Paraneoplastic Focal Segmental Glomerulosclerosis Associated With Gastrointestinal Stromal Tumors With Cutaneous Metastasis: a Case Report

Paraneoplastic Focal Segmental Glomerulosclerosis Associated With Gastrointestinal Stromal Tumors With Cutaneous Metastasis: a Case Report | 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 Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Paraneoplastic Focal Segmental Glomerulosclerosis Associated With Gastrointestinal Stromal Tumors With Cutaneous Metastasis: a Case Report Jun Zhou, Zhen Yang, Cuishun Yang, Hua Lin, Wanqiong Yuan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-141429/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Gastrointestinal stromal tumor (GIST) is one of most common mesenchymal neoplasms occurring in different areas of the gastrointestinal tract. GISTs with cutaneous metastasis is very rare and its rarity cutaneous GISTs have not been well characterized. Focal segmental glomerulosclerosis (FSGS) is also rare among paraneoplastic nephritic syndromes (PNS). Case presentation: In this case report, we described a 64-year-old patient with cutaneous metastasis GIST accompanied by nephrotic syndrome as PNS, in whom symptomatic treatment was ineffective, but clinical remission was achieved after surgery. Moreover, the patient has a missense mutation of NPHP4 . NPHP4 served as a negative regulator of the Hippo pathway. Hippo signaling pathway is involved in the development and progression of FSGS. NPHP4 is also indeed a driving force for proliferation in tumor cells. Therefore, the mutation of NPHP4 in this patient could explain the occurrence of GIST and FSGS and this was therefore not a random association. Conclusions: This is the first reported case of a GIST with cutaneous metastasis accompanied by nephrotic syndrome as PNS. Pathology Gastrointestinal stromal tumors Cutaneous metastisis Paraneoplastic nephritic syndromes NPHP4 Figures Figure 1 Figure 2 Figure 3 Background Gastrointestinal stromal tumor (GIST) is one of most common mesenchymal neoplasms occurring in different areas of the gastrointestinal tract. The most frequent site of GISTs occurs in stomach (60%), followed by the small bowel (35%) and colon rectum (< 5%) [ 1 ]. Immunohistochemistry would be helpful for the diagnosis because GISTs show immunoreactivity for CD117 (95%), CD34 (70%) and DOG-1, a complementary stain of CD117 [ 2 ]. GISTs are usually benign with a malignant transformation rate of 10–30%. With regard to metastatic GISTs, DeMatteo’s group [ 3 ] has previously reviewed 200 cases and reported that 61% of the metastases showed liver involvement, 20% had intraabdominal involvement and 6% had bone involvement. Since 2002, 10 cases of a cutaneous metastasis from GISTs have been described and one report estimated these occurrences to represent 1% of advanced GISTs [ 4 ]. Paraneoplastic syndrome (PNS) is a disorder or symptom caused by cancer or a reaction to tumors, but does not result from the local presence of cancer cells [ 5 ]. The signs and symptoms of PNS are diverse, but there are common features in PNS, including neuropathy, skin disease, and nephrotic syndrome. In this case report, we describe a patient with cutaneous metastatic GIST accompanied by nephrotic syndrome as PNS, in whom symptomatic treatment was ineffective but clinical remission was achieved after surgery. To the best of our knowledge, this is the first time to present a unique case of cutaneous metastasis GIST accompanied by FSGS as PNS. Case Presentation A 64-year-old Chinese man was admitted to our hospital complaining of edema of the face and lower limbs for more than four months. Laboratory examinations revealed severe proteinuria (3.77 g/24 h; normal range, 0–0.15 g/24 h), hypoalbuminemia (1.8 g/dL), and hyperlipidemia (cholesterol 15.7 mmol, triglyceride 3.34 mmol/L) and increased serum creatinine level (152 µmol; normal range, 44–133 µmol). These clinical parameters suggested that it was the nephrotic syndrome. A kidney biopsy was performed and the results showed that there were nine glomeruli, including one glomerulosclerosis and one segmental glomerulosclerosis with peripheral podocytosis, vascuole and granular degeneration in the renal tubular epithelial cells (Fig. 1 a, b). These pathological findings suggested that it was considered to be the focal segmental glomerulosclerosis (FSGS), not the otherwise specified (NOS). The immunohistochemistry of the kidney revealed that CD117 (Fig. 1 c) is positive in the proximal tubule cells and CD34 (Fig. 1 d) is positive in the glomerular capillary loop, peritubular capillary and arterioles, but DOG-1 was negative. Physical examination revealed multiple nodules and lumps with a smooth surface that could be seen throughout the body (Fig. 1 e). Enlargement of the cervical, axillary and inguinal lymph nodes was observed obviously. Fat degeneration and necrosis were observed in lymph node and no tumor metastasis was revealed (Fig. 1 f). H&E staining of the skin showed spindle cell tumor-like hyperplasia, which was slightly heteromorphic with focal necrosis and rarely mitotic (Fig. 1 g). Immunohistochemistry staining revealed that the tumor cells were positive for CD34, Bcl-2, CD99, Ki67 and vimentin, but negative for smooth muscle actin (SMA) and S-100. Immunohistochemistry staining of CD34 was shown as representativeness (Fig. 1 h). The diagnosis was a desmoid tumor (DT) basing on the above detection results. Then, gastroscopy was performed and the results showed that a 0.6 cm mucosal bulge that was hard to the touch, and