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BACKGROUND: Pathogenic AXIN2 variants cause absence of permanent teeth (hypodontia), sparse hair and eye brows (ectodermal dysplasia), and gastrointestinal polyps and cancer. Inheritance is autosomal dominant with variable penetrance. Only twenty- five patients have been reported from five families. A Mayo Clinic pilot program tested 3009 newly diagnosed cancer patients for pathogenic germline variants in 83 hereditary cancer genes, including AXIN2. We found only one patient with a pathogenic AXIN2 variant. CASE PRESENTATION: The proband was a 49 year-old female who came to Otolaryngology clinic complaining of right-sided nasal obstruction. Biopsy of identified nasal polyp revealed olfactory neuroblastoma (esthesioneuroblastoma). Surgical resection with gross, total tumor resection was followed by radiation therapy. The patient enrolled in a clinical pilot of genetic testing and a pathogenic variant in AXIN2, c.1822del (p.Leu608Phefs*81) (NM_004655.3) was found. She was seen in Medical Genetics clinic and found to have a personal history of hypodontia. Her eyebrows, hair, and nails were all normal. She underwent upper endoscopy and colonoscopy. A four mm gastric adenoma was found and removed. CONCLUSIONS: This is the first case reported on a patient with a pathogenic, germline AXIN2 variant and an olfactory neuroblastoma or a gastric adenoma. We propose that these could be features of the AXIN2 phenotype. The known association between gastric adenomas and familial adenomatous polyposis, the other Wnt/beta-catenin disorder, supports the hypothesis that pathogenic AXIN2 variants increase risk as well. As the odds of a chance co-occurrence of a pathogenic AXIN2 variant and an olfactory neuroblastoma are so rare, it is worth exploring potential causation. We are building a clinical registry to expand understanding of the AXIN2 phenotype and request any clinicians caring for patients with pathogenic AXIN2 variants to contact us.
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Adenoma/genética , Proteína Axina/genética , Estesioneuroblastoma Olfatório/genética , Células Germinativas/metabolismo , Neoplasias Gástricas/genética , Estesioneuroblastoma Olfatório/diagnóstico por imagem , Estesioneuroblastoma Olfatório/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Radiografia Panorâmica , Neoplasias Gástricas/diagnóstico por imagemRESUMO
BACKGROUND & AIMS: There have been few studies of abdominal imaging screening of individuals at high risk for pancreatic cancer (based on family history or genetic variants). We performed a meta-analysis of prospective cohort studies to determine the diagnostic yield and outcomes of abdominal imaging screening for asymptomatic individuals at high risk. METHODS: Through a systematic review of multiple electronic databases and conference proceedings through July 2017, we identified prospective cohort studies (>20 patients) of asymptomatic adults determined to be at high-risk of pancreatic cancer (lifetime risk >5%, including specific genetic-associated conditions) who were screened by endoscopic ultrasound (EUS) and/or magnetic resonance imaging (MRI) to detect pancreatic lesions. Our primary outcome was identification of high-risk pancreatic lesions (high-grade pancreatic intraepithelial neoplasia, high-grade dysplasia, or adenocarcinoma) at initial screening, and overall incidence during follow up. Summary estimates were reported as incidence rates per 100 patient-years. RESULTS: We identified 19 studies comprising 7085 individuals at high risk for pancreatic cancer; of these, 1660 patients were evaluated by EUS and/or MRI. Fifty-nine high-risk lesions were identified (43 adenocarcinomas: 28 during the initial exam and 15 during follow-up surveillance) and 257 patients underwent pancreatic surgery. Based on our meta-analysis, the overall diagnostic yield screening for high-risk pancreatic lesions was 0.74 (95% CI, 0.33-1.14), with moderate heterogeneity among studies. The number needed to screen to identify 1 patient with a high-risk lesion was 135 (95% CI, 88-303). The diagnostic yield was similar for patients with different genetic features that increased risk, and whether patients were screened by EUS or MRI. CONCLUSIONS: Based on meta-analysis, 135 patients at high-risk for pancreatic cancer must be screened to identify 1 patient with a high-risk pancreatic lesion. Further studies are needed to determine whether screening reduces mortality and is cost effectiveness for individuals at high-risk of pancreatic cancer.
