The impact of the genetic background in a patient with papillary thyroid cancer and familial adenomatous polyposis

SUMMARY Thyroid cancer is the most common endocrine malignancy, and papillary thyroid carcinoma (PTC) is the main subtype. The cribriform morular variant is a histological phenotype of PTC characterized by its relationship with familial adenomatous polyposis (FAP). Description of the case: We report the genetic assessment of a 20-year-old female patient diagnosed with a cribriform-morular variant of PTC and FAP. We aimed to assess the genetic background of the reported patient, looking for variants that would help us explain the predisposition to tumorigenesis. Genomic DNA was extracted from peripheral blood lymphocytes, and whole exome sequencing was performed. We applied an overrepresentation and gene-set enrichment analysis to look for an accumulation of effects of variants in multiple genes at the genome. We found an overrepresentation of single nucleotide variants (SNVs) in extracellular matrix interactions and cell adhesion genes. Underrepresentation of SNVs in genes related to the regulation of autophagy and cell cycle control was also observed. We hypothesize that the package of alterations of our patient may help to explain why she presented colonic manifestations and thyroid cancer. Our findings suggest that multiple variants with minor impact, when considered together, may be helpful to characterize one particular clinical condition.

The fluctuation of APC gene in WNT signaling with adenine deletion of adenomatous polyposis coli, is associated in colorectal cancer / A flutuação do gene da APC na via de sinalização WNT com deleção de adenina na polipose adenomatosa do cólon está associada ao câncer colorretal

ABSTRACT Colorectal cancer is one of the most important malignancies in the classification of gastrointestinal cancers. One of the predisposing factors at molecular level for this cancer is via WNT signaling which is associated with the vast numbers of different genes. Thus, in this study, we aimed to investigate whether Adenomatous Polyposis Coli gene (APC) mutation of rs41115in two locations such as 132.002 and 131.989 acts as a trigger or cause of colorectal cancer. Relatively, 30 blood samples of colorectal cancer patients and 30 normal blood samples as control group after colonoscopy and also confirmation of pathology report at Rohani Hospital in Babol (Iran) were investigated. The primers were designed in order to be included the rs41115 to identify the particular polymorphisms of gene. The polymerase chain reaction (PCR direct sequencing method) was used. Conclusively, deletion of adenine in two specific locations such as 131.989 and 132.002 has been identified, but there was no relationship between rs41115 polymorphisms located in adenomatous polyposis coli gene and colorectal cancer.

RESUMO O câncer colorretal é uma das neoplasias malignas mais importantes na classificação dos cânceres gastrointestinais. Um dos fatores predisponentes no âmbito molecular para esse câncer é através da via de sinalização WNT, que está associada a um grande número de genes diferentes. Portanto, neste estudo, objetivamos investigar se a mutação rs41115 do gene da polipose adenomatosa do cólon (Adenomatous Polyposis Coli - APC) em dois locais como 132.002 e 131.989 atua como gatilho ou como causa do câncer colorretal. Relativamente, 30 amostras de sangue de pacientes com câncer colorretal e 30 amostras de sangue normal (grupo controle) foram analisadas após a colonoscopia, bem como a confirmação do laudo da patologia no Rohani Hospital em Babol (Irã). Os primers foram projetados de modo a incluir o rs41115 para identificar os polimorfismos particulares do gene. A reação em cadeia da polimerase (método de sequenciamento direto por PCR) foi utilizada. Conclusivamente, a deleção de adenina em dois locais específicos, como 131.989 e 132.002, foi identificada, mas não houve relação entre o polimorfismo rs41115 localizado no gene da polipose adenomatosa do cólon e o câncer colorretal.

Diagnóstico de Cáncer Colorrectal en paciente con sospecha de Poliposis Adenomatosa Familiar / Diagnosis of colonrectal cancer in patient with suspicion of Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is a rare, hereditary disease whose main characteristic is the presence of a large number of polyps in the colon and rectum, which, in the absence of timely treatment, 100% progresses to colorectal cancer. The early diagnosis of this condition is the pillar of the prevention of complications. We present the case of a patient with a low digestive tract syndrome, without previous diagnosis, who after a careful review of clinical and family history, the diagnosis of PAF and later colorectal cancer, is reached. A review of the literature on current advances and recommendations on this disease is made.

