Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer

PURPOSE: Hereditary leiomyomatosis and renal cell cancer is a recently described hereditary cancer syndrome in which affected individuals are at risk for cutaneous and uterine leiomyomas, and kidney cancer. Our initial experience revealed the aggressive behavior of these renal tumors, often with early metastasis, despite small primary tumor size. We report the clinical characteristics and urological treatment of patients with hereditary leiomyomatosis and renal cell cancer associated renal tumors. MATERIALS AND METHODS: A total of 19 patients with hereditary leiomyomatosis and renal cell cancer associated renal tumors were evaluated. The 11 women and 8 men had a median age at diagnosis of 39 years (range 22 to 67), and a median clinical and radiological followup of 34 months (range 6 to 141). Hereditary leiomyomatosis and renal cell cancer manifestations in patients with renal tumors included cutaneous leiomyomas in 11 of 17 evaluable patients (65%) and uterine leiomyomas in 7 of 7 evaluable females (100%). RESULTS: Median pathological tumor size was 7.8 cm (range 1.5 to 20). Histological subtypes were consistent with hereditary leiomyomatosis and renal cell cancer renal carcinoma. Four of 7 patients with 2.0 to 6.7 cm T1 tumors had spread to regional lymph nodes or metastases at nephrectomy. Overall 9 of 19 patients (47%) presented with nodal or distant metastases. CONCLUSIONS: Renal tumors in patients with hereditary leiomyomatosis and renal cell cancer syndrome are significantly more aggressive than those in patients with other hereditary renal tumor syndromes. In contrast to other familial renal cancer syndromes, the observation of 3 cm or less renal tumors associated with hereditary leiomyomatosis and renal cell cancer is not recommended. Careful followup of affected and at risk individuals in families is necessary.     

Hereditary colorectal cancer syndromes: familial adenomatous polyposis and lynch syndrome

Familial colorectal cancer (CRC) accounts for 10% to 20% of all cases of CRC. Two major autosomal dominant forms of heritable CRC are familial adenomatous polyposis (FAP) and Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer). Along with the risk for CRC, both syndromes are associated with elevated risk for other tumors. Improved understanding of the genetic basis of these diseases has not only facilitated the identification and screening of at-risk individuals and the development of prophylactic or early-stage intervention strategies but also provided better insight into sporadic CRC. This article reviews the clinical and genetic characteristics of FAP and Lynch syndrome, recommended screening and surveillance practices, and appropriate surgical and nonsurgical interventions.     

Hereditary renal cell carcinoma syndromes: diagnosis,surveillance and management

Purpose

Genetic factors have been implicated in the pathogenesis of renal cell carcinoma (RCC), with around 3% of cases having a family history. A greater knowledge of the genetics of inherited RCC has the potential to translate into novel therapeutic targets for sporadic RCC.

Methods

A literature review was performed summarising the current knowledge on hereditary RCC diagnosis, surveillance and management.

Results

Familial RCC is usually inherited in an autosomal dominant manner, although inherited RCC may present without a relevant family history. A number of familial RCC syndromes have been identified. Familial non-syndromic RCC is suspected when ≥?2 relatives are affected in the absence of syndromic features, although clear diagnostic criteria are lacking. Young age at onset and bilateral/multicentric tumours are recognised characteristics which should prompt molecular genetic analysis. Surveillance in individuals at risk of inherited RCC aims to prevent morbidity and mortality via early detection of tumours. Though screening and management guidelines for some inherited RCC syndromes (e.g. von Hippel–Lindau disease, Birt–Hogg–Dube syndrome, hereditary leiomyomatosis) are well defined for rare cause of inherited RCC (e.g. germline BAP1 mutations), there is limited information regarding the lifetime RCC risks and the most appropriate screening modalities.

Conclusion

Increasing knowledge of the natural history and genetic basis has led to characterisation and tailored management of hereditary RCC syndromes. International data sharing of inherited RCC gene variant information may enable evidence-based improvements in the diagnosis, surveillance protocols and management of these rare conditions.

     

Bilateral transitional cell carcinoma of the renal pelvis in the cancer family syndrome

The cancer family syndrome is an unusual hereditary disease rarely associated with transitional cell carcinoma of the urinary tract. We describe the occurrence of this syndrome in a patient with bilateral transitional cell malignancies.     

Paraneoplastic syndrome of renal cell carcinoma

We report a case of renal cell carcinoma who presented with the classic triad of flank pain, hematuria and fever as well as progressively developed multisystem disease, including a massive anteroseptal myocardial infarction. This was diagnosed as paraneoplastic syndrome of renal cell carcinoma and the decision to proceed with nephrectomy was taken after 3 weeks of acute myocardial infarction, despite predicted high cardiac risk under general anaesthesia; following removal of tumour, all symptoms and signs regressed. He has remained well till the time of last follow-up 4 months later.     