poor mobility could be seen on the greater curvature of the stomach (Fig. 2 a). Many 0.4-2 cm bulges can be seen in the anterior wall of the middle and upper of the gastric fundus with fractured surface and fresh blood (Fig. 2 b). Moreover, pathologic examination revealed the destruction of the gastric solid membrane structure and spindle cell tumor–like hyperplasia with mild dysplasia (Fig. 2 c) and epithelioid cells are occasionally seen with 6–8 mitoric figures/50 HPF (Fig. 2 d). By immunohistochemistry staining, CD117 (Fig. 2 e), CD34 (Fig. 2 f) and SMA were positive, DOG1 was probable positive, and S-100 and CK were negative. These findings supported the diagnosis of GISTs. In addition, a heterozygous missense mutation was found in NPHP4 gene of the subject (NPHP4: NM_015102: exon17: c.2198G > A: p.G733D), could explain the occurrence of GIST and FSGS and this was therefore not a random association. Partial gastrectomy was performed.102–105 Cyclosporine was used in the outpatient setting for three days, and the patient’s feelings of discomfort stopped. Despite of receiving prednisone acetate 50 mg QD for three months, the patient’s severe proteinuria and hypoalbuminemia did not improve. Additional immunohistochemistry of the skin revealed that CD117 (Fig. 2 g) and DOG1 (Fig. 2 h), the two most sensitive and specific markers for diagnosis of GIST [ 6 ] were positive. Finally, the diagnosis was a metastatic cutaneous GIST. Two weeks after removing the tumor by operation, the patient’s serum albumin and urinary protein levels improved remarkably (Fig. 3 ). Discussion And Conclusions GISTs arise from the interstitial cells of Cajal, which serve as a pacemaker for the gastrointestinal tract by creating slow wave potentials that direct smooth muscle to contract. GISTs primarily metastasize to the liver and peritoneum, while cutaneous metastases are the least common. While, the mechanism of GISTs metastasis to the skin remains unknown. It is hypothesized that the presence may indicate the multiple internal metastases [ 3 ]. It was misdiagnosed as DT at the beginning until the recognition of skin metastasis of GISTs by detecting the expression of CD117, CD34 and DOG1 in skin. It should also be advised for patients with a history of GISTs to have a full skin exam to detect any visible clues of the status of metastatic tumor burden. In our case, the patient had a missense mutation of NPHP4 . NPHP4 locates on chromosome 1p36 and encodes a protein called nephrocystin-4/nephroretinin [ 7 ]. Nephrocystin-4 colocalises and interacts with nephrocystin 1,3 and inversin in primary cilia and associated appendages, adherens junctions, and focal adhesions [ 8 ]. Individuals with mutations in NPHP4 most frequently have an associated with the nephronophthisis [ 9 ]. Some data identify that NPHP4 served as a negative regulator of the Hippo pathway [ 10 ]. In acute renal injury, Hippo signaling pathway may be involved in the apoptosis of tubule epithelial cells, epithelial-mesenchymal transition and acute renal injury progress to chronic kidney disease and other processes [ 11 ]. In addition, Hippo signaling pathway is also involved in the development and progression of a variety of chronic kidney disease, including FSGS, diabetic nephropathy, polycystic kidney disease [ 12 ]. The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and plays an essential role in tumor suppression and the cell prolifiration [ 13 ]. NPHP4 is indeed a driving force for proliferation in tumor cells. Therefore, the mutation of NPHP4 in this study could explain the occurrence of GIST and FSGS and this was therefore not a random association. Our patient had a cutaneous metastatic GIST, and needed to be differentiated from Gardner’s syndrome, an autosomal hereditary disease with multiple adenomatous polyps in colorectal and some extracolonic lesions. It is characterized by multiple adenomatous polyps in the colorectal region with osteoma, soft-tissue tumor, and tooth abnormality. In addition, 30–75% of patients with Gardner’s syndrome also have dental abnormalities [ 14 ]. Osteomas is a necessary diagnosis of Gardner’s syndrome. Its molecular genetic basis is the mutation of the APC in 5q21. Unfortunately, this patient did not undergo colonoscopy. However, based on the absence of an APC mutation, family history, and the fact that the patient had no osteoma or dental abnormalities, the etiology can be differentiated the Gardner’s syndrome. Theoretically, the diagnosis of paraneoplastic glomerulopathy should rely on three strong criteria. Firstly, a clinical and histologic remission occurs after complete surgical removal of the tumor or chemotherapy-induced complete remission of the disease. In this case, symptomatic treatment was ineffective but clinical remission was achieved after surgery. So, the nephrotic syndrome can be diagnosed as PNS. Secondly, a renal relapse accompanies recurrence of the neoplasia. In other words, proteinuria should directly correlate with tumor activity. Thirdly, a pathophysiologic link is established between the two diseases, including the detection of tumor antigens and antitumor antibodies within subepithelial immune deposits [ 15 ]. In our case, the immunohistochemistry on the kidney revealed positive for CD117 and CD34, but negative for DOG-1. Telocytes (TCs) were indicated as a distinctive cell type by after being previously described as “Interstitial Cajal-Like Cells” [ 16 ]. Qi reported TCs in the interstitium of the human kidney cortex. Renal TCs were found to express CD34 and CD117 with variable intensity [ 17 ]. Therefore, the positive CD34 and CD117 in the kidney were not significant. Nephrotic syndrome can occur as malignancy-associated PNS, and previous studies have estimated that cancer occurs in 11–22% of patients with nephrotic syndrome [ 5 ]. The most common pathological type of tumor-associated nephropathy is membranous nephropathy (44–49%). FSGS is extremely rare among PNS and it has been reported that FSGS can be seen in renal cell carcinoma, invasive thymoma, and lung cancer [ 18 ]. There has been only one case of GIST of the stomach that was associated with nephrotic syndrome as PNS. Nephrotic syndrome improved after surgery in 78% of patients [ 5 ]. Considering cancer is a potential cause of nephrotic syndrome, surgical resection should be performed in the presence of PNS condition. In our case, the patient’s proteinuria and hypoalbuminemia did not respond to symptomatic treatment. After tumor removal, the clinical remission of nephrotic syndrome was immediately achieved. Thus, FSGS can be considered a GIST-associated PNS. However, the variant of FSGS that has been reported in PNS was the collapsing variant, duo to the overexpression of vascular endothelial growth factor, which leads to collapsing FSGS. This was not FSGS NOS. Some studies have proven that α-actinin-4 mutations play an important role in the development of PNS [ 19 ]. Unfortunately, this patient did not have any ACTN4 mutations. However, these hypotheses seem insufficient to explain the case of GIST accompanied by FSGS as PNS. Tyrosine kinase inhibitors (TKIs) are effective in GISTs, but reports have focused on TKIs-associated renal injury leading to FSGS. In the future, we will use cytotoxic chemotherapy for this patient under intensive follow-up. GISTs are currently regarded as potentially malignant tumors. Discrimination of a benign GISTs from a malignant GIST is by postoperative histological analysis (tumor diameter, mitotic index, whether the tumor has metastasized and Ki67 expression level) [ 20 ]. According to the cutaneous metastasis GIST, this case is a high-risk patient with poor prognosis. Joensuu’s group recommended for high-risk patients shorter imaging intervals of about 3–4 months during the time period of approximately two years following discontinuation of imatinib [ 21 ]. Our patient risk of recurrence would be reduced based on the follow-up schedules. In conclusion, FSGS caused by cutaneous metastasis GIST is quite rare, and to the best of our knowledge, this is the first time to report such a case. The NPHP4 mutation in this case can explain the occurrence GISTs and FSGS. It was not a random association. Abbreviations ACTN4: α-Actinin-4; APC: adenomatous polyposis coli; CTNNB1: β-Catenin gen 1; DT: desmoid tumor; FSGS: Focal segmental glomerulosclerosis; GIST: gastrointestinal stromal tumor; PNS: paraneoplastic nephritic syndromes; TCs: Telocytes; TKIs: Tyrosine kinase inhibitors. Declarations Ethics approval and consent to participate Not applicable Consent for publication Written informed consent was obtained from the patient. A copy of the consent form is available for review and can be provided on request. This Case Report was done in adherence to the CARE Guidelines. Availability of data and materials The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests Funding This resarch was sponsored by the Healthy department of Hainan province (grant number, 2001320243A2011). Author’s contributions Jun Zhou wrote the manuscript and conducted the literature review. Zhen Yang, Cuishun Yang and Hua Lin participated in the clinical care of the patient. Wanqiong Yuan participated in paper submitting and revising. All authors assisted the results interpretation and manuscript revision. All authors read and approved the final manuscript. Acknowledgements We thank Professor Ping Qiu for editing the manuscript. References Vassos N, Agaimy A, Hohenberger W, Croner RS. Coexistence of gastrointestinal stromal tumors (GIST) and malignant neoplasms of different origin: prognostic implications. J Surg. 2014.12(5):371-7. Phan M, Jones S, Jenkins J, Pant S, Khawandanah M. Pancreatic GIST in a patient with limited stage small cell lung cancer: a case report and review of published cases. Case Rep Oncol Med. 2016.2016:9604982. Kim YJ, LeeW J, Won CH, Choi JH, Lee MW. Metastatic cutaneous duodenal gastrointestinal stromal tumor: a possible clue to multiple metastases. Ann Dermatol. 2018. Jun;30(3):345-347. Aickara DJ, McBride J, Morrison B, Romanelli P. Multidrug resistant gastrointestinal stromal tumor with multiple metastasis to the skin and subcutaneous soft tissue: A case report and review of literature. J Cutan Pathol. 2020.Apr;47(4):398-401. Takane K, Midorikawa Y, Yamazaki S, Kajiwara T, Yoshida N, Kusumi Y, Takayama. Gastrointestinal stromal tumor with nephrotic syndrome as a paraneoplastic syndrome: a case report. Med Case Rep. 2014;27:8. Novelli M, Rossi, S, Rodriguez-Justo M, Taniere P, Seddon B, Toffolatti L, Sartor, C, et al. DOG1 and CD117 are the antibodies of choice in the diagnosis of gastrointestinal stromal. Histopathology. 