Genetic profile, risk factors and therapeutic approach of desmoid tumors in familial adenomatous polyposis / Perfil genético, fatores de risco e abordagem terapêutica dos tumores desmóides na Polipose Adenomatosa Familiar

ABSTRACT Introduction: Desmoid tumors are the main extraintestinal manifestation of FAP, presenting high morbidity and mortality. It is a neoplasia without metastasis capacity, but with infiltrative growth and with a high rate of recurrence. In familial forms, these tumors are associated with a germinal mutation in the APC gene, with a genotype-phenotype correlation influenced by other risk factors. Materials and methods: A review of articles published since the year 2000 in Portuguese, English or Spanish on desmoid tumors in patients with FAP was carried out. A total of 49 publications were included. Results: The site of the mutation in the APC gene is related to the severity of FAP and to the frequency of desmoid tumor. Mutations located distally to codon 1309 are associated with a more attenuated polyposis, but with higher frequency of desmoid tumors. Clinically, these tumors may or may not be symptomatic, depending on their size and location. In their treatment, priority should be given to medical therapy, especially in intra-abdominal tumors, with surgery being the last option if there are no other complications. Discussion: These tumors are associated with certain risk factors: genetic (mutation site), hormonal (estrogenic environment) and physical (surgical trauma) ones. In young women, a later prophylactic colectomy is suggested. Moreover, the laparoscopic approach to prophylactic surgery seems to be an option that reduces surgical trauma and consequently the appearance of desmoid tumors. Conclusion: The step-up medical approach has been shown to be valid in the treatment of intra-abdominal desmoid tumors, and medical treatment should be the first therapeutic option.

RESUMO Introdução: Os tumores desmóides são a principal manifestação extraintestinal da PAF, apresentando elevada morbimortalidade. É uma neoplasia sem capacidade de metastização, mas com crescimento infiltrativo e com alta taxa de recorrência. Nas formas familiares associa-se a uma mutação germinativa no gene APC, havendo uma correlação genótipo-fenótipo influenciada por outros fatores de risco. Materiais e métodos: Foi efetuada uma revisão de artigos publicados desde o ano 2000, em português, inglês ou espanhol, acerca de tumores desmóides em doentes com PAF. Foram incluídas, no total, 49 publicações. Resultados: O local da mutação no gene APC relaciona-se com a gravidade da PAF e frequência de tumor desmóide. Mutações localizadas distalmente ao codão 1309 associam-se a uma polipose mais atenuada, mas a maior frequência de tumor desmóide. Clinicamente podem ser, ou não, sintomáticos, dependendo do seu tamanho e localização. No seu tratamento deve ser dada prioridade à terapêutica médica, sobretudo nos tumores intra-abdominais, colocando a cirurgia como última opção, caso não hajam outras complicações. Discussão: Estes tumores associam-se a determinados fatores de risco: genéticos (local da mutação), hormonais (ambiente estrogénico) e físicos (trauma cirúrgico). Nas mulheres jovens sugere-se a realização de colectomia profilática mais tardiamente. Além disso, a abordagem laparoscópica para a cirurgia profilática parece ser uma opção que diminui o trauma cirúrgico e consequentemente o aparecimento de tumores desmóides. Conclusão: A abordagem médica em step-up mostrou ser válida no tratamento de tumores desmóides intra-abdominais, devendo o tratamento médico ser a primeira opção terapêutica.

Se justifica el seguimiento después de una colectomía en pacientes con poliposis adenomatosa familiar / The follow up after colectomy in patients with familial adenomatous polyposis is justified

