Added text to state that endocrine function is nearly always maintained; occasionally, however, patients with extensive cystic disease requiring pancreatic surgery may ultimately require pancreatic exocrine supplementation.
Added text to state that the risk of pancreatic neuroendocrine tumor (NET) metastasis was analyzed in a large cohort of patients (cited Blansfield et al. as reference 86). The risk of metastasis was lower in patients with small primary lesions, in patients without an exon 3 pathogenic variant, and in patients whose tumor had a slow doubling time. Nonfunctional pancreatic NETs can be followed by imaging surveillance with intervention when tumors reach 3 cm. Lesions in the head of the pancreas can be considered for surgery at a smaller size to limit operative complexity
Added text to state that much of the preclinical data that forms the basis for current systemic treatment strategies stem from the study of VHL alteration. All the large randomized phase III trials investigating aldesleukin, vascular endothelial growth factor (VEGF) receptor tyrosine kinase inihibitors, mTOR inhibitors, and checkpoint inhibitors are based on data from the treatment of sporadic clear cell kidney cancer. Despite limited studies investigating these agents in the VHL population with metastatic kidney cancer, they are believed to be efficacious and are available as treatment options.
Added text to state that archival VHL-related tumor specimens were evaluated to determine expression of relevant sunitinib targets.
Revised text about a study of intravitreally administered pegaptanib, an anti-VEGF therapy, that was evaluated in five patients with VHL-associated retinal hemangioblastomas (cited Dahr et al. as reference 130). Only two patients were able to complete the intended therapy, and no responses were seen in the primary tumors. Two patients had decreased retinal thickening and reduced hard exudates. Although the agent is approved by the U.S. Food and Drug Administration for macular degeneration, it is not approved for the treatment of VHL retinal lesions.
Revised text to state that the renal cell cancer (RCC) mortality rate is thought to have diminished significantly because of adherence to RCC treatment recommendations including the 3 cm rule.
Revised text to state that there is a clear unmet need for better management strategies in VHL and development of targeted systemic therapy.
Revised text to state that it is estimated that several hundred families with HLRCC have been seen at the National Institutes of Health and at other centers around the world.
Revised text to state that the estimated cumulative lifetime incidence of RCC varies widely, with most estimates ranging from 15% to 30% in families with germline FH pathogenic variants.
Added text to state that using bidirectional DNA sequencing methodology, pathogenic variants in FH have been detected in more than 85% of individuals with HLRCC.
Revised text to state that only a very low frequency of somatic FH pathogenic variants have been identified in sporadic forms of kidney cancer (cited Linehan et al. as reference 17).
Added text to state that accumulated fumarate can activate the antioxidant response pathway which enables cancer cells to survive in an environment of oxidative stress. Fumarate, an electrophile, is able to posttranslationally modify KEAP1 by succination on cysteine sulfhydryls (cited Alderson et al. as reference 22), thereby releasing KEAP1 inhibition of NRF2. Also revised text to state that the resultant stabilization of NRF2 leads to transcriptional upregulation of antioxidant response element–controlled genes.
Added text to state that HLRCC is phenotypically variable.
Added text to state that patients with seemingly sporadic tumors who have a negative family history and a single, histologically confirmed cutaneous leiomyoma may test positive for the presence of a germline FH pathogenic variant. Although the percentage of germline pathogenic variants in such patient populations is not known, many centers may refer for genetic counseling and testing any patient with even a single cutaneous leiomyoma, independently of family history.
Revised text to state that some individuals have HLRCC as the result of a de novo gene pathogenic variant or parental mosaicism.
Revised text to state that although some individuals diagnosed with HLRCC have an affected parent, the family history may appear to be negative because of limited family history, failure to recognize the disorder in family members, early death of the affected parent before the onset of syndrome-related symptoms, or late onset of the disease in the affected parent.
Revised text to state that annual gynecologic consultation is recommended, accompanied by periodic imaging including magnetic resonance imaging (MRI) of the pelvis or ultrasound (cited Patel et al. as reference 52). Also added text to state that MRI has the advantage of sparing the patient radiation exposure and for this reason it may be preferred over computed tomography (CT) for lifetime surveillance of HLRCC patients.
