e, without \u003cem\u003eGNAS\u003c/em\u003e mutation \u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e. Choi et al. studied molecular alterations in primary ovarian mucinous tumor associated with teratoma and PMP. They revealed \u003cem\u003eKRAS\u003c/em\u003e and \u003cem\u003eGNAS\u003c/em\u003e associated mutations \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. These results, as ours, could indicate that ovarian mucinous tumors associated with teratomas and responsible for PMP are in fact of a teratomatous digestive origin. Molecular data on PMP of other origins than appendiceal and ovarian are not available, those cases being very rare.\u003c/p\u003e"},{"header":"Conclusions:","content":"\u003cp\u003ePMP is a rare neoplastic disease, deriving in most cases from a mucinous appendiceal tumor from LAMN, HAMN or adenocarcinoma, all associated with \u003cem\u003eKRAS\u003c/em\u003e and \u003cem\u003eGNAS\u003c/em\u003e associated mutations. Mucinous tumors of other origins, mostly adenocarcinomas, can also cause PMP, among them mucinous ovarian tumors, almost always in a context of concomitant ovarian teratoma. In the literature, molecular data show that \u003cem\u003eKRAS\u003c/em\u003e and \u003cem\u003eGNAS\u003c/em\u003e co-mutations are also present in primary ovarian PMP associated with teratoma.\u003c/p\u003e \u003cp\u003eBy reporting here the presence of \u003cem\u003eKRAS\u003c/em\u003e and \u003cem\u003eGNAS\u003c/em\u003e mutations in this extremely rare case of primary ovarian PMP derived from the rupture of a teratomatous appendiceal-like mucocele with LAMN arising in an ovarian teratoma, our results suggest the teratomatous digestive origin of the mucinous ovarian tumors causing PMP. This finding emphasizes the need to actively search for teratomatous signs in a context of primary ovarian PMP.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eHAMN: High-grade Appendiceal Mucinous Neoplasm\u003c/p\u003e\n\u003cp\u003eHIPEC: Hyperthermic IntraPEritoneal Chemotherapy\u003c/p\u003e\n\u003cp\u003eLAMN: Low-grade Appendiceal Mucinous Neoplasm\u003c/p\u003e\n\u003cp\u003eMRI: Magnetic Resonance Imaging\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePMP: PseudoMyxoma Peritonei\u003c/p\u003e\n\u003cp\u003eTDM: TomoDensitoMetry\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWHO: World Health Organization\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ethics committee of Rouen University Hospital has approved this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent for publication was obtained according to the policies of the institutional review board of Rouen University Hospital and the French Ministry of Scientific Research.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConcerning clinical and sample collection, approval was obtained according to the agreement of the tumor biobank of Rouen University Hospital (tissue sample collection n\u0026deg; DC2008-689).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest regarding this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSource of funding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was not funded by any grant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMCB and JCS performed histological examination of the left ovary and appendix.\u003c/p\u003e\n\u003cp\u003eFB and AL realized molecular analyses.\u003c/p\u003e\n\u003cp\u003eMCB and JCS were major contributors in writing the manuscript.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are indebted to Nikki Sabourin-Gibbs (Rouen University Hospital) for assistance with language editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eCarr NJ, Bibeau F, Bradley RF, Dartigues P, feakins RM, Geisinger KR, Gui X, Isaac S, Milione M, Misdraji J, Pai RK, Rodriguez-Justo M, Sobin LH, van Velthuysen MF, Yantiss RK. The histopathological classification, diagnosis and differential diagnosis of mucinous appendiceal adenocarcinomas and pseudomyxoma peritonei. Histopathology. 2017;6.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eVan den Heuvel MG, Lemmens VE, Verhoeven RH, de Hingh IH. The incidence of mucinous appendiceal malignancies: a population-based study. Int J Colorectal Dis. 2013;28:1307\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003ede Bree E, Witkamp A, Van De Vijver M, Zoetmulde F. Unusual origins of pseudomyxoma peritonei. J Surg Oncol. 2000;75.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eIkejiri K, Anai H, Kitamura K, Yakabe S, Saku M, Yoshida K. Pseudomyxoma peritonei concomitant with early gastric cancer: report of a case. Surg Today 1996;26.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eChejfec G, Rieker WJ, Jablokow VR, Gould VE. Pseudomyxoma peritonei associated with colloid carcinoma of the pancreas. Gastroenterology 1986;90.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMizuta Y, Akazawa Y, Shiozawa K, et al. Pseudomyxoma peritonei accompanied by intraductal papillary mucinous neoplasm of the pancreas. Pancreatology 2005;5.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eAgrawal AK, Bobin\u0026acute;ski P, Grzebieniak Z, et al. Pseudomyxoma peritonei originating from urachus: case report and review of the literature. Curr Oncol. 2014;21.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eKurita M, Komatsu H, Hata Y, et al. Pseudomyxoma peritonei due to adenocarcinoma of the lung: case report. J Gastroenterol 1994;29.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eDario Baratti S, Kusamura M, Milione, et al. Pseudomyxoma peritonei of extra-appendiceal origin: a comparative study. Ann Surg Oncol 2016;23.