phenotypic expression is the presence of múltiple colorectal adenomatous polyps (more than 100), with high probability developing colorrectal cancer (CRC) before the fifth decade of life. Prophylactic surgery (total colectomy or restorative proctocolectomy) reduces the risk of developing CRC. However, the risk of developing tumors in other organs remains present. Objetive: Analyze the frequency and type of tumors associated with classic familial adenomatous polyposis syndrome (FAPc) patients undergoing prophylactic colectomy. Material and Methods: Cohort study. From the registry of hereditary colorrectal cancer (CRC) at our institution, we identified patients with FAPc who underwent total colectomy with ileorrectal anastomosis (TC-IRA) or restorative proctocolectomy (RTPC), from 1999 to 2014. In the follow-up we analyzed related tumors and mortality. Results: 27 patients, of whom 18 (66.7%) underwent TC-IRA and 9 (33.3%) underwent RTPC. At the time of surgery, 4 patients had CRC (15%) and 5 had extracolonic tumors (osteomas). In a mean follow-up of 49, 4 months (i: 2 y 178) the following lesions were diagnosed: digestive tract adenomas in 17 (63%) patients, of these 2 required a proctectomy and 3 resection of duodenal adenomas. Eight patients developed desmoid tumors (30%), and 3 of them underwent surgery. One patient had an extradigestive tumor (thyroid cancer) and only 8/27 (29.6%) did not develop other tumors. One patient died due to progression of his CCR. Discussion: In this series it is confirmed that most patients will develop neoplasms FAPc after colectomy. conclusion: The removal of the colon and/or rectum is able to prevent the development of CRC. However, two thirds of the patients develop other tumors in which systematic surveillance allowed early detection and treatment.

Objetivo: Analizar la frecuencia y tipo de tumores asociados en pacientes con poliposis adenomatosa familiar clásica (PAFc) sometidos a una colectomía profiláctica. Materiales y Métodos: Estudio de cohorte. Desde el registro de cáncer colorrectal (CCR) hereditario, se identificaron las familias con PAFc, y de estas a los pacientes que se les practicó una colectomía total con anastomosis íleorrectal (CT-AIR) o proctocolec-tomía restauradora (PCTR), desde 1999 al 2014. En el seguimiento se analizaron los tumores asociados y su mortalidad. Resultados: Se identificaron 27 pacientes, de los cuales 18 (66,7%) fueron sometidos a CT-AIR y 9 (33,3%) a PCTR. Al momento de la cirugía, 4 pacientes presentaban CCR (15%) y 5 tenían tumores extracolónicos (osteomas). En un seguimiento promedio de 49,4 meses (i: 2 y 178) se diagnosticaron: adenomas del tracto digestivo en 17 (63%) pacientes, de éstos 2 requirieron una proctectomía y 3 resecciones de adenomas duodenales. Ocho pacientes desarrollaron tumores desmoides (30%), y 3 de ellos fueron sometidos a una cirugía. Un paciente presentó un tumor extradigestivo (cáncer de tiroides) y sólo 8/27 (29,6%) pacientes no desarrollaron otros tumores. Un paciente falleció por progresión de su CCR. Discusión: En esta serie se confirma que la mayoría de los pacientes con PAFc seguirán desarrollando neoplasias después de su colectomía. conclusiones: La extirpación del colon y/o recto permitió evitar el desarrollo de CCR. Sin embargo, dos tercios de los pacientes presentaron otros tumores en quienes su seguimiento permitió una detección y tratamiento temprano.

Cáncer gástrico temprano o precoz: revisión de la literatura / Early gastric cancer: review of the literature

El cáncer gástrico precoz, se diagnostica cada día con más frecuencia no solo en Japón sino en todo el mundo y, aunque su tratamiento endoscópico es relativamente sencillo, en nuestro medio hay poca experiencia sobre la resección de lesiones sospechosas. El pronóstico de cáncer gástrico temprano es muy bueno y la tasa de supervivencia a los 5 años es del 90%. Por ello, basado en el criterio del tratamiento temprano de cáncer gástrico tiene mejor pronóstico, es importante la detección temprana masiva esta enfermedad antes de que evolucione a un estado avanzado.

Polipose juvenil: relato de 2 casos / Juvenile polyposis: case two report

A Polipose Juvenil é uma afecção rara e faz parte do grupo das poliposes hamartomatosas familiares (PHF). É uma síndrome autossômica dominante que pode ser desencadeada por mutações no gene SMAD4/DPC4 (que codifica um sinalizador intermediário de TGF-b). Caracteriza-se pelo aparecimento de 10 ou mais pólipos hamartomatosos (juvenis) no trato gastrintestinal, predominando no cólon. Costuma manifestar-se entre 4 e 14 anos de idade. Alguns pólipos adquirem focos adenomatosos apesar da natureza hamartomatosa das lesões e há chance de malignização. Relato de 2 casos de pacientes portadores de Polipose Juvenil colônica associada a focos de adenoma com displasia e revisão da literatura.