Hereditary renal cell carcinoma: genetics,clinical features,and surgical considerations

Objectives

Hereditary renal cancer syndromes have been described and have illuminated novel methods to treat sporadic renal cell carcinoma. In this work, we aimed to review the genetic basis, molecular pathology and clinical manifestations of hereditary syndromes, as well as outline principles of surgical management and use of targeted therapy.

Methods

We performed a comprehensive review of selected peer-reviewed publications regarding hereditary renal cancer syndromes, their genetic basis, and recommendations for surgical management.

Results

The major syndromes contributing to hereditary renal cell carcinoma are discussed along with relevant literature guiding their management. The evolving surgical and molecular treatments are discussed.

Conclusions

Identification of genetic basis of hereditary carcinomas provides opportunity for targeted therapy of metastatic sporadic renal cell carcinoma.  Appropriate and timely surgical management of hereditary renal cancers decreases the possibility of development of metastatic disease, and allows for preservation of renal function despite the need for repeat surgical interventions.     

Stauffer''s syndrome variant associated with renal cell carcinoma

Cholestasis, as a paraneoplastic syndrome, has been well described in patients with malignant lymphohyperplastic diseases and renal cell cancer. Non-metastatic nephrogenic hepatic dysfunction syndrome without jaundice has often been described in patients with Stauffer's syndrome. Paraneoplastic cholestatic jaundice is extremely uncommon. We report, a patient who presented with pruritus and cholestatic jaundice and was diagnosed with renal cell carcinoma (RCC) in the right kidney. Liver malfunction and cholestatic icterus was attributed to RCC. Jaundice and liver dysfunction gradually restored to normal after surgical resection of the tumor. Malignancies may cause cholestatic jaundice through well-recognized mechanisms. Paraneoplastic syndromes associated with malignancy, can induce a reversible form of cholestasis through an unclear pathogenetic mechanism.     

Hereditary leiomyomatosis and renal cell cancer without cutaneous manifestations in two Japanese siblings

Hereditary leiomyomatosis and renal cell cancer is a rare genetic disorder characterized by cutaneous and uterine leiomyomatosis, and an aggressive type 2 papillary renal cell carcinoma. The disease is caused by a germline mutation in the fumarate hydratase gene. We report a familial hereditary leiomyomatosis and renal cell cancer in two siblings. A 34‐year‐old woman underwent nephrectomy for treatment of a renal cell carcinoma. The patient's sister had been diagnosed with renal cell carcinoma at 28 years‐of‐age and died of the disease. Neither sister had apparent skin tumors. Histopathology of the renal cell carcinomas of the siblings showed tubulocystic and papillary architectures with high nuclear grades. Immunostaining showed no fumarate hydratase expression in either tumor. Genomic DNA sequencing of the patient showed a germline mutation in the fumarate hydratase gene (c.675delT). Although there is no epidemiological information on Asian hereditary leiomyomatosis and renal cell cancer, physicians should be aware that typical cutaneous leiomyomatosis might not always be present in patients with hereditary leiomyomatosis and renal cell cancer.     

Bilateral renal cell carcinoma and renal cell carcinoma in the solitary kidney

We report on 43 patients with renal cell carcinoma in a solitary kidney, 39 of whom underwent a potentially curative resection. Of 36 patients who had a nephron salvaging procedure only 4 required ex vivo surgical resection. The survival curves of patients with solitary or bilateral lesions are similar, and depend more on the adequacy of tumor resection and tumor stage than on the fate of the contralateral kidney. Crude survival in this series was 64 per cent for patients followed for more than 1 year.     

Treatment of metastatic renal cell carcinoma and renal pelvic cancer

A better understanding of the molecular biology of renal cell carcinoma (RCC) and the emergence of molecular targeted drugs have revolutionized the treatment for patients with metastatic RCC (mRCC). Multi-targeted tyrosine kinase inhibitors (sorafenib and sunitinib) and mammalian target of rapamycin inhibitors (temsirolimus and everolimus) have recently shown superiority over interferon-α or placebo. However, while the molecular targeted drugs have demonstrated encouraging results, these drugs have also sometimes induced unexpected adverse events. Control of adverse events is important to obtain the maximum effectiveness and sustain quality of life for patients. Because renal pelvic cancer has many similarities in pathogenesis with urinary bladder cancer, the same chemotherapeutic regimen is often proposed for patients with metastatic renal pelvic cancer. Combined chemotherapy with gemcitabine and cisplatin is now widely considered to be first-line chemotherapy against these metastatic diseases; however, there are still unresolved problems with this treatment, including the limited survival benefit. To select new therapeutic modalities, a more profound understanding of the molecular biology of renal pelvic cancer is crucial. The purpose of this review is to summarize the current evidence supporting the role and activities of new chemotherapeutic agents and to reveal potential future directions in the management of mRCC and renal pelvic cancer.     