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eHawes D, Robinson R, Wira R. Pseudomyxoma peritonei from metastatic colloid carcinoma of the breast. Gastrointest Radiol 1991;16.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eLamps LW, Gray GF Jr, Dilday BR, Washington MK. The coexistence of low grade mucinous neoplasms of the appendix and appendiceal diverticula: a possible role in the pathogenesis of pseudomyxoma peritonei. Mod Pathol. 2000;13.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eDupre MP, Jadavji I, Matshes E, Urbanski SJ. Diverticular disease of the vermiform appendix: a diagnostic clue to underlying appendiceal neoplasm. Hum Pathol 2008;39.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMinguillon C, Friedmann W, Vogel M, Wessel J, Lichtenegger W. Mucinous metaplasia of fallopian tube mucous membrane as a cause of peusomyxoma peritonei. Zentralbl Pathol. 1992;138.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSugarbaker PH. Pseudomyxoma peritonei: a cancer whose biology is characterized by a redistribution phenomenon. Ann Surg 1994;219.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eBibi R, Pranesh N, Saunders MP, Wilson MS. O\u0026rsquo;dwyer ST, Stern.\u0026nbsp;\u003c/span\u003e\u003cspan\u003ePL. et al. A specific cadherin phenotype may characterise the disseminating yet non-metastatic behaviour of pseudomyxome peritonei. Br J Cancer 2006;95.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSugarbaker PH. Cytoreductive surgery and peri-operative intraperitoneal chemotherapy as a curative approach to pseudomyxoma peritonei syndrome. Eur J Surg Oncol.2001; 27.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eDartigues P, Isaac S, Villeneuve L, et al. Mise au point sur le pseumdomyxome periton\u0026eacute;al. Aspects anatomo-apthologiques, et implications th\u0026eacute;rapeutiques. Ann Pathol. 2014;34.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eChua TC, Moran BJ, Sugarbaker PH, et al. Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin Oncol 2012;30.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eNagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, Washington KM, Carneiro F, Cree IA. \u0026amp; WHO Classification of Tumours Editorial Board (2020). The 2019 WHO classification of tumours of the digestive system. Histopathology, 76;2.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eYoung RH, Gilks CB, Scully RE. Mucinous tumors of the appendix associated with mucinous tumors of the ovary and pseudomyxoma peritonei: A clinicopathologic analysis of 22 cases supporting an origin in the appendix. Am J Surg Pathol 1991;15.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003ePrayson RA, Hart WR, Petras RE. Pseudomyxoma peritonei: A clinicopathologic study of 19 cases with emphasis on site of origin and nature of associated ovarian tumors. Am J Surg Pathol 1994;18.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eRonnett BM, Kurman RJ, ZAHN, CM, et al. Pseudomyxoma peritonei in women: a clinicopathologic analysis of 30 cases with emphasis on site of origin, prognosis and relationship to ovarian mucinous tumors of low malignant potential. Hum pathol 1995;26.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eStewart CJ, Ardakani NM, Doherty DA, Young RH. An evaluation of the morphologic features of low-grade mucinous neoplasms of the appendix metastatic in the ovary, and comparison with primary ovarian mucinous tumors. Int J Gynecol Pathol. 2014;33.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eFerreira CR, Carvalho JP, Soares FA, Siquiera SA, Carvalho FM. Mucinous ovarian tumors associated with pseudomyxoma peritonei of adenomucinosis type: immunohistochemical evidence that they are secondary tumors. Int J Gynecol Cancer 2008;18.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSaluja M, Kenwright DN, Keating JP. Pseudomyxome peritonei arising from a mucinous borderline ovarian tumor: case report and literature review. Aust N Z J Obstet Gynaecol. 2010;50.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eO\u0026rsquo;Connell JT, Hacker CM, Barsky SH. MUC2 is a molecular marker for pseudomyxome peritonei. Mod Pathol. 2002;15.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eO\u0026rsquo;Connell JT, Tomlinson JS, Roberts AA, McGonigle KT, Barsky SH. Pseudomyxoma peritonei is a disease of MUC2-expressing goblet cells. Am J Pathol. 2002;161.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eRonnett BM, Seidman JD. Mucinous tumors arising in ovarian mature cystic teraromas: relationship to the clinical syndrome of pseudomyxome peritonei. Am J Surg Pathol. 2003;27.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMcKenney JK, Soslow RA, Longacre TA. Ovarian mature teratomas with mucinous epithelial neoplasms: morphologic heterogeneity and association with pseudomyxome peritonei. Am J Surg Pathol 2008;32.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003ePranesh N, Menasce LP, Wilson MS, O\u0026rsquo;Dwyer ST. Pseudomyxoma peritonei: unusual origin from an ovarian mature cystic teratoma. J Clin Pathol 2005;58.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMarquette S, Amant F, Vergote I, Moerman P. Pseudomyxoma peritonei associated with a mucinous ovarian tumor arising from a mature cystic teratoma. A case report. Int J Gynecol Pathol; 2006;25.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eHwang JH, So MD, Modi KA, Lee G, Lee JK, Lee NW, Kim KW. I; Borderline-like mucinous tumor arising in mature cystic teratoma of the ovary associated with pseudomyxome peritonei. Int J Gynecol Pathol. 2009;28.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eNishikawa G, Sekine S, Ogawa R, et al. Frequent GNAS mutations in low-grade appendiceal mucinous neoplasms. B. J. Cancer 2013;108.