Renal cell carcinoma (RCC) is the most common malignant neoplasm of the kidneys. While most cases are sporadic, chromosomal or gene aberrations may predispose for RCC. Accordingly, affected individuals are diagnosed with hereditary renal cell carcinoma (hRCC). Because hRCC is caused by germline mutations of tumor suppressor genes or proto-oncogenes, hRCC are usually associated with additional, extrarenal neoplasms. The clinical presentation of the individual patient may indicate the underlying tumor syndrome and thus facilitate targeted genetic analyses. From a histological point of view, hRCC may correspond to either type of RCC recognized by the World Health Organization, e.g., clear cell, papillary, or chromophobe RCC.
The symptom triad of flank pain, hematuria and a palpable abdominal mass is sometimes described as characteristic of RCC - and it should surely prompt further studies - but patients tend to remain asymptomatic for prolonged periods of time. Therefore, most RCC are detected incidentally when patients undergo imaging studies, which may be carried out as part of a surveillance program or for unrelated reasons .
In case of advanced disease, patients may present constitutional symptoms like fatigue, fever, night sweats, loss of appetite and weight. If metastases have formed in other organs, e.g., in liver, lungs, or bones, these may interfere with organ function. Accordingly, RCC patients may suffer from nausea and vomiting, dyspnea, and bone pain, among others.
Most commonly, pathological findings in diagnostic imaging studies provide first hints as to the presence of RCC. Tumors may be displayed by means of sonography, computed tomography, magnetic resonance imaging, and other techniques. Features to be evaluated on images comprise homogeneity, signal attenuation, and enhancement after contrast agent administration. They may indicate a certain type of RCC, may reveal the presence of cysts and necrotic lesions, and allow for the differentiation of hypovascular and hypervascular neoplasms. With regard to hRCC, the involvement of both kidneys and/or the presence of multiple tumors highly suggests an underlying genetic disorder. However, this is not to be considered an exclusion criterion since tumors developing due to hereditary leiomyomatosis and renal cell cancer often occur as a single, solid mass .
All findings have to be interpreted in the context of the patient's medical and family history . For instance, patients suffering from hereditary leiomyomatosis and renal cell cancer may have undergone hysterectomy for uterine leiomyomas at an early age . hRCC patients may also describe an apparent susceptibility for cancer in their relatives. Such indications should raise suspicion as to a possible genetic cause of RCC and prompt analyses in order to confirm the presence of DNA sequence anomalies.
While surgical removal is the treatment of choice for patients with sporadic RCC, the decision for surgery is often postponed in hRCC patients. This is due to the fact that hRCC patients are at high risk of relapse. In order to delay the need for dialysis, nephron-sparing approaches including non-surgical treatments are to be preferred over radical interventions whenever possible . Unfortunately though, there are few alternatives to surgery: Most RCC are highly resistant to both chemotherapy and radiotherapy, and ablative therapies like cryotherapy, radiofrequency ablation, and embolization are recommended for stage 1 renal cancer only . Consequently, the following recommendations are given regarding the management of hRCC  :
An individual patient's prognosis depends on the underlying disorder, the histological type of RCC and present comorbidities. While hRCC is the most common cause of death in patients with von Hippel-Lindau disease, renal tumors in Birt–Hogg–Dubé syndrome have low malignant potential . This is in agreement with the histological types of RCC developing in patients suffering from either disease: Clear cell RCC are to be expected in von Hippel-Lindau disease and are associated with an unfavorable prognosis. By contrast, hybrid oncocytoma/chromophobe RCC as well as chromophobe RCC are related to a favorable prognosis and high survival rates. Hereditary papillary renal cancer also tends to run an indolent course, but, as has been indicated above, tumors developing due to hereditary leiomyomatosis and renal cell cancer tend to grow aggressively. They are of the clear cell subtype.
Patients with hereditary tumor syndromes such as von Hippel-Lindau disease, hereditary papillary renal cancer, hereditary leiomyomatosis and renal cell cancer, or Birt–Hogg–Dubé syndrome, are prone to develop hRCC and extrarenal neoplasms. These diseases are caused by mutations in tumor suppressor genes or proto-oncogenes, and they are inherited in an autosomal dominant manner. Nevertheless, few patients present with all types of tumors attributed to a certain disease since penetrance is incomplete for all of them. For instance, less than 50% of those suffering from von Hippel-Lindau disease are diagnosed with hRCC during their life. Those that never develop hRCC may still present with retinal angiomas or hemangioblastomas of the central nervous system, or remain asymptomatic. In Birt–Hogg–Dubé syndrome, the penetrance of renal cancer is 20 to 40% .
