Papillary thyroid carcinoma in three siblings with familial adenomatous polyposis

The authors report three siblings (two sisters and their aunt, aged 20, 22 and 36, respectively) with familial adenomatous polyposis (FAP) and papillary thyroid carcinoma. After diagnosis of FAP, a single, non palpable nodule was revealed in each patient by routine screening ultrasonography of the gland. The diagnosis of papillary carcinoma was made by fine-needle-aspiration biopsy of the nodules and confirmed by histologic examination of surgical specimens. A review of the literature reveals about 40 reports of such an association, that is considered not fortuitous. Nevertheless, in this family the association seems to be a distinctive, clinical feature of the syndrome, affecting three out of five members intensively screened for extracolonic lesions.

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Résumé Les auteurs rapportent trois cas de polypose familiale multiple (FAP) et de carcinome papillaire de la thyroïde chez deux soeurs et une tante. Après diagnostic de polypose, un dépistage de routine ultrasonographique de la thyroïde a permis de mettre en évidence un nodule non palpable chez chacun des patients. Le diagnostic de carcinome papillaire a été fait sur la base d'une ponction-biopsie à l'aiguille fine du nodule et confirmé lors de l'analyse histologique des pièces opératoires. Une revue de la littérature montre que 40 cas d'une telle association ont été publiés qui ne peut dès lors plus être considérée comme fortuite. Néanmoins, dans cette famille, l'association semble correspondre à une entité clinique particulière étant donné qu'elle affecte trois des cinq membres qui ont fait l'object d'investigations intensive à la recherche de lésions extra-coliques.

     

Papillary carcinoma of the thyroid and familial polyposis coli

A 22-year-old white woman in whom multicentric papillary carcinoma of the thyroid developed two years after prophylactic colectomy for intestinal polyposis is reported. This association has been observed by others. Patients with familial polyposis coli are at risk for a variety of malignancies other than colonic, and careful life-long surveillance is necessary.     

Is screening for thyroid carcinoma indicated in familial adenomatous polyposis?

Forty-five polyposis patients with thyroid carcinoma constituted 1.2% of the patients in the Leeds Castle Polyposis Group database. The patients were diagnosed during 1959–1995; 44 were females at a median age of 25 years (range 10–40) and 37 (82%) had papillary carcinoma. At the end of 1995 only one patient (9%) had died from thyroid carcinoma, and the ten-year cumulative survival was 84% (95% confidence limits 72–97). Due to the low incidence of thyroid carcinoma in FAP and the good prognosis we do not recommend a regular thyroid screening in polyposis, as this is unlikely to result in a reduction of the mortality, but will only aggravate existing cancrophobia in these strained patients.

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Résumé. Quarante-cinq patients atteints de polypose et porteurs d'un cancer de la thyro?de constituent 1,2% du collectif enregistré dans la banque des données du Leeds Castle Polyposis Group. Les patients ont été diagnostiqués entre 1959 et 1995; it s'agit de 44 femmes avec un age moyen de 25 ans (age 10–40) et étaient porteuses pour 37 d'un carcinome papillaire (82%). A la fin de 1995, seule une patiente (9%) était décédéee de son cancer thyro?dien et le taux de survie cumuléà 10 ans était de 84% (95% avec des limites de confidence allant de 72 à 97). En raison de la faible incidence du cancer de la thyro?de chez les patients atteints de polypose et en raison du bon pronostic de ces tumeurs, nous ne recommandons pas un dé-pistage systématique de l'atteinte thyro?dienne chez les patients porteurs d'une polypose étant donné que ceci n'entra?nerait pas de réduction significative de la mortalité mais ne ferait qu'augmenter la cancérophobie chez ce collectif de malades.

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Accepted: 22 March 1997     

Mortality in patients with familial adenomatous polyposis

The authors identified 132 patients who died with a documented diagnosis of familial adenomatous polyposis (FAP). A review of the medical records, autopsy reports, and in-depth discussion with local physicians and well-informed family members was performed. It was impossible, even after the review, to ascertain the exact cause of death in 22 patients. In the remaining patients, the cause of death was as follows: metastatic colorectal carcinoma, 64 patients (58.2 percent), (colon, 49 [44.5 percent], rectal, 15 [13.6 percent]); desmoid tumors, 12 (10.9 percent); periampullary carcinoma, 9 (8.2 percent); brain tumors, 8 (7.3 percent); perioperative mortalities, 5 (4.5 percent); adrenal carcinoma, 1 (0.9 percent); and abdominal carcinomatosis, 1 (0.9 percent). Ten patients died of causes not related to FAP. The major causes of death in 36 patients who underwent prophylactic colectomy were desmoid tumor and periampullary malignancy. This finding underscores the importance of lifelong surveillance and periodic endoscopic evaluation in patients with FAP.Read at the Tripartite Meeting, Birmingham, United Kingdom, June 19 to 22, 1989.     

Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis.

Familial adenomatous polyposis has been associated with several extraintestinal cancers, but the relative and absolute risks of these malignancies have not been determined. Extraintestinal cancers reportedly associated with adenomatous polyposis (thyroid gland, adrenal gland, pancreas, and biliary tract) were identified in polyposis patients and their at risk relatives in The Johns Hopkins Registry. The incidence rates of identified tumours were then compared with the general population through person year analysis with adjustment for population. For comparison, the incidence rates of the two most common cancers not associated with polyposis (breast cancer in women and lung cancer) were also calculated. There was an increased relative risk of thyroid cancer (relative risk 7.6; 95% confidence limits (CL) 2.5-17.7) and pancreatic adenocarcinoma (relative risk 4.46; 95% CL 1.2-11.4) in polyposis patients and at risk relatives. The absolute risk was 26.8 and 21.4 cases/100,000 person years, respectively. No cases of adrenal or biliary cancer were found in this cohort. There was no increased relative risk of lung cancer (95% CL 0.04-1.4) or breast cancer (95% CL 0.04-1.4) over the general population. The relative risks of thyroid and pancreatic cancer are increased in familial adenomatous polyposis, but the absolute lifetime risk is low. Screening for pancreatic cancer may not be worthwhile with currently available methods, but careful physical examination of the thyroid gland is warranted along with consideration for ultrasonography.     

Papillary thyroid carcinoma associated with familial adenomatous polyposis: molecular analysis of pathogenesis in a family and review of the literature

We found a case of a papillary thyroid carcinoma that was accompanied by a familial adenomatous polyposis (FAP) in a 29-year-old female. She had hundreds of adenomas inside the entire colon and a congenital hypertrophy of the retinal pigmented epithelium (CHRPE). The patient underwent a total thyroidectomy and a central compartment neck node dissection. Gross examination of the thyroid identified two solid and cystic lesions. The pathological finding of thyroid cancer revealed a mixture of a peculiar nuclear clearing, cribriform, morula formation, trabecular and papillary pattern. The patient's brother had undergone a total colectomy due to FAP at the age of 25. Genetic analyses of the patient's family members revealed that she and her brother had the same germline mutation, in which five nucleotides (AAAGA) were deleted from codon 1309 of the adenomatous polyposis coli (APC) gene exon 15. Strong and frequent immunoreactivities of beta-catenin and p53 were evident in the tumor tissue. At the time of writing, a preventive colectomy was still under consideration for the patient. Genetic counseling was given to the other family members, who were not attacked by this disease, in order to allay their fears of cancer.     