2010 Aug;57(2):259-70. Remi Salomon, Sophie Saunier, Patric Niaudet. Nephronophthisis. Pediatr Nephrol.2009,24(12):2333-44. Marion Delous, Nathan E. Hellman, Helori-Mael Gaude, et al. Nephrocystin-1 and nephrocystin-4 are required for epithelial morphogenesis and associate with PALS1/PATJ and Par6. Human Molecuar Genetics, 2009,18(24):4711-4723. Simms, Ann Marie Hynes, Lorraine Eley, et al. Nephronophthisis: a genetically diverse ciliopathy. Int J Nephrol, 2011,527137. Sandra Habbig, Malte P, Bartram, Roman U. Muller et al. NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway. J Cell Biol,2011,193(4)：633-42. Zhao S, Yin J, Zhou L, et al. Hippo/mst1 signaling mediates microglial activation following acute cerebral ischemia-reperfusion injury[J]. Brain Behav Immun, 2016,17(6):1503-1520. Kirtida Mistry, MBBCh, DCH, MRCPCH, et al. Novel mutations in NPHP4 in a consanguineous family with histological findings of focal segmental glomerulosclerosis. Am J Kidney Dis, 2007,50(5):855-864. Zanconato F, Piccolo S. Eradicating tumor drug resistance at its YAP-biomechanical roots. EMBO J, 2016, 35(5):459-461. Seehra J, Patel S, Bryant C. Gardner’s syndrome revisited clinical case and overview of the literature. Orthod. 2016, Mar;43(1):59-64. Ronco PM. Paraneoplastic glomerulopathies: new insights into an old entity[J]. Kidney Int, 1999,56(1):355-377. L M Popescu, Maria-Simonetta Faussone-Pellegrini. TELOCYTES-a case of serendipity: the winding way from Intersititial Cells of Cajal (ICC), via Ineterstitial Cajal-Like Cells (ICLC) to TELOCYTES. J Cell Mol Med. 2010 Aprl;14(4):729-40. Qi G, Lin M, Xu M, Manole CG, Wang X, Zhu T. J Cell Mol Med. 2012 Dec;16(12):3116-22. Jeyabalan A, Geara AS, Frey Nv, Palmer MD, Hoqan JJ. Paraneoplastic focal segmental glomerulosclerosis associated with acute lymphocytic leukemia. Kidney Int Rep. 2019. Jun;4(10):1494-1498. Meng L, Cao S, Lin N, Zhao J, Cai X, Liang Y, Huang K, et al. Identification of a novel ACTN4 gene mutation which is resistant to primary nephrotic syndrome therapy. BioMed Res Int. 2019 Dec;14;5949485. Akahoshi K, Oya M, Koga T, Shiratsuchi Y. Current clinical management of gastrointestinal stromal tumor. World J Gastroenterol. 2018 Jul;24(26):2806-2817. Joensuu J, Martin-Broto J, Nishida T, Reichardt P, S choffski P, Maki RG. Follow-up strategies for patients with gastrointestinal stromal tumour treated with or without adjuvant imatinib after surgery. Eur J Cancer. 2015 Aug;51(12):1611-7. Supplementary Files CAREchecklistEnglish2013.pdf Cite Share Download PDF Status: Posted Version 1 posted 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. 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(a). HE staining of kidney biopsy. (b). Periodic acid-silver metheramine staining of kidney. (c). Representative immunohistochemical staining for expression of CD34 in the kidney. (d). Representative immunohistochemical staining for expression of CD117 in the kidney. (e). Infiltrative plaques scattered throughout the body. (f). H\u0026E staining of lymph node. (g). H\u0026E staining of the skin. (h). Representative immunohistochemical staining for expression of CD34.","description":"","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-141429/v1/2d263935af78ca99cbd797b2.jpg"},{"id":4877339,"identity":"cd1aa054-d021-4f04-8daa-cafb1092f98c","added_by":"auto","created_at":"2021-01-11 23:42:37","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":10349322,"visible":true,"origin":"","legend":"The findings of the gastroscopy and pathological findings of the tumors. (a). Representative photomicrograph taken by gastroscopy with a diameter of 0.6 cm mucosal bulge on the greater curvature of the stomach. (b). Representative photomicrograph taken by gastroscopy with 0.4-2 cm bulges in the anterior wall of the middle and upper part of the gastric fundus. (c). H\u0026E staining of the muscular layer of the gastric wall is composed of spindle cells. (d). H\u0026E staining of Epithelioid cells are occasionally seen with 6-8 mitoric figures/50 HPF. (e). Representative immunohistochemical staining for expression of CD117 in the stomach. (f). Representative immunohistochemical staining for expression of CD34 in the stomach. (g). Representative immunohistochemical staining for expression of CD117 in skin. (h). Representative immunohistochemical staining for expression of DOG1 in skin.","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-141429/v1/82f96b81b17ce1d7b20ddd7d.jpg"},{"id":4877337,"identity":"16e80dd3-7bab-4d41-8b2c-55edc1f0c15f","added_by":"auto","created_at":"2021-01-11 23:42:37","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":181313,"visible":true,"origin":"","legend":"The patient’s clinical course. A graph of the urine protein levels post the administration.","description":"","filename":"Onlinefigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-141429/v1/0e2b8b167b356b6e1b52d1cd.png"},{"id":13644820,"identity":"4bc1172c-2a92-4d13-8213-8bf255119090","added_by":"auto","created_at":"2021-09-17 09:16:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":621273,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-141429/v1/570ddd2a-4634-445c-917e-4bdf6cc1d95a.pdf"},{"id":4877295,"identity":"ea687a9c-5453-42dc-8bc1-3292760c610f","added_by":"auto","created_at":"2021-01-11 23:39:37","extension":"pdf","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":671443,"visible":true,"origin":"","legend":"","description":"","filename":"CAREchecklistEnglish2013.pdf","url":"https://assets-eu.researchsquare.com/files/rs-141429/v1/8f228bc95304a66cd5d2d8d9.