Juvenile Polyposis Syndrome is a rare disease and is included in the Hamartomatous Familial Polyposis's (HFP) group. It's an autosomal dominant syndrome which can be determinated by SMAD4/DPC4 germline mutations (which codifies an intermediary mediator of TGF-b). It's characterized by 10 or more hamartomatous polyps (juveniles) throughout the gastrointestinal tract, especially in the colon. The symptoms usually appears between the ages of 4 and 14 years old. Some polyps can acquire adenomatous changes despite the lesion's hamartomatous nature and there's chance of colorectum malignization. Case report of two patients with Juvenile Polyposis coli associated to adenomatous changes with dysplasia and literature review.

Pólipos del colon y recto / Polyps of colon and rectum

Polyp is a descriptive term used with reference to any mass of tisue that projects outward from the normal surface of th gastrointestinal tract. Morson and col. classified this disorder in 1962 in two categories: non-neoplasic (hamartomas) and neoplasic (tubular, villous and mixed). At preent, they are classified between polypoid formations termed serrated polyps, out of whom some can be assigned as potentially malignant. The author of this report describe successively the foloowing conditions: mlignant colorectal polyps, are those presenting an invasive carcinoma, that is with penetration through the muscularis mucosae, involving the regional lymph nodes. Other types: intestinal polyposis, familial adenomatous polyposis Turcot syndrome (malingnant tumors of the central nervous system associated with familial polyposis of the colon) juvenile polyposis; Cowden disease: described since the disease suffered by the patient Rachel Cowden (also termed as multiple hamartomas syndrome) hereditary and preneoplasic with autosomic and dominant transmission, Peutz-Jeghers syndrome: hereditary disease with autonomic and dominant transmission, characterized by a harmatous gastrointestinal polyposis with melanin pigmentation of the skin, and melanin spots of the bucal mucous membrane. Bleeding and anemia are frequent complications. Syndrome of De Ruvalcalva-Myre-Smith: associates hamartosus polyposis juvenile and other disorders as macrocephalia, psychomotor madurative delay and pigmentary changes of the genitalia, and Cronkhite-Canada syndrome, a generalized gastrointestinal polyposis, even those considered benign, can suffer by different causes, a malignant transformation. The author also refers the surgical manament, adenomas and malignant transformation and the development of carcinogenesis. The genetic of adenomas and colerectal cancer, are also considered.

Poliposis familiar hereditaria: a propósito de un caso / Polyposis family hereditary: a purpose of a case

La Poloposis Familiar Hereditaria es un desorden autosómico dominante, caracterizado por la presencia de cientos a miles de pólipos adenomatosos a todo lo largo de la mucosa colónica. La principal causa de muerte es el cáncer colorrectal el cual se presenta en todos los pacientes que no reciben tratamiento preventivo. Presentamos un caso de una paciente femenina de 32 años de edad la cual consultó por presentar rectorragia de 6 meses de evolución. Al examen físico se evidenció un tumor circunferencial a los 3 cm del margen anal, con obstrucción del 80 por ciento de la luz. La colonoscopia reveló la presencia múltiples pólipos de diferentes tamaños desde el margen anal hasta cecoascendente. Se le realizó una colectomía total evolucionando satisfactoriamente. La biopsia reportó un adenocarcinoma bien diferenciado de recto, con infiltración de la serosa y ganglios positivos, y miles de pólipos adenomatosos vellosos, tubulares y túbulovellosos.