Added text to state that generally, asymptomatic cutaneous leiomyomas require no treatment. Treatment of symptomatic cutaneous leiomyomas may be difficult if a patient has diffuse disease in a wide distribution.
Revised text to state that when women desire preservation of fertility, myomectomy to remove leiomyomas while preserving the uterus is the treatment of choice.
Added text to state that surgical excision of these malignancies at the first sign of disease is recommended unlike management of other hereditary cancer syndromes. The propensity for lymph node involvement even with small renal tumors may necessitate a lymph node dissection for more appropriate staging (cited Shuch et al. as reference 51).
Revised text to state that the 15% to 30% of HLRCC patients who develop RCC are at high risk of developing metastatic disease. Also added text to state that retrospective cohorts demonstrate that these cancers have worse outcomes than other conventional forms of kidney cancer (cited Chen et al. as reference 60).
Revised text to state that the ability to predict who will develop RCC to allow detection earlier and with a higher degree of precision is a major unmet need in the management of patients with HLRCC.
Added Nickerson et al. and 2015 Schmidt et al. as references 2 and 4, respectively. Also revised text to state that the median age at tumor diagnosis is 46 to 50 years.
Added text to state that BHD is characterized by phenotypic heterogeneity. Also added text to state that renal tumors associated with BHD can be aggressive, but generally are fairly indolent. Most appropriately managed patients will require no more than one partial nephrectomy on each kidney during their lifetimes.
Added text to state that FLCN, a novel tumor suppressor gene, comprises 14 exons located at chromosome 17p11.2. In BHD patients, FLCN pathogenic variants have been identified in all translated exons (cited Kunogi et al. as reference 17).
Revised text to state that more than 200 families affected with BHD from various populations have been described in various countries (cited Leter et al. as reference 19, Kluger et al. as reference 20, and Houweling et al. as reference 21).
Revised text to state that both somatic point mutations in the wild-type FLCN allele and loss of heterozygosity at chromosome 17p have been identified, although the former appears to be the more common mechanism of inactivation of the second FLCN allele. Also added text to state that the C-terminal domain of FLCN is required for its interaction with FNIP1 and FNIP2. Most, but not all, tumor-associated FLCN variants predict for a truncated protein missing this C-terminal domain or they appear to destabilize the FLCN protein (cited 2011 Nahorski et al. as reference 26).
Added text to state that tissue-specific activation of mTORC1 was demonstrated in a kidney-specific FLCN knockout mouse model (cited Baba et al. as reference 27), in which both mTORC1 and mTORC2 were activated in renal tumors that developed in FLCN heterozygous knockout mice subsequent to loss of the wild-type allele (cited Hasumi et al. as reference 28). Also added text to state that more research on the mechanism(s) of tumor suppressor function of FLCN is required.
Revised text to state that the three major features of BHD include fibrofolliculomas, pulmonary cysts and spontaneous pneumothorax, and renal tumors.
Added text to state that this syndromic phenotype is highly penetrant in affected individuals. In two large BHD family studies, 73% and 84% of affected patients in whom skin lesions were biopsied were found to have fibrofolliculomas.
Revised text to state that lung cysts are present in 85% to 87% of BHD patients when CT imaging is performed.
Revised text to state that in a study of 198 BHD-affected patients, the occurrence of spontaneous pneumothorax was comparable between men (20%) and women (29%). The age range for initial pneumothorax was 22 to 75 years, but the median age for first occurrence was 38 years and is typically before the fifth decade.
Added text to state that although initial epidemiologic observations linked BHD with an increased risk of colonic polyps, subsequent epidemiologic studies did not appear to confirm this link (cited 2010 Nahorski et al. as reference 45).
Revised text to state that bidirectional DNA sequencing of all FLCN coding exons resulted in a pathogenic variant detection rate of 84%, which has been improved by the development of real time-quantitative polymerase chain reaction and multiplex ligation-dependent probe amplification assays to detect intragenic deletions and duplications and is available on a clinical basis (cited Benhammou et al. as reference 47).
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