Desmoid disease in patients with familial adenomatous polyposis

PURPOSE: The aim of this retrospective study was to review the clinical features, and surgical and medical management of patients with familial adenomatous polyposis-associated desmoid tumors. METHODS: From 1980 to 1997, 97 of 780 patients with familial adenomatous polyposis developed desmoid disease. Clinical and demographic data; operative notes; and histologic, radiologic, and follow-up reports were retrieved from patients' medical records. Risk factors for desmoid disease, such as prior surgery, age at desmoid tumor diagnosis, pregnancy, and family history were sought. The outcome after noncytotoxic and cytotoxic therapy was evaluated with respect to improvement of symptoms. RESULTS: There were 38 males with a mean age of 32.1 years and 59 females with a mean age of 29.1 years. A family history of desmoid tumors was found in 41 patients (42 percent), and a history of pregnancy was documented in 33 females (56 percent). The most common clinical presentation was small-bowel obstruction (58 percent). One-half of the desmoids were located in the mesentery, and 32 percent were located in the mesentery and the abdominal wall. Desmoids developed after colectomy in 77 cases (80 percent), after a mean time of 4.6 years. Partial resection of desmoid tumor was performed in 46 patients (47 percent), resection of extra-abdominal desmoid tumors was performed in 17 cases (17 percent), and biopsy only was performed in 34 patients (35 percent). Postoperative morbidity was 23 percent after desmoid tumor resection. Eight patients (8 percent) died of their intra-abdominal desmoid. Mean follow-up time was 5.3 years. Sulindac, tamoxifen, or toremifene therapy was able to alleviate symptoms in only 4 of 31 patients. Symptomatic improvement was noted after chemotherapy in six of ten patients with extremely complex desmoids. CONCLUSION: Desmoid disease was found in 12.4 percent of our patients with familial adenomatous polyposis. In view of the high rate of morbidity, indication for surgery should be limited mainly to acute or chronic small-bowel obstruction, because resection triggers a high recurrence rate. Noncytotoxic therapy was not effective for progressive desmoid tumors, whereas chemotherapy was effective in aggressive cases of intra-abdominal desmoid tumors.Poster presentation at the meeting of the Society for Surgery of the Alimentary Tract during Digestive Disease Week, New Orleans, Louisiana, May 16 to 22, 1998. Read at the meeting of the Royal College of Physicians and Surgeons, Toronto, Ontario, Canada, September 16 to 20, 1998.     

Adrenal masses in patients with familial adenomatous polyposis

PURPOSE: The aims of this study were 1) to report the characteristics and the clinical outcome of familial adenomatous polyposis (FAP) patients with adrenal masses in the FAP registry at the Cleveland Clinic Foundation and 2) to estimate the prevalence of adrenal masses detected by computed tomography in FAP patients compared with that expected in a normal population. METHODS: A retrospective review was undertaken of the FAP registry database at our institution. Only 738 patients treated at the Cleveland Clinic Foundation were included in the study. A metaanalysis was conducted to determine the relative risk of adrenal incidentaloma in this series of FAP patients and in a general population as reported in the four largest pertinent studies published in the past 15 years. RESULTS: Fifteen patients (11 females) were identified. Two patients had symptoms related to cortisol hypersecretion (arterial hypertension) and underwent surgery. The final pathology was adrenocortical carcinoma and bilateral nodular hyperplasia. Adrenal masses were found incidentally (incidentalomas) in 13 patients: 12 were detected by computed tomography and one during laparotomy for total abdominal colectomy. Only one patient underwent left adrenalectomy for a 5-cm mass. Pathologic report revealed adrenocortical adenoma. Among the 738 patients considered in this study, only 162 underwent abdominal computed tomographic scan, mainly for assessing intra-abdominal desmoid. The prevalence of incidentaloma in our series compared with that reported in the literature is significantly different (7.4 vs.0.6–3.4 percent;P <0.001 (chi-squared test)). DISCUSSION: Although the presence of other extracolonic manifestations represents a selection bias for computed tomographic study in our series, the incidence of incidentalomas in FAP patients seems to be higher than in a general population. However, incidental detection of an adrenal mass in FAP patients has probably a limited clinical relevance, and the management should be the same as that for the normal population.     

Gastroduodenal polyps in patients with familial adenomatous polyposis

A review of the endoscopy reports and pathology results from esophagogastroduodenoscopy (EGD) of all patients with familial adenomatous polyposis (FAP) undergoing such an examination was performed. Two hundred fortyseven patients were identified, with an overall prevalence of duodenal adenomas of 66 percent and of fundic gland polyps of 61 percent. Analysis of our more recent experience (1986 to 1990) shows the prevalence to be 88 percent and 84 percent, respectively. A normal-appearing papilla was adenomatous in 50 percent of cases. No case of periampullary carcinoma developed in patients under surveillance. Routine EGD is indicated for patients with FAP. Duodenal adenomas and fundic gland polyps will occur in the majority of patients.Read at the meeting of The American Society of Colon and Rectal Surgeons, Boston, Massachusetts, May 12 to 17, 1991.     