Poliposis familiar: Alternativas terapéuticas y estudio de los familiares / Treatment of familial adenomatous polyposis and family screening

Background: To reduce the mortality associated to Familial Adenomatous Polyposis (FAP), screening of close relatives of patients with the disease is crucial. Aim: To analyze the results of the surgical treatment of patients with FAP, and to evaluate the family screening. Patients and Methods: Clinical records of patients operated in our institution since 1977, were reviewed analyzing surgical and pathological results, and follow up. In their family members, we evaluated and analyzed the performance of screening tests, former surgeries, history of disease-related cancer and mortality, all due to FAP. Results: Between January 1977 and August 2002, 15 patients were operated on. Of these, only 33 percent consulted on the setting of a familial screening. A proctocolectomy and terminal ileostomy was performed in 27 percent of patients; 20 percent had a proctocolectomy and ileal pouch, and 53 percent underwent a total colectomy with ileo-rectal anastomosis. Morbidity and mortality were 7 percent and 0 percent, respectively. Twenty percent had a colorectal cancer. During a median of 68 months follow-up, the disease-related survival was 92 percent; no cancer of the rectal stump was detected. Of the 122 family members identified, only 33 percent with clear indication of screening underwent a colonoscopy. Twenty-nine percent had a confirmed FAP and were operated: in 61 percent of them a colorectal cancer was found, and 91 percent of these died. Conclusions: The results of the surgical treatment of FAP are satisfactory. Nevertheless, family screening should be improved to reduce the high rates of mortality revealed in the study of other family members (Rev Méd Chile 2005; 133: 1043-50).

Juvenile polyposis with macrocephaly and mental retardation (? Ruvalcava-Myhre-Smith syndrome)--a case report.

A male child aged one and a half years with a history of rectal bleeding, on examination was found to have severe degree of anaemia with grade -III protein-energy-malnutrition and pneumonia. Colonoscopy revealed features of colonic polyposis. An upper gastro-intestinal endoscopy showed a duodenal polyp while barium meal follow-through did not reveal any polyps in the small intestine. Total colectomy and ileo-rectal anastomosis was done. Following histopathological study, the diagnosis of Juvenile polyposis syndrome was made, a very rare entity and is known to lead to adenocarcinoma of the gastrointestinal tract. In addition the child was found to have macrocephaly and mental retardation. The rarity and importance of the diagnosis of juvenile polyposis syndrome associated with macrocephaly and mental retardation (?Ruvalcava-Myhre-Smith syndrome) prompted the documentation of this case.

Cáncer colorectal heredofamiliar no polipoideo / Hereditary familial non polypoid colorectal cancer

El CCRHNP es la forma más común de cáncer hereditario y representa aproximadamente el 15 % de todos los cánceres colorectales. En este artículo se destaca, a partir de un caso probable de presentación atípica, la importancia de los antecedentes familiares, la histología típica del tumor, la reacción inflamatoria peritumoral simil enfermedad de Crohn, la investigación de la inestabilidad microsatelital, el defecto genético de los genes MMR y la recomendación de um screening apropiado para el estudio de estos pacientes. Finalmente se destaca la posibilidad de lograr mayor difusión a nivel nacional sobre los centros donde se pueda realizar los estudios genéticos que permitan detectar portadores de esta enfermedad: asimismo al formación de grupos de estudio nos van a permitir obtener estadísticas propias, proyectar trabajos conjuntos y elaborar campañas de prevención.

Colonoscopia com magnificaçäo de imagem no diagnóstico de carcinoma colorretal invasivo da submucosa na polipose adenomatosa familiar / Magnifying colonoscopy diagnosis of submucosal invasive colorectal carcinoma in familial adenomatous polyposis

The development of colonoscopy with image magnification has enable to study the colonic mucosa in detail and to do differential diagnosis between neoplastic and non-neoplastic lesions from the observation of pit patterns. The results are comparable to stereomicroscopy being possible to predict the histologic diagnosis. In a patient with familial adenomatous polyposis magnifying colonoscopy was performed and this method demonstrated a wide variation of benign polypoid lesions and the morphological features of early colorectal cancer. In this patient, the evaluation by image magnification, together with indigo carmin 0.4 per cent chromoscopy, showed a wide variety of lesions in the colon and rectum: laterally spreading tumor in the cecum, with IIIL + IV pits, subpediculate polyp in the transverse colon with approximately 2.0 cm diameter and IV + V pits, flat elevated lesions IIIL type, and in the sigmoid colon IIa + Iic lesion with V type of Kudo's classification were observed. The evaluation of pit patterns of the lesions in the transverse and sigmoid colon has enable to do the endoscopic diagnosis of the lesion with submucosal invasion

Turcot's syndrome in an Arab child.