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Doenças Assintomáticas , Detecção Precoce de Câncer/métodos , Imagem Óptica/métodos , Neoplasias Pancreáticas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
A 46-year-old female presents with a pelvic mass and is diagnosed as having a high-grade endometrial stromal sarcoma. During surgery, she is noted to have areas of intussusception of the small bowel secondary to large hamartomatous polyps. The patient had a previous history of small bowel obstruction secondary to what had been thought to be hyperplastic polyps but represented hamartomatous polyps on further review. Additional examination revealed the presence of subtle hyperpigmented macules on the fingers leading to a diagnosis of Peutz-Jeghers Syndrome (PJS). The diagnosis was confirmed by the presence of a germ-line STK11 mutation. Immunohistochemistry analysis of the tumor showed decreased expression of STK-11 as compared to one of the patient's hamartomatous polyps. Next generation sequencing of the tumor specimen failed to demonstrate a "second hit" somatic mutation in STK-11. This case represents the first case of endometrial stromal sarcoma associated with PJS and illustrates the importance of increased awareness of this condition among oncologists. PJS is associated with dysregulation of the mTOR pathway; treatment with an mTOR inhibitor was not effective in this case.
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There is increasing recognition that genomic medicine as part of individualized medicine has a defined role in patient care. Rapid advances in technology and decreasing cost combine to bring genomic medicine closer to the clinical practice. There is also growing evidence that genomic-based medicine can advance patient outcomes, tailor therapy and decrease side effects. However the challenges to integrate genomics into the workflow involved in patient care remain vast, stalling assimilation of genomic medicine into mainstream medical practice. In this review we describe the approach taken by one institution to further individualize medicine by offering, executing and interpreting whole exome sequencing on a clinical basis through an enterprise-wide, standalone individualized medicine clinic. We present our experience designing and executing such an individualized medicine clinic, sharing lessons learned and describing early implementation outcomes.
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Instituições de Assistência Ambulatorial/organização & administração , Exoma/genética , Genética Médica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Padrões de Prática Médica/tendências , Medicina de Precisão/métodos , Instituições de Assistência Ambulatorial/tendências , Temas Bioéticos , Biologia Computacional/métodos , Aconselhamento Genético/métodos , Genética Médica/tendências , Humanos , Medicina de Precisão/tendênciasRESUMO
BACKGROUND & AIMS: Cultural, religious, and financial barriers can hinder uptake of colorectal cancer (CRC) screening in Arab communities. We aim to understand attitudes and barriers that contribute to the low rate of CRC screening among Palestinians in the West Bank. METHODS: We performed a national, cross-sectional study of Palestinian adults older than 50 years. A self-administered questionnaire was developed and validated. Data were randomly collected in all major districts of the West Bank. The primary outcome was the willingness to undergo CRC screening. Multivariable logistic regression models were used to assess the strength of association between the primary outcome and its predictors while controlling for possible confounders. RESULTS: Of 1601 people approached for an interview, 1352 agreed to participate (response rate, 84%). Only 193 had undergone CRC screening (14%); 1069 (79%) agreed to take a fecal occult blood test, 906 (67%) agreed to a colonoscopy examination, and 1098 (81%) were willing to undergo CRC screening if recommended by a physician. Only 194 (14%) said they had been informed about CRC screening by a physician. Urban residents were more likely to be screened for CRC than nonurban residents (odds ratio, 0.73; 95% confidence interval, 0.56-0.93; P = .011). Multivariable analysis showed that lack of education beyond elementary school or familiarity with CRC screening, distrust of Western medicine, religious objection, and finding the test to be embarrassing were all associated with decreased odds of accepting CRC screening. CONCLUSIONS: Based on a national, cross-sectional study of Palestinian adults, there are many cultural and religious barriers to CRC screening. Improving our understanding of these could increase screening among Arab populations in the Middle East and in Western countries.