Inverted papilloma of the renal pelvis associated with renal cell carcinoma: a case report.

Twenty-one cases of inverted papilloma of the renal pelvis have been described in the literature. A 71-year-old man was admitted to our hospital to examine a right renal mass. We diagnosed a right renal tumor on the basis of the findings from excretory urogram (IVP), computerized tomography (CT) and magnetic resonance imaging (MRI). Surgical material revealed an inverted papilloma in the renal pelvis. We report on the first case of an invested papilloma of the renal pelvis associated with renal cell carcinoma.     

Ureteral and bladder metastases of renal cell carcinoma following synchronous renal cell carcinoma and bladder cancer; a case report

A 73-year-old man presented with gross hematuria. Ultrasonography and computerized tomography showed small bladder tumors and a left renal mass protruding to renal pelvis. Transurethral resection of bladder tumor and ureteroscopic tumor biopsy were performed, and pathological examinations revealed transitional cell carcinoma in the bladder and renal cell carcinoma in the kidney. He underwent left radical nephrectomy. A 4-month postoperative cystoscopy revealed a solitaly non-papillary tumor in the bladder. Transurethral resection was performed and pathological diagnosis was metastasis from renal cell carcinoma. At that time, multiple metastases to ureteral stump and lung were found. He had undergone palliative treatment because of his poor general condition until he died 26 months postoperatively. Care should be taken for management of ureteral stump when diagnostic ureteroscopy was done for renal cell carcinoma invading the renal pelvis.     

Hereditary leiomyomatosis and renal cell cancer (HLRCC): Case series and review of the literature

BackgroundHereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant syndrome caused by heterozygous pathogenic germline variants in the fumarate hydratase (FH) gene. It is characterized by cutaneous and uterine leiomyomas and an increased risk of developing renal cell carcinoma (RCC). HLRCC-related RCC tends to be aggressive. To date, only a few publications have described HLRCC-related RCC, and the clinical, morphological and molecular aspects of HLRCC-related RCC need to be further studied.MethodsWe retrospectively analyzed the clinical and pathological data of 3 patients with HLRCC recently diagnosed. Immunohistochemistry and Whole-exome sequencing was performed on 3 patients. The function of the DNA variant was predicted in silico.ResultsWe reported 3 patients from unrelated Chinese families, with HLRCC-related RCC and identified 3 different germline FH mutations (2 missense and 1 nonsense). A novel missense mutation of FH gene (c.454A>G, p.N152D) was predicted to be probably pathogenic and deleterious by multiple protein function predicting software. This study indicated that the novel mutation may be responsible for the occurrence of HLRCC-related RCC. 100% (2/2) female RCC patients had uterine fibroids. No cutaneous manifestations were identified.ConclusionWe indicate that germline screening should be encouraged in early-onset patients. Clinicopathological data, such as family history and immunohistochemical results can provide valuable clinical information for the differential diagnosis of HLRCC-associated RCC in advance.     

Chromophobe cell renal carcinoma: a case report

Chromophobe cell renal carcinoma is an uncommon subtype of renal cell carcinoma and the number of cases studied is still limited in Japan. We here report a case of chromophobe cell renal carcinoma in a 41-year-old Mexican male. He visited our branch hospital with the symptom of upper abdominal pain. Ultrasound examination showed a left renal mass. He was admitted to our hospital for treatment of a left renal mass. Radiological examinations revealed a hypervascular tumor in the left kidney. Under the clinical diagnosis of possible renal cell carcinoma, left radical nephrectomy was performed. This tumor was diagnosed as chromophobe cell renal carcinoma with a microscopic examination of H & E stained specimens, histochemical staining using Hale's colloidal iron and an ultrastructural study.     

Chromophobe cell renal carcinoma: a case report

We report a case of chromophobe cell renal carcinoma. A 45-year-old woman with a chief complaint of macrohematuria and left backache was introduced to our hospital in October 1998. Abdominal computed tomographic scan (CT) revealed a solitary, solid mass (16 x 14 x 12 cm) at the upper pole of the left kidney. Angiography showed a hypervascular character but irregular neovasculizations were found. We performed a radical nephrectomy with a preoperative diagnosis of malignant renal tumor. The cut surface appearance of the tumor was homogeneous, grey-beige and solid. Light microscopic findings revealed voluminous cells with light, but not clear cytoplasm displaying a fine reticular pattern. Histochemical staining with Hale's colloidal iron stain demonstrated a distinctly positive cytoplasmic reaction. Since the ultrastructural study revealed numerous intracytoplasmic microvesicles, we finally reached the diagnosis of chromophobe cell renal carcinoma. We report our case here with reference to the relevant literature.