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 . 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 . Nephrocystin-4 colocalises and interacts with nephrocystin 1,3 and inversin in primary cilia and associated appendages, adherens junctions, and focal adhesions . Individuals with mutations in NPHP4 most frequently have an associated with the nephronophthisis . Some data identify that NPHP4 served as a negative regulator of the Hippo pathway . 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 . 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 . 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 . 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 . 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 . 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” . Qi reported TCs in the interstitium of the human kidney cortex. Renal TCs were found to express CD34 and CD117 with variable intensity . 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 . 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 . 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 . 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 . 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) . 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 . 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.