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Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/estatística & dados numéricos , Aceitação pelo Paciente de Cuidados de Saúde , Populações Vulneráveis , Idoso , Idoso de 80 Anos ou mais , Árabes , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Masculino , Área Carente de Assistência Médica , Pessoa de Meia-Idade , Oriente Médio , Inquéritos e QuestionáriosRESUMO
Heterozygous loss-of-function SMAD4 mutations are associated with juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia. Some carriers exhibit symptoms of both conditions, leading to juvenile polyposis-hereditary hemorrhagic telangiectasia syndrome. Three families have been reported with connective tissue abnormalities. To better understand the spectrum and extent of clinical findings in SMAD4 carriers, medical records of 34 patients (20 families) from five clinical practices were reviewed. Twenty-one percent of the patients (7/34) had features suggesting a connective tissue defect: enlarged aortic root (n = 3), aortic and mitral insufficiency (n = 2), aortic dissection (n = 1), retinal detachment (n = 1), brain aneurysms (n = 1), and lax skin and joints (n = 1). Juvenile polyposis-specific findings were almost uniformly present but variable. Ninety-seven percent of the patients had colon polyps that were generally pan-colonic and of variable histology and number. Forty-eight percent of the patients (15/31) had extensive gastric polyposis. Hereditary hemorrhagic telangiectasia features, including epistaxis (19/31, 61%), mucocutaneous telangiectases (15/31, 48%), liver arteriovenous malformation (6/16, 38%), brain arteriovenous malformation (1/26, 4%), pulmonary arteriovenous malformation (9/17, 53%), and intrapulmonary shunting (14/23, 61%), were documented in 76% of the patients. SMAD4 carriers should be managed for juvenile polyposis and hereditary hemorrhagic telangiectasia because symptoms of both conditions are likely yet unpredictable. Connective tissue abnormalities are an emerging component of juvenile polyposis-hereditary hemorrhagic telangiectasia syndrome, and larger studies are needed to understand these manifestations.
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Tecido Conjuntivo/patologia , Polipose Intestinal/congênito , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Proteína Smad4/genética , Telangiectasia Hemorrágica Hereditária/genética , Telangiectasia Hemorrágica Hereditária/patologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Humanos , Lactente , Polipose Intestinal/genética , Polipose Intestinal/patologia , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , Transdução de Sinais , Fator de Crescimento Transformador beta/genética , Adulto JovemRESUMO
PURPOSE: The Muir-Torre syndrome variant of Lynch syndrome is characterized by the presence of sebaceous neoplasms (adenoma, epithelioma/sebaceoma, carcinoma) and Lynch syndrome-associated cancers (colon, endometrial, and others). Several clinical scoring systems have been developed to identify patients with colon cancer at high risk of Lynch syndrome. However, no such system has been described for patients presenting with sebaceous neoplasms. METHODS: Based on logistic regression analysis, a scoring system was developed for patients with sebaceous neoplasm to identify those with the highest likelihood of having Muir-Torre syndrome. The final version of the scoring system included variables such as age at presentation of initial sebaceous neoplasm, total number of sebaceous neoplasms, personal history of a Lynch-related cancer, and family history of Lynch-related cancers. RESULTS: Patients with a score of 3 or more were more likely to have Muir-Torre syndrome (28 of 29 patients), those with a score of 2 had intermediate likelihood (12 of 20 patients), and no patient with a score of 0 or 1 was diagnosed with Muir-Torre syndrome. CONCLUSION: The Mayo Muir-Torre syndrome risk scoring system appears to identify whether patients who present with sebaceous neoplasms are in need of further Lynch syndrome evaluation using easily ascertained clinical information. Abnormal mismatch repair gene immunohistochemistry of a sebaceous neoplasm is a poor predictor in regard to diagnosing Lynch syndrome.
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Síndrome de Muir-Torre/epidemiologia , Síndrome de Muir-Torre/etiologia , Risco , Neoplasias das Glândulas Sebáceas/complicações , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Feminino , Estudos de Associação Genética , Loci Gênicos , Mutação em Linhagem Germinativa , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/genética , Mutação , Fatores de Risco , Neoplasias das Glândulas Sebáceas/diagnósticoRESUMO
BACKGROUND: Patients with familial adenomatous polyposis (FAP) are known to have an increased risk for gastric adenomas. The clinical features of gastric adenomas in FAP have not been well characterized, and there is a lack of standardized approaches to the management of these lesions. AIMS: To study the endoscopic appearance, risk factors, clinical course, and response to therapy of gastric adenomas in patients with FAP. METHODS: We retrospectively reviewed the records of 97 patients with FAP who underwent esophagogastroduodenoscopy (EGD) at Mayo Clinic (Florida, Rochester and Arizona) between 2004 and 2013. RESULTS: Nine patients (9%) had biopsy-proven gastric adenomas. Adenomas were located in the antrum (five patients), in the body and fundus in the setting of background fundic gland polyps (FGP) (three patients), and in the body not associated with FGP (one patient). Adenoma size was 3-40 mm and the number of adenomas per patient ranged from one to 20. Adenomas in the antrum were flat and subtle, whereas those in the gastric body or fundus were polypoid and difficult to differentiate from the cystic FGPs seen in patients with FAP. The performing endoscopists reported difficulty with identifying adenomas, and six patients had at least one EGD within the previous three years where gastric adenomas were not reported. Adenomas were classified as tubular in eight patients and tubulovillous in one patient. High grade dysplasia was noted in one patient. After a median follow-up of 63 months (interquartile range: 20-149 months), no patient in our entire cohort (with or without gastric adenomas) developed gastric cancer. The patients in whom gastric adenoma developed, compared to those without gastric adenoma, were more likely to be younger [36 ± 12 vs. 48 ± 15 years, p = 0.02], have concomitant chronic gastritis [22% vs. 0%, p = 0.008], and have desmoid tumors [5 (56%) vs. 19 (22%), p = 0.04]. CONCLUSIONS: Gastric adenomas are not uncommon in patients with FAP and are often difficult to identify endoscopically. Endoscopists should have a high degree of suspicion for gastric adenomas in these patients and a low threshold to biopsy. Given the benign clinical course, recommended initial management is conservative with endoscopic therapy and periodic surveillance.