A 12 year old female child of Arab origin presented with chronic bloody diarrhoea and growth failure. Physical examination confirmed a growth failure and cafe-au-lait patches. Colonoscopy and colon biopsies showed adenocarcinoma of the colon and laparotomy confirmed metastases to the liver. A diagnosis of Turcot's Syndrome was entertained in this child.

Cuerpos de Leuchtenberger (cuerpos apoptóticos) en adenomas de intestino grueso / Leuchtenberger bodies (apoptotic bodies) in adenomas of the large bowel

En 1954 Leuchtenberger describió unos cuerpos de inclusión de 1 a 2 micras de diámetro, que se tiñen con la técnica de Feulgen, en el citoplasma de las células epiteliales de pólipos rectales. Rubio y col mencionaron que el hallazgo de numerosos cuerpos de Leuchtenberger (CL) en adenomas colo-rectales debe hacer sospechar una poliposis múltiple familiar(PMF). El objetivo de este trabajo fue conocer la frecuencia de los CL en los adenomas tubulares de la PMF y compararla con la frecuencia observada en adenomas no familiares y otras lesiones hiperplásicas e inflamatorias del tubo digestivo. Los CL fueron más frecuentes en al PMF (88 por ciento) y los adenomas papilares 75 por ciento) que en los pólipos tubulares no familiares (38 por ciento), los pólipos hiperplásicos del estómago (45 por ciento), los pólipos inflamatorios de colon (45 por ciento) y la colitis ulcerosa inespecífica (12 por ciento). Aunque el hallazgo de numeros CL es más común en la PMF que en pólipos tubulares no familiares (p<0.0001), la ausencia de estas partículas en un adenoma no descarta la posibilidad de una PMF. Por sus caracteres histológicos, histoquímicos y ultraestructurales sugiere que los CL corresponden a cuerpos apoptóticos que se forman probablemente por necrosis de las células epiteliales

Familial polyposis coli with villous adenoma of ampulla of Vater.

Adenoma of the ampulla of Vater is one of the extracolonic manifestations of familial polyposis coli (FPC). We report three patients with FPC in whom villous adenoma of the ampulla was detected. An adenoma carcinoma sequence has been suggested in such lesions.

Polipose familiar colônica juvenil / Juvenile colonic familial polyposis

A investigaçäo de sangramento anal em crianças deve incluir um exame retal, por ser este sinal comum na presença de pólipos retais. A maioria säo pólipos únicos que freqüentemente auto-amputam-se, possivelmente por torçäo e necrose do pedículo, sendo o sangramentoe retal indolor a manifestaçäo clínica típica. Quando múltiplos, o comprometimento pode ser sistêmico, e também extra-colônico, dependendo da síndrome específica. Dentre estas, temos a polipose juvenil, uma das sídromes familiares de polipose hamartomatosa do trato gastro-intestinal, que deve ser histologicamente confirmada e diferenciada de outras poliposes do tubo digestivo, pois esta entidade, a princípio benigna, tem possibilidades de transformaçäo maligna se apresentar focos de tecido adenomatoso nos pólipos hamartomatosos. Neste trabalho, será relatado um caso de polipose juvenil em um paciente de 12 anos, com sinais e sintomas de malabsorçäo e hematoquesia, além de manifestaçöes extra-colônicas. Ao exame, comprometimento pancolônico, por inúmeros pólipos. A investigaçäo familiar, todos os irmäos apresentavam a síndrome, mas assintomáticos. Como o número de pólipos era reduzido, foram tratados com polipectomia por via endoscópica. O paciente evoluiu bem, após colectomia total e anastomose ileoretal

Síndrome de Turcot: relato de dois casos / Turcot syndrome: report of 2 cases

Os autores descrevem dois pacientes com associaçäo de polipose intestinal e tumor do sistema nervoso central (síndrome de Turcot), discutindo aspectos clínicos, genéticos e terapêuticos