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eParaneoplastic Focal Segmental Glomerulosclerosis Associated With Gastrointestinal Stromal Tumors With Cutaneous Metastasis: a Case Report\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eGastrointestinal stromal tumor (GIST) is one of most common mesenchymal neoplasms occurring in different areas of the gastrointestinal tract. The most frequent site of GISTs occurs in stomach (60%), followed by the small bowel (35%) and colon rectum (\u0026lt;\u0026thinsp;5%) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Immunohistochemistry would be helpful for the diagnosis because GISTs show immunoreactivity for CD117 (95%), CD34 (70%) and DOG-1, a complementary stain of CD117 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. GISTs are usually benign with a malignant transformation rate of 10\u0026ndash;30%. With regard to metastatic GISTs, DeMatteo\u0026rsquo;s group [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] has previously reviewed 200 cases and reported that 61% of the metastases showed liver involvement, 20% had intraabdominal involvement and 6% had bone involvement. Since 2002, 10 cases of a cutaneous metastasis from GISTs have been described and one report estimated these occurrences to represent 1% of advanced GISTs [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Paraneoplastic syndrome (PNS) is a disorder or symptom caused by cancer or a reaction to tumors, but does not result from the local presence of cancer cells [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The signs and symptoms of PNS are diverse, but there are common features in PNS, including neuropathy, skin disease, and nephrotic syndrome.\u003c/p\u003e \u003cp\u003eIn this case report, we describe a patient with cutaneous metastatic GIST accompanied by nephrotic syndrome as PNS, in whom symptomatic treatment was ineffective but clinical remission was achieved after surgery. To the best of our knowledge, this is the first time to present a unique case of cutaneous metastasis GIST accompanied by FSGS as PNS.\u003c/p\u003e "},{"header":"Case Presentation","content":"\u003cp\u003eA 64-year-old Chinese man was admitted to our hospital complaining of edema of the face and lower limbs for more than four months. Laboratory examinations revealed severe proteinuria (3.77\u0026nbsp;g/24\u0026nbsp;h; normal range, 0\u0026ndash;0.15\u0026nbsp;g/24\u0026nbsp;h), hypoalbuminemia (1.8\u0026nbsp;g/dL), and hyperlipidemia (cholesterol 15.7\u0026nbsp;mmol, triglyceride 3.34\u0026nbsp;mmol/L) and increased serum creatinine level (152\u0026nbsp;\u0026micro;mol; normal range, 44\u0026ndash;133\u0026nbsp;\u0026micro;mol). These clinical parameters suggested that it was the nephrotic syndrome. A kidney biopsy was performed and the results showed that there were nine glomeruli, including one glomerulosclerosis and one segmental glomerulosclerosis with peripheral podocytosis, vascuole and granular degeneration in the renal tubular epithelial cells (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ea, b). These pathological findings suggested that it was considered to be the focal segmental glomerulosclerosis (FSGS), not the otherwise specified (NOS). The immunohistochemistry of the kidney revealed that CD117 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ec) is positive in the proximal tubule cells and CD34 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ed) is positive in the glomerular capillary loop, peritubular capillary and arterioles, but DOG-1 was negative. Physical examination revealed multiple nodules and lumps with a smooth surface that could be seen throughout the body (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ee). Enlargement of the cervical, axillary and inguinal lymph nodes was observed obviously. Fat degeneration and necrosis were observed in lymph node and no tumor metastasis was revealed (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ef). H\u0026amp;E staining of the skin showed spindle cell tumor-like hyperplasia, which was slightly heteromorphic with focal necrosis and rarely mitotic (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eg). Immunohistochemistry staining revealed that the tumor cells were positive for CD34, Bcl-2, CD99, Ki67 and vimentin, but negative for smooth muscle actin (SMA) and S-100. Immunohistochemistry staining of CD34 was shown as representativeness (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eh). The diagnosis was a desmoid tumor (DT) basing on the above detection results.\u003c/p\u003e\n\u003cp\u003eThen, gastroscopy was performed and the results showed that a 0.6\u0026nbsp;cm mucosal bulge that was hard to the touch, and poor mobility could be seen on the greater curvature of the stomach (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea). Many 0.4-2\u0026nbsp;cm bulges can be seen in the anterior wall of the middle and upper of the gastric fundus with fractured surface and fresh blood (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eb). Moreover, pathologic examination revealed the destruction of the gastric solid membrane structure and spindle cell tumor\u0026ndash;like hyperplasia with mild dysplasia (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ec) and epithelioid cells are occasionally seen with 6\u0026ndash;8 mitoric figures/50 HPF (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ed). By immunohistochemistry staining, CD117 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ee), CD34 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ef) and SMA were positive, DOG1 was probable positive, and S-100 and CK were negative. These findings supported the diagnosis of GISTs. In addition, a heterozygous missense mutation was found in \u003cem\u003eNPHP4\u003c/em\u003e gene of the subject (NPHP4: NM_015102: exon17: c.2198G\u0026thinsp;\u0026gt;\u0026thinsp;A: p.G733D), could explain the occurrence of GIST and FSGS and this was therefore not a random association. Partial gastrectomy was performed.102\u0026ndash;105 Cyclosporine