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Fístula Biliar/complicações , Hemorragia Gastrointestinal/etiologia , Hemobilia/etiologia , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Falso Aneurisma/complicações , Falso Aneurisma/diagnóstico , Angiografia/métodos , Fístula Biliar/diagnóstico , Embolização Terapêutica/métodos , Endoscopia/métodos , Feminino , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/terapia , Hemobilia/diagnóstico , Artéria Hepática/patologia , Humanos , Complicações Pós-Operatórias , UltrassonografiaRESUMO
PURPOSE: Guidelines recommend germline genetic testing (GT) for patients with pancreatic ductal adenocarcinoma (PDAC). This study aims to evaluate the utilization and outcomes of multigene panel GT in patients with PDAC. METHODS: This retrospective, multisite study included patients with PDAC diagnosed between May 2018 and August 2020 at Mayo Clinic Arizona, Florida, and Minnesota. Discussion, uptake, and outcomes of GT were compared before (May 1, 2018-May 1, 2019) and after (August 1, 2019-August 1, 2020) the guideline update, accounting for a transition period. RESULTS: The study identified 533 patients with PDAC, with 321 (60.2%) preguideline and 212 (39.8%) postguideline. Patient characteristics did not differ between the preguideline and postguideline periods. GT was discussed in 34.3% (110 of 321) of preguideline and 39.6% (84 of 212) of postguideline patients (odds ratio [OR], 1.26 [95% CI, 0.88 to 1.80]) and subsequently performed in 80.9% (89 of 110) of preguideline and 75.0% (63 of 84) of postguideline patients (OR, 1.10 [95% CI, 0.75 to 1.61]). Of 152 tested patients, 26 (17.1%) had a pathogenic variant (PV), of whom 17 (11.2%; 17 of 152) were PDAC-associated. Over the entire study period, GT was more likely in younger patients (65 v 70 years; P < .001), those seen by a medical oncologist (82.9% v 69.0%; P < .001), and those surviving more than 12 months from diagnosis (70.4% v 43.4%; P < .001). Demographics and personal/family cancer history were comparable between patients with and without a PDAC PV. CONCLUSION: GT remains underutilized despite National Comprehensive Cancer Network guideline recommendations. Given the poor prognosis of PDAC and potential implications of GT, efforts to increase utilization are needed to provide surveillance and support to both patients with PDAC and at-risk family members.
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Carcinoma Ductal Pancreático , Testes Genéticos , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/genética , Feminino , Masculino , Testes Genéticos/métodos , Testes Genéticos/normas , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genética , Estudos Retrospectivos , Idoso , Idoso de 80 Anos ou mais , AdultoRESUMO
Screening for the Muir-Torre variant of Lynch Syndrome (LS) using Mismatch Repair (MMR) gene immunohistochemistry (IHC) on sebaceous neoplasms (SNs) is technically feasible. To date, research into the clinical utility of MMR IHC for this indication is limited. We conducted a retrospective chart review of 90 patients with MMR IHC completed on at least one SN from January 2005 to May 2010. SNs included were adenomas, epitheliomas, carcinomas and basal and squamous cell carcinomas with sebaceous differentiation. Of the 90 patients, 13 (14 %) had genetically confirmed or fulfilled clinical criteria for a diagnosis of MTS and 51 patients (57 %) presented with an abnormal MMR IHC result (loss of one or more MMR proteins) on at least one SN. Abnormal IHC had a sensitivity of 85 %, specificity of 48 %, positive predictive value (PPV) of 22 % and negative predictive value (NPV) of 95 % when evaluating for MTS. When personal or family history of colorectal cancer (≥2 family members with a history of colorectal cancer) was taken into consideration, ignoring IHC results, sensitivity was 92 %, specificity was 99 %, PPV was 92 % and NPV was 99 %. MMR IHC on SNs when used to screen for MTS has poor diagnostic utility. We recommend that MMR IHC not be performed routinely on SNs when the patient does not have either personal or family history of colorectal cancer.