The following list shall provide an overview of diseases with Mendelian inheritance that predispose for hRCC  :
It should be noted that genetic factors may also play a role in the onset of RCC deemed sporadic: First-degree relatives of RCC patients are twice as likely to develop RCC than the general population .
RCC accounts for about 3% of malignancies diagnosed in adult patients and is the most common type of malignant tumor originating from the kidneys. Only 3% of RCC are familial .
Because the incidence of RCC peaks in the 5th and 6th decade of life, early-onset RCC should raise suspicion as to an underlying cancer susceptibility syndrome. In this context, "early onset" frequently refers to the appearance of symptoms in people aged <40 years, but patients aged 40 to 50 years may also be considered relatively young .
hRCC are caused by mutations in tumor suppressor genes or proto-oncogenes. These genes encode for proteins implicated in the regulation of cell cycle, growth, differentiation, and proliferation. The pathophysiological mechanisms underlying tumor growth vary between distinct hereditary kidney cancer syndromes and range from constitutively active tyrosine kinases, which should remain inactive in the absence of determined growth factors, to the stabilization of transcription factors .
Although affected families may benefit from genetic counseling, no recommendations can be given to prevent the development of hRCC in patients carrying predisposing mutations. However, regular surveillance facilitates an early diagnosis of renal tumors . They may then be removed before progressing to advanced stages, and nephron-sparing surgery may be opted for instead of radical nephrectomy.
Approximately 90% of all kidney cancers are RCC, so this type of tumor is the most common malignancy affecting the kidneys . RCC are generally classified according to their histological features: The Classification of Tumors of the Urinary System, as published by the World Health Organization, contains descriptions of clear cell, papillary, chromophobe and rare variants of RCC . In the majority of cases, these tumors are sporadic. Nevertheless, all types of RCC have also been reported in patients prone to tumor development due to certain hereditary conditions.
Most diseases associated with hRCC are inherited in an autosomal dominant manner. They are caused by germline mutations in genes involved in cell cycle regulation, differentiation and growth. The expression of these genes is not limited to the kidneys and thus, tumors are likely to develop in other tissues and organs, too. For instance, patients suffering from von Hippel-Lindau disease, the most common disorder predisposing for RCC, may also present with angioma and hemangioblastoma of the retina or the central nervous system, and pheochromocytoma. By contrast, hRCC is often associated with leiomyomas in people with hereditary leiomyomatosis and renal cell cancer. Hereditary papillary renal cancer, however, manifests papillary RCC only .
The diagnosis of hRCC relies on the identification of the underlying mutation. While histological features don't allow for the distinction between sporadic and hereditary forms of RCC, certain findings suggest an inherited condition: hRCC are often diagnosed in early to mid-adulthood and frequently affect both kidneys. Even if one kidney is spared, multiple tumors may be detected in the affected organ. Patients are likely to relapse even though tumors are resected completely, and, as has been indicated above, they may develop extrarenal neoplasms .
Treatment doesn't differ from that of sporadic RCC and mainly consists in the surgical removal of the neoplastic tissue. All possible efforts should be made to spare unaffected renal tissue and to maintain kidney function for as long as possible.
Renal cell carcinoma is the most common malignancy of the kidneys. Renal cancer is sporadic in the vast majority of cases, but about 3% of patients are genetically predisposed. They are carriers of determined mutations that interfere with the regulation of cell growth, differentiation, and proliferation, and that facilitate the development of tumors. Because these mutations may also affect the control of cell proliferation elsewhere in the body, patients suffering from hereditary renal cell carcinoma are prone to neoplasms in other tissues and organs. For instance, those suffering from von Hippel-Lindau disease are at high risk of renal cancer, retinal angiomas, and hemangioblastomas of the central nervous system. Hereditary leiomyomatosis and renal cell cancer is associated with renal cancer, uterine and cutaneous leiomyomas.
Comorbidities present in individual patients are the basis of targeted genetic analyses, which are necessary to identify the causal mutation. Unfortunately, there is no cure for the hereditary disorder causing renal cancer. Kidney tumors may eventually be removed to prevent disease progression and the formation of metastases, but those suffering from hereditary renal cell carcinoma are likely to relapse and repeated surgical interventions will impair kidney function. The patient's prognosis varies depending on the underlying disease, the histological type of renal cancer and present comorbidities: Tumors may grow aggressively, but the disease may also run an indolent course.