was used in the outpatient setting for three days, and the patient\u0026rsquo;s feelings of discomfort stopped. Despite of receiving prednisone acetate 50\u0026nbsp;mg QD for three months, the patient\u0026rsquo;s severe proteinuria and hypoalbuminemia did not improve. Additional immunohistochemistry of the skin revealed that CD117 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eg) and DOG1 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eh), the two most sensitive and specific markers for diagnosis of GIST [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e] were positive. Finally, the diagnosis was a metastatic cutaneous GIST. Two weeks after removing the tumor by operation, the patient\u0026rsquo;s serum albumin and urinary protein levels improved remarkably (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e"},{"header":"Discussion And Conclusions","content":"\u003cp\u003eGISTs arise from the interstitial cells of Cajal, which serve as a pacemaker for the gastrointestinal tract by creating slow wave potentials that direct smooth muscle to contract. GISTs primarily metastasize to the liver and peritoneum, while cutaneous metastases are the least common. While, the mechanism of GISTs metastasis to the skin remains unknown. It is hypothesized that the presence may indicate the multiple internal metastases [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]. It was misdiagnosed as DT at the beginning until the recognition of skin metastasis of GISTs by detecting the expression of CD117, CD34 and DOG1 in skin. It should also be advised for patients with a history of GISTs to have a full skin exam to detect any visible clues of the status of metastatic tumor burden.\u003c/p\u003e\n\u003cp\u003eIn our case, the patient had a missense mutation of \u003cem\u003eNPHP4\u003c/em\u003e. \u003cem\u003eNPHP4\u003c/em\u003e locates on chromosome 1p36 and encodes a protein called nephrocystin-4/nephroretinin [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]. Nephrocystin-4 colocalises and interacts with nephrocystin 1,3 and inversin in primary cilia and associated appendages, adherens junctions, and focal adhesions [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]. Individuals with mutations in \u003cem\u003eNPHP4\u003c/em\u003e most frequently have an associated with the nephronophthisis [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]. Some data identify that NPHP4 served as a negative regulator of the Hippo pathway [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]. In acute renal injury, Hippo signaling pathway may be involved in the apoptosis of tubule epithelial cells, epithelial-mesenchymal transition and acute renal injury progress to chronic kidney disease and other processes [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]. In addition, Hippo signaling pathway is also involved in the development and progression of a variety of chronic kidney disease, including FSGS, diabetic nephropathy, polycystic kidney disease [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]. The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and plays an essential role in tumor suppression and the cell prolifiration [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]. NPHP4 is indeed a driving force for proliferation in tumor cells. Therefore, the mutation of \u003cem\u003eNPHP4\u003c/em\u003e in this study could explain the occurrence of GIST and FSGS and this was therefore not a random association.\u003c/p\u003e\n\u003cp\u003eOur patient had a cutaneous metastatic GIST, and needed to be differentiated from Gardner\u0026rsquo;s syndrome, an autosomal hereditary disease with multiple adenomatous polyps in colorectal and some extracolonic lesions. It is characterized by multiple adenomatous polyps in the colorectal region with osteoma, soft-tissue tumor, and tooth abnormality. In addition, 30\u0026ndash;75% of patients with Gardner\u0026rsquo;s syndrome also have dental abnormalities [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]. Osteomas is a necessary diagnosis of Gardner\u0026rsquo;s syndrome. Its molecular genetic basis is the mutation of the \u003cem\u003eAPC\u003c/em\u003e in 5q21. Unfortunately, this patient did not undergo colonoscopy. However, based on the absence of an \u003cem\u003eAPC\u003c/em\u003e mutation, family history, and the fact that the patient had no osteoma or dental abnormalities, the etiology can be differentiated the Gardner\u0026rsquo;s syndrome.\u003c/p\u003e\n\u003cp\u003eTheoretically, the diagnosis of paraneoplastic glomerulopathy should rely on three strong criteria. Firstly, a clinical and histologic remission occurs after complete surgical removal of the tumor or chemotherapy-induced complete remission of the disease. In this case, symptomatic treatment was ineffective but clinical remission was achieved after surgery. So, the nephrotic syndrome can be diagnosed as PNS. Secondly, a renal relapse accompanies recurrence of the neoplasia. In other words, proteinuria should directly correlate with tumor activity. Thirdly, a pathophysiologic link is established between the two diseases, including the detection of tumor antigens and antitumor antibodies within subepithelial immune deposits [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]. In our case, the immunohistochemistry on the kidney revealed positive for CD117 and CD34, but negative for DOG-1. Telocytes (TCs) were indicated as a distinctive cell type by after being previously described as \u0026ldquo;Interstitial Cajal-Like