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Pareamento Incorreto de Bases , Síndrome de Muir-Torre/diagnóstico , Neoplasias das Glândulas Sebáceas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Síndrome de Muir-Torre/genética , Linhagem , Estudos Retrospectivos , Neoplasias das Glândulas Sebáceas/genéticaRESUMO
Prognosis is generally poor for patients with pancreatic ductal adenocarcinoma. However, patients with germline BRCA1 or BRCA2 mutations (gBRCAm) may benefit from first-line platinum-based chemotherapy and maintenance therapy with the poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib following at least 16 weeks of first-line platinum-based chemotherapy without disease progression. Germline breast cancer gene (BRCA) testing is therefore important to ensure that patients receive the most effective treatment. In addition, testing for other DNA damage response gene mutations beyond gBRCAm may also guide treatment decisions. However, clinical pathways for genetic testing are often suboptimal, leading to delays in treatment initiation or missed opportunities for personalized therapy. Barriers to testing include low rates of referral and uptake, delays to referral and slow result turnaround times, cost, and biopsy and assay limitations if somatic testing is performed, leading to the requirement for subsequent dedicated germline testing. Low rates of referral may result from lack of awareness among physicians of the clinical value of testing, coupled with low confidence in interpreting test results and poor availability of genetic counseling services. Among patients, barriers to uptake may include similar lack of awareness of the clinical value of testing, anxiety regarding the implications of test results, lack of insurance coverage, fear of negative insurance implications, and socioeconomic factors. Potential solutions include innovative approaches to testing pathways, including 'mainstreaming' of testing in which BRCA tests are routinely arranged by the treating oncologist, with the involvement of genetic counselors if a patient is found to have a gBRCAm. More recently, the utility of multigene panel analyses has also been explored. Access to genetic counseling may also be improved through initiatives such as having a genetic counseling appointment for all new patient visits and telemedicine approaches, including the use of telephone consultations or DVD-assisted counseling. Educational programs will also be beneficial, and cost effectiveness is likely to improve as the number of targeted treatments increases and when the earlier detection of tumors in family members following cascade testing is considered.
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BACKGROUND: Ampullary and extensive periampullary lesions can be difficult to treat and often require pancreaticoduodenectomy (PD) for complete removal, even if benign. However, PD may be overtreatment for noninvasive lesions, and pancreas-sparing total duodenectomy (PSTD) is an emerging valid surgical option for selected cases. METHODS: We reviewed patients undergoing PSTD at our institution over 16 months and a comparison group who had undergone PD for benign duodenal disease over the past 15 years. We also reviewed cases in the English-language literature and performed a meta-analysis of those patients who had undergone PSTD. RESULTS: PSTD had been performed in four patients, who had an average hospital length of stay (LOS) of 13 days; two of them experienced complications. None required conversion to PD, experienced a postoperative fistula or endocrine or exocrine insufficiency, or required intensive care. Two of the PSTDs were performed laparoscopically. Open PD for benign duodenal disease was performed in 22 patients, with overall morbidity and pancreas fistula rates of 82 and 27 %, respectively. The meta-analysis found 128 unique cases of PSTD with morbidity and mortality rates of 46.4 and 2.3 %, respectively. Pancreaticobiliary leak was seen in 20 %, with an average LOS of 17 days. CONCLUSIONS: Although PSTD can be used to avoid PD and can be performed laparoscopically, it is technically challenging and still associated with morbidity.
