Radical nephrectomy and regional lymph node dissection for locally advanced type 2 papillary renal cell carcinoma in an at-risk individual from a family with hereditary leiomyomatosis and renal cell cancer: a case report

Kamai et al. BMC Cancer (2016) 16:232 DOI 10.1186/s12885-016-2272-7 CASE REPORT Open Access Radical nephrectomy and regional lymph node dissection for locally advanced type 2 papillary renal cell carcinoma in an at-risk individual from a family with hereditary leiomyomatosis and renal cell cancer: a case report Takao Kamai1*, Hideyuki Abe1, Kyoko Arai1, Satoshi Murakami2, Setsu Sakamoto3, Yasushi Kaji4 and Ken-Ichiro Yoshida1 Abstract Background: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant tumor susceptibility syndrome, and the disease-related gene has been identified as fumarate hydratase (fumarase, FH). HLRCC-associated kidney cancer is an aggressive tumor characterized by early metastasis to regional lymph nodes and distant organs. Since early diagnosis and provision of definitive therapy is thought to be the best way to reduce the tumor burden, it is widely accepted that germline testing and active surveillance for an at-risk individual from a family with HLRCC is very important. However, it still remains controversial how we should treat HLRCC-associated kidney cancer. We successfully treated the patient with locally advanced HLRCC-associated kidney cancer, who has received active surveillance because of at-risk individual, by radical nephrectomy and extended retroperitoneal lymph node dissection, and examined surgically resected samples from a molecular point of view. Case presentation: We recommended that 13 at-risk individuals from a family with HLRCC should receive active surveillance for early detection of renal cancer. A 48-year-old woman with a left renal tumor and involvement of multiple regional lymph nodes with high accumulation of fluorine-18-deoxyglucose on positron emission tomography was treated with axitinib as a neoadjuvant therapy. Preoperative axitinib induced the shrinkage of the tumor with decreased fluorine-18-deoxyglucose accumulation. Resected samples showed two thirds tumor tissue necrosis as well as high expression of serine/threonine kinase Akt and low expression of nuclear factor E2-related factor 2 (Nrf2) which activates anti-oxidant response and protects against oxidative stress in viable cancer cells. Targeted next-generation sequencing revealed that FH mutation and loss of the second allele were completely identical between blood and tumor samples, suggesting that FH mutation plays a direct role in FH-deficient RCC. She has remained well after radical operation for over 33 months. Conclusions: FH mutation plays a role in tumorigenic feature, a metabolic shift to aerobic glycolysis, and increased an anti-oxidant response phenotype in HLRCC-associated kidney cancer. Keywords: Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), Type 2 papillary renal cell carcinoma, Axitinib, Fumarate hydratase (FH), Targeted next-generation sequencing * Correspondence: 1 Department of Urology, Dokkyo Medical University, 880 Kitakobayashi Mibu, Tochigi 321-0293, Japan Full list of author information is available at the end of the article © 2016 Kamai et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kamai et al. BMC Cancer (2016) 16:232 Background Hereditary leiomyomatosis and renal cell cancer (HLRCC, Online Mendelian Inheritance in Man accession number 605839) is a recently identified autosomal dominant tumor susceptibility syndrome that is characterized by a predisposition to develop benign leiomyomas of the skin and the uterus (fibroids and myomas), as well as aggressive renal cell cancer with papillary type 2 (pRCC2) or collecting duct histology [1–3]. The disease-related gene has been identified as fumarate hydratase (fumarase, FH, Online Mendelian Inheritance in Man accession number 136850) located at 1q43. FH encodes an enzyme that is part of the mitochondrial tricarboxylic acid (TCA) cycle involved in cellular energy metabolism and appears to function as a tumor suppressor since its activity is very low or absent in tumors from individuals with HLRCC. HLRCC-associated kidney cancer has distinctive architectural and morphologic features, is particularly aggressive, and tends to metastasize to regional lymph nodes and distant organs early [4]. Therefore, a high detection rate of mutations in HLRCC families may enable early identification of at-risk individuals and allow early initiation of therapy while their tumors are still small. However, it stills remains controversial how we should treat HLRCC-associated kidney cancer [5]. So far, there have been several case reports regarding HLRCC-associated kidney cancer, however, most of those were reporting the mutation analysis of FH, pathological features, and clinical course. Furthermore, to our knowledge, there have been no case reports of the patients of at-risk of HLRCC-associated with kidney cancer who received active surveillance and were treated successfully, and little is known about the relationship between the clinicopathological features and molecular changes associated with targeting therapy in this disease. In the present study, we successfully treated a patient with locally advanced HLRCC-associated pRCC2 by neoadjuvant administration of axitinib and subsequent radical nephrectomy and extended retroperitoneal lymph node dissection. FH-deficient RCC is characterized by enhanced aerobic glycolysis and increased anti-oxidant response phenotype [6, 7]. Overactivation of phosphatidylinositol 3‘kinase (PI3K), serine/threonine protein kinase B (Akt), and mammalian target of rapamycin (mTOR) pathway has been reported in RCC. Inhibition of Akt disrupts transcription of glucose transporter protein-1 (GLUT1) and its translocation to the plasma membrane to promote glucose utilization independent of an effect on cell proliferation [8]. Phosphorylation at two sites is required for full activation of Akt, since it is phosphorylated by PI3K-dependent kinase-1 (PDK1) at a threonine residue in the catalytic domain (Thr-308) and by PI3K-dependent kinase-2 (PDK2) at a serine residue (Ser-473) in the carboxy-terminal hydrophobic motif [9]. mTOR has dual Page 2 of 10 rapamycin-sensitive (mTOR-raptor complex: mTORC1) and rapamycin-insensitive (mTOR-rictor complex: mTORC2) functions. mTORC1 is activated by PI3K-Akt and it phosphorylates S6 and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), thereby promoting translation and protein synthesis. mTORC2 regulates the actin cytoskeleton and also possesses (...truncated)