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eNummela P, SaarinenL, Thiel A, et al. Genomic profile of pseudomyxome peritonei analyzed using next-generation sequencing and immunohistochemistry. Int J Cancer 2015;136.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eChoi YJ, Lee SH, Kim MS, et al. Whole-exome sequencing identified the genetic origin of a mucinous neoplasm in a mature cystic teratoma. Pathology 2016;48.\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"diagnostic-pathology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dpat","sideBox":"Learn more about [Diagnostic Pathology](http://diagnosticpathology.biomedcentral.com)","snPcode":"13000","submissionUrl":"https://submission.nature.com/new-submission/13000/3","title":"Diagnostic Pathology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Pseudomyxoma peritonei, Ovarian pseudomyxoma peritonei, Appendiceal pseudomyxoma peritonei, Ovarian teratoma, KRAS / GNAS mutations, LAMN","lastPublishedDoi":"10.21203/rs.3.rs-907797/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-907797/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/p\u003e\u003cp\u003ePseudomyxoma peritonei (PMP) is a complex and partially understood disease defined by mucin deposits in the peritoneal cavity, mostly of appendiceal origin caused by the rupture of a mucocele often containing Low or High grade Appendiceal Mucinous Neoplasm (LAMN/HAMN). Other origins include primary ovarian mucinous cystadenoma or cystadenocarcinoma almost always with an associated teratoma, but to our knowledge no case of ovarian teratomatous appendiceal-like mucocele with LAMN has been reported as a cause of PMP.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCase presentation:\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eA 25-year old female with infertility was diagnosed with an isolated left ovarian tumor in a context of PMP. Histological examination revealed an ovarian teratoma containing an appendiceal-like structure with mucocele and LAMN, without any associated lesion of the appendix on full histological analysis. Molecular characterization of the ovarian lesion showed co-\u003cem\u003eKRAS\u003c/em\u003e and \u003cem\u003eGNAS\u003c/em\u003e mutations, as described in PMP of appendiceal origin, while only \u003cem\u003eKRAS\u003c/em\u003e mutations are reported in primary ovarian mucinous tumor.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eDetection of co-\u003cem\u003eKRAS\u003c/em\u003e and \u003cem\u003eGNAS \u003c/em\u003emutations in our case of ovarian teratomatous appendiceal-like mucocele with LAMN shows that when PMP derives from a mucinous ovarian lesion (with histological proof of none-appendiceal involvement), it is probably of a digestive teratomatous origin, emphasizing the need to actively search for tetatomatous signs in a context of ovarian PMP.\u003c/p\u003e","manuscriptTitle":"A case of Pseudomyxoma Peritonei of an unexpected origin.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-10-05 15:13:18","doi":"10.21203/rs.3.rs-907797/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2021-10-21T00:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"decision","content":"Minor Revision","date":"2021-10-21T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-10-20T00:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2021-10-12T00:00:00+00:00","index":5,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-10-12T00:00:00+00:00","index":4,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"editorInvitedReview","content":"","date":"2021-10-12T00:00:00+00:00","index":3,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2021-10-11T00:00:00+00:00","index":4,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-10-07T00:00:00+00:00","index":3,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-10-06T01:00:00+00:00","index":2,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-10-06T00:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-10-01T00:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2021-09-30T00:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-09-30T00:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2021-09-29T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2021-09-29T23:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"diagnostic-pathology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dpat","sideBox":"Learn more about [Diagnostic Pathology](http://diagnosticpathology.biomedcentral.com)","snPcode":"13000","submissionUrl":"https://submission.nature.com/new-submission/13000/3","title":"Diagnostic Pathology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a694ec1d-a0b6-467b-9eef-48117d9b81b8","owner":[],"postedDate":"October 5th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":7651308,"name":"Pathology"},{"id":7651309,"name":"Laboratory Diagnostics"}],"tags":[],"updatedAt":"2021-12-20T12:48:45+00:00","versionOfRecord":{"articleIdentity":"rs-907797","link":"https://doi.org/10.1186/s13000-021-01179-z","journal":{"identity":"diagnostic-pathology","isVorOnly":false,"title":"Diagnostic Pathology"},"publishedOn":"2021-12-01 12:48:45","publishedOnDateReadable":"December 1st, 2021"},"versionCreatedAt":"2021-10-05 15:13:18","video":"","vorDoi":"10.1186/s13000-021-01179-z","vorDoiUrl":"https://doi.org/10.1186/s13000-021-01179-z","workflowStages":[]},"version":"v1","identity":"rs-907797","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-907797","identity":"rs-907797","version":["v1"]},"buildId":"iFTdqyg4nuje_uAy1AHro","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}