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Adenoma/cirurgia , Ampola Hepatopancreática , Neoplasias Duodenais/cirurgia , Polipose Intestinal/cirurgia , Idoso , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas , Estudos RetrospectivosRESUMO
CONTEXT: The surgical management of pancreatic endocrine tumors in patients with multiple endocrine neoplasia type 1 (MEN-1) is controversial and complicated by the fact that these tumors are frequently multifocal. The degree of tumor resection is determined by weighing the risk of malignancy or tumor recurrence against the risks of endocrine/exocrine insufficiency with complete gland removal. METHODS: A retrospective review was performed identifying 4 patients with MEN-1 and pancreatic endocrine tumors treated with pancreatic resection over a 2-year period at our institution. RESULTS: Mean age at operation was 35 years. Surgical approach was determined by size of tumor(s) and presence of multifocality. MRI and EUS were performed in all patients. While EUS identified a greater number of tumors when compared to MRI (median 5 versus 1), both studies grossly underestimated the total number of tumors found on final pathology. Three patients underwent laparoscopic total pancreatectomy for multifocal disease with diffuse pancreatic involvement, finding a median of 12 tumors. One patient underwent laparoscopic subtotal pancreatectomy for a presumed single pancreatic tail mass, but was found to have multifocal disease on final pathology consisting of 7 tumors. The average number of tumors found on final pathology was 13.5 with an average size of 2.6 cm. The median number of lymph nodes analyzed was 14. Diffuse, multifocal disease was present in all 4 patients. No major postoperative complications were observed. CONCLUSION: In patients with MEN-1 and pancreatic endocrine tumors, preoperative workup underestimates extent of disease and total pancreatectomy should be considered for complete tumor removal.
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Neoplasia Endócrina Múltipla Tipo 1/cirurgia , Pancreatectomia/métodos , Neoplasias Pancreáticas/cirurgia , Adulto , Endossonografia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Neoplasia Endócrina Múltipla Tipo 1/patologia , Estudos RetrospectivosRESUMO
OBJECTIVES: The Lynch syndrome (LS) is an inherited cancer syndrome showing a preponderance of colorectal cancer (CRC) in context with endometrial cancer and several other extracolonic cancers, which is due to pathogenic mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2. Some families were found to show a LS phenotype without an identified MMR mutation, although there was microsatellite instability and absence of MSH2 expression by immunohistochemistry. Studies of a subset of these families found a deletion at the 3' end of the epithelial cell adhesion molecule (EPCAM) gene, causing transcription read-through resulting in silencing of MSH2 through hypermethylation of its promoter. The tumor spectrum of such families appears to differ from classical LS. METHODS: Our study of two large families (USA Family R and Dutch Family A) with an EPCAM deletion was carried out using each institution's standard family study protocol. DNA was extracted from peripheral blood and EPCAM deletion analysis was performed. RESULTS: Both families were found to harbor the same deletion at the 3' end of EPCAM. Analysis showed that the deletion originated from a common ancestor. Family R and Family A members showed segregation of CRC with the presence of this EPCAM mutation. Compared with classic LS, there were almost no extracolonic cancers. CONCLUSIONS: Members of Family R and Family A, all with the same EPCAM deletion, predominantly presented with CRC but no LS-associated endometrial cancer, confirming findings seen in other, smaller, LS families with EPCAM mutations. In these EPCAM mutation carriers, cancer surveillance should be focused on CRC.
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Antígenos de Neoplasias/genética , Moléculas de Adesão Celular/genética , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais Hereditárias sem Polipose/genética , Deleção de Genes , Inativação Gênica , Proteína 2 Homóloga a MutS/genética , Adulto , Idoso , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/etnologia , Metilação de DNA , Molécula de Adesão da Célula Epitelial , Feminino , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Países Baixos , Linhagem , Regiões Promotoras Genéticas , Estados UnidosRESUMO
We are reporting what we believe to be the first published case of patient initiated direct to consumer (DTC) genetic testing to test for the presence of a known familial mutation. Our client in this case is from a known MSH2 family; both his/her parent and associated grandparent have previously tested positive for the known familial MSH2 mutation. Using 23andme's "family inheritance genome-wide comparison" option we were able to determine that our client most likely inherited the known familial MSH2 mutation without pursuing single site genetic testing. Our client pursued DTC genetic testing instead of single site genetic testing due to the fear of genetic discrimination. This case shows that patients are still fearful of genetic discrimination, despite the passage of the Genetic Information Nondiscrimination Act (GINA), and that DTC genetic testing may be useful despite the overall negative feeling towards this type of testing in the genetic counseling community.