Cells\u0026rdquo; [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]. Qi reported TCs in the interstitium of the human kidney cortex. Renal TCs were found to express CD34 and CD117 with variable intensity [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]. Therefore, the positive CD34 and CD117 in the kidney were not significant. Nephrotic syndrome can occur as malignancy-associated PNS, and previous studies have estimated that cancer occurs in 11\u0026ndash;22% of patients with nephrotic syndrome [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e]. The most common pathological type of tumor-associated nephropathy is membranous nephropathy (44\u0026ndash;49%). FSGS is extremely rare among PNS and it has been reported that FSGS can be seen in renal cell carcinoma, invasive thymoma, and lung cancer [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]. There has been only one case of GIST of the stomach that was associated with nephrotic syndrome as PNS. Nephrotic syndrome improved after surgery in 78% of patients [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e]. Considering cancer is a potential cause of nephrotic syndrome, surgical resection should be performed in the presence of PNS condition. In our case, the patient\u0026rsquo;s proteinuria and hypoalbuminemia did not respond to symptomatic treatment. After tumor removal, the clinical remission of nephrotic syndrome was immediately achieved. Thus, FSGS can be considered a GIST-associated PNS. However, the variant of FSGS that has been reported in PNS was the collapsing variant, duo to the overexpression of vascular endothelial growth factor, which leads to collapsing FSGS. This was not FSGS NOS.\u003c/p\u003e\n\u003cp\u003eSome studies have proven that \u0026alpha;-actinin-4 mutations play an important role in the development of PNS [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]. Unfortunately, this patient did not have any \u003cem\u003eACTN4\u003c/em\u003e mutations. However, these hypotheses seem insufficient to explain the case of GIST accompanied by FSGS as PNS. Tyrosine kinase inhibitors (TKIs) are effective in GISTs, but reports have focused on TKIs-associated renal injury leading to FSGS. In the future, we will use cytotoxic chemotherapy for this patient under intensive follow-up. GISTs are currently regarded as potentially malignant tumors. Discrimination of a benign GISTs from a malignant GIST is by postoperative histological analysis (tumor diameter, mitotic index, whether the tumor has metastasized and Ki67 expression level) [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]. According to the cutaneous metastasis GIST, this case is a high-risk patient with poor prognosis. Joensuu\u0026rsquo;s group recommended for high-risk patients shorter imaging intervals of about 3\u0026ndash;4\u0026nbsp;months during the time period of approximately two years following discontinuation of imatinib [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. Our patient risk of recurrence would be reduced based on the follow-up schedules.\u003c/p\u003e\n\u003cp\u003eIn conclusion, FSGS caused by cutaneous metastasis GIST is quite rare, and to the best of our knowledge, this is the first time to report such a case. The \u003cem\u003eNPHP4\u003c/em\u003e mutation in this case can explain the occurrence GISTs and FSGS. It was not a random association.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACTN4: \u0026alpha;-Actinin-4; APC: adenomatous polyposis coli; CTNNB1: \u0026beta;-Catenin gen 1; DT: desmoid tumor; FSGS: Focal segmental glomerulosclerosis; GIST: gastrointestinal stromal tumor; PNS: paraneoplastic nephritic syndromes; TCs: Telocytes; TKIs: Tyrosine kinase inhibitors.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient. A copy of the consent form is available for review and can be provided on request. This Case Report was done in adherence to the CARE Guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis resarch was sponsored by the Healthy department of Hainan province (grant number, 2001320243A2011).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJun Zhou wrote the manuscript and conducted the literature review. Zhen Yang, Cuishun Yang and Hua Lin participated in the clinical care of the patient. Wanqiong Yuan participated in paper submitting and revising. All authors assisted the results interpretation and manuscript revision. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Professor Ping Qiu for editing the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eVassos N, Agaimy A, Hohenberger W, Croner RS. Coexistence of gastrointestinal stromal tumors (GIST) and malignant neoplasms of different origin: prognostic implications. J Surg. 2014.12(5):371-7.\u003c/li\u003e\n\u003cli\u003ePhan M, Jones S, Jenkins J, Pant S, Khawandanah M. Pancreatic GIST in a patient with limited stage small cell lung cancer: a case report and review of published cases. Case Rep Oncol Med. 2016.2016:9604982.\u003c/li\u003e\n\u003cli\u003eKim YJ, LeeW J, Won CH, Choi JH, Lee MW. Metastatic cutaneous duodenal gastrointestinal stromal tumor: a possible clue to multiple metastases. Ann Dermatol. 2018. Jun;30(3):345-347.\u003c/li\u003e\n\u003cli\u003eAickara DJ, McBride J, Morrison B, Romanelli P. Multidrug resistant gastrointestinal stromal tumor with multiple metastasis to the skin and subcutaneous soft tissue: A case report and review of literature. J Cutan Pathol. 2020.Apr;47(4):398-401.\u003c/li\u003e\n\u003cli\u003eTakane K, Midorikawa Y, Yamazaki S, Kajiwara T, Yoshida N, Kusumi Y, Takayama. Gastrointestinal stromal tumor with nephrotic syndrome as a paraneoplastic syndrome: a case report. Med Case Rep. 2014;27:8.\u003c/li\u003e\n\u003cli\u003eNovelli M, Rossi, S, Rodriguez-Justo M, Taniere P, Seddon B, Toffolatti L, Sartor, C, et al. DOG1 and CD117 are the antibodies of choice in the diagnosis of gastrointestinal stromal. Histopathology. 2010 Aug;57(2):259-70.\u003c/li\u003e\n\u003cli\u003eRemi Salomon, Sophie Saunier, Patric Niaudet. Nephronophthisis. Pediatr Nephrol.2009,24(12):2333-44.\u003c/li\u003e\n\u003cli\u003eMarion Delous, Nathan E. Hellman, Helori-Mael Gaude, et al. Nephrocystin-1 and nephrocystin-4 are required for epithelial morphogenesis and associate with PALS1/PATJ and Par6. Human Molecuar Genetics, 2009,18(24):4711-4723.\u003c/li\u003e\n\u003cli\u003eSimms, Ann Marie Hynes, Lorraine Eley, et al. Nephronophthisis: a genetically diverse ciliopathy. Int J Nephrol, 2011,527137.\u003c/li\u003e\n\u003cli\u003eSandra Habbig, Malte P, Bartram, Roman U. Muller et al. NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway. J Cell Biol,2011,193(4)：633-42.\u003c/li\u003e\n\u003cli\u003eZhao S, Yin J, Zhou L, et al. Hippo/mst1 signaling mediates microglial activation following acute cerebral ischemia-reperfusion injury[J]. Brain Behav Immun, 2016,17(6):1503-1520.\u003c/li\u003e\n\u003cli\u003eKirtida Mistry, MBBCh, DCH, MRCPCH, et al. Novel mutations in NPHP4 in a consanguineous family with histological findings of focal segmental glomerulosclerosis. Am J Kidney Dis, 2007,50(5):855-864.\u003c/li\u003e\n\u003cli\u003eZanconato F, Piccolo S. Eradicating tumor drug resistance at its YAP-biomechanical roots. EMBO J, 2016, 35(5):459-461.\u003c/li\u003e\n\u003cli\u003eSeehra J, Patel S, Bryant C. Gardner\u0026rsquo;s syndrome revisited clinical case and overview of the literature. Orthod. 2016, Mar;43(1):59-64.\u003c/li\u003e\n\u003cli\u003eRonco PM. Paraneoplastic glomerulopathies: new insights into an old entity[J]. Kidney Int, 1999,56(1):355-377.\u003c/li\u003e\n\u003cli\u003eL M Popescu, Maria-Simonetta Faussone-Pellegrini. TELOCYTES-a case of serendipity: the winding way from Intersititial Cells of Cajal (ICC), via Ineterstitial Cajal-Like Cells (ICLC) to TELOCYTES. J Cell Mol Med. 2010 Aprl;14(4):729-40.\u003c/li\u003e\n\u003cli\u003eQi G, Lin M, Xu M, Manole CG, Wang X, Zhu T. J Cell Mol Med. 2012 Dec;16(12):3116-22.\u003c/li\u003e\n\u003cli\u003eJeyabalan A, Geara AS, Frey Nv, Palmer MD, Hoqan JJ. Paraneoplastic focal segmental glomerulosclerosis associated with acute lymphocytic leukemia. Kidney Int Rep. 2019. Jun;4(10):1494-1498.\u003c/li\u003e\n\u003cli\u003eMeng L, Cao S, Lin N, Zhao J, Cai X, Liang Y, Huang K, et al. Identification of a novel ACTN4 gene mutation which is resistant to primary nephrotic syndrome therapy. BioMed Res Int. 2019 Dec;14;5949485.\u003c/li\u003e\n\u003cli\u003eAkahoshi K, Oya M, Koga T, Shiratsuchi Y. Current clinical management of gastrointestinal stromal tumor. World J Gastroenterol. 2018 Jul;24(26):2806-2817.\u003c/li\u003e\n\u003cli\u003eJoensuu J, Martin-Broto J, Nishida T, Reichardt P, S choffski P, Maki RG. Follow-up strategies for patients with gastrointestinal stromal tumour treated with or without adjuvant imatinib after surgery. Eur J Cancer. 2015 Aug;51(12):1611-7.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Gastrointestinal stromal tumors, Cutaneous metastisis, Paraneoplastic nephritic syndromes, NPHP4","lastPublishedDoi":"10.21203/rs.3.rs-141429/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-141429/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Gastrointestinal stromal tumor (GIST) is one of most common mesenchymal neoplasms occurring in different areas of the gastrointestinal tract. GISTs with cutaneous metastasis is very rare and its rarity cutaneous GISTs have not been well characterized. Focal segmental glomerulosclerosis (FSGS) is also rare among paraneoplastic nephritic syndromes (PNS).\u003c/p\u003e\u003cp\u003eCase presentation: In this case report, we described a 64-year-old patient with cutaneous metastasis GIST accompanied by nephrotic syndrome as PNS, in whom symptomatic treatment was ineffective, but clinical remission was achieved after surgery. Moreover, the patient has a missense mutation of \u003cem\u003eNPHP4\u003c/em\u003e. NPHP4 served as a negative regulator of the Hippo pathway. Hippo signaling pathway is involved in the development and progression of FSGS. NPHP4 is also indeed a driving force for proliferation in tumor cells. Therefore, the mutation of \u003cem\u003eNPHP4\u003c/em\u003e in this patient could explain the occurrence of GIST and FSGS and this was therefore not a random association.\u003c/p\u003e\u003cp\u003eConclusions: This is the first reported case of a GIST with cutaneous metastasis accompanied by nephrotic syndrome as PNS. \u003c/p\u003e","manuscriptTitle":"Paraneoplastic Focal Segmental Glomerulosclerosis Associated With Gastrointestinal Stromal Tumors With Cutaneous Metastasis: a Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-01-11 23:39:35","doi":"10.21203/rs.3.rs-141429/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5439ff8a-71af-49f7-a2e5-9ddcec90ca2b","owner":[],"postedDate":"January 11th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":1768465,"name":"Pathology"}],"tags":[],"updatedAt":"2021-01-11T23:42:37+00:00","versionOfRecord":[],"versionCreatedAt":"2021-01-11 23:39:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-141429","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-141429","identity":"rs-141429","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}