Pancreatic acinar cell carcinoma in familial adenomatous polyposis

Pancreatic carcinoma is rarely associated with familial adenomatous polyposis (FAP). Ten patients with this association have been reported in the literature. However, detailed data were available in only a few cases. The first case of pancreatic acinar cell carcinoma associated with FAP is reported. A 51-year-old man who had undergone total colectomy and ileoproctostomy for colonic polyposis 29 years previously was admitted with a cancer in the residual rectum. Preoperative examinations revealed a tumor in the head of the pancreas. Pancreaticoduodenectomy and very low anterior resection of the rectum were performed. Histologically, the tumor of the pancreas was acinar cell carcinoma. In patients with FAP, we recommend careful surveillance of not only the gastrointestinal tract but also of other organs such as those of the pancreaticobiliary system and the endocrine organs.     

Serum gastrin values in patients with familial adenomatous polyposis

PURPOSE: An evaluation of the importance of gastrin in the colorectal carcinogenesis in patients with familial adenomatous polyposis was conducted. METHODS: Blood samples from 168 family members of 26 families were investigated for circulating gastrin. Blood was drawn from 65 affected patients, 66 clinically unaffected first-degree relatives, and 37 spouses. RESULTS: We did not find any difference in distribution of serum gastrin among these groups. CONCLUSION: Our results seem to exclude gastrin from being relevant in early carcinogenesis in patients with familial adenomatous polyposis.     

Duodenal adenoma surveillance in patients with familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is a hereditary disorder caused by Adenomatous Polyposis Gene mutations that lead to the development of colorectal polyps with great malignant risk throughout life. Moreover, numerous extracolonic manifestations incorporate different clinical features to produce varied individual phenotypes. Among them, the occurrence of duodenal adenomatous polyps is considered an almost inevitable event, and their incidence rates increase as a patient’s age advances. Although the majority of patients exhibit different grades of duodenal adenomatosis as they age, only a small proportion (1%-5%) of patients will ultimately develop duodenal carcinoma. Within this context, the aim of the present study was to review the data regarding the epidemiology, classification, genetic features, endoscopic features, carcinogenesis, surveillance and management of duodenal polyps in patients with FAP.     

Familial papillary thyroid carcinoma is genetically distinct from familial adenomatous polyposis coli.

Familial papillary thyroid carcinoma (fPTC) is an inherited tumor syndrome characterized by isolated papillary thyroid carcinoma (PTC) in affected subjects. Its etiology is unknown. Large multigeneration families with PTC are very rare, and therefore, modern genetic linkage studies have not been applied extensively to this disorder. Familial adenomatous polyposis coli (FAP) is an inherited tumor syndrome enriched in PTC. FAP is caused by germline mutations of the adenomatous polyposis coli (APC) gene that is located in the 5q21 region. It is not known if fPTC is a phenotypic variant of FAP, or if it is a genetically distinct disorder. We report a large 3-generation fPTC kindred and use linkage analysis to test the hypothesis that fPTC and FAP are genetically distinct. In this kindred there are 25 living informative subjects; 5 have PTC, and 1 is an obligate carrier. Inheritance is autosomal dominant with incomplete penetrance. There is vertical transmission, multifocal disease, an average age of onset of 36 years, and 1 subject has colon cancer. The probability is approximately 1 in 2 billion against the clustering of 5 sporadic PTC cases in this kindred. To test for linkage to the APC gene we used 2 highly polymorphic markers, D5S656 and D5S421, which are located within a maximum distance of 1.7 megabase (Mb) of the APC gene and within an estimated genetic region of less than 1 centimorgan (cM) from each other. After polymerase chain reaction (PCR) amplification 18 family members were genotyped. Construction and inspection of haplotypes showed that the affected subjects do not share the same allelic composition. Using a penetrance ratio of 75%, linkage was excluded at 2 cM and 3 cM on both sides of D5S656 and D5S421, respectively. The combined haplotype of these 2 markers provided an exclusion region of 4 cM. We conclude that fPTC is genetically distinct from FAP.     

Thyroid carcinoma usually occurs in patients with familial adenomatous polyposis in the absence of biallelic inactivation of the adenomatous polyposis coli gene

Papillary thyroid carcinoma (PTC) is a rare extracolonic manifestation of familial adenomatous polyposis, determined by germline mutations of the adenomatous polyposis coli (APC) gene. The aim of this study was to assess the presence of loss of heterozygosity of APC in the thyroid tumoral tissue. Specimens from six female patients, aged 20-36, were analyzed for germline and somatic mutations of the APC gene by restriction enzyme analysis and sequence analysis. Five of the six also had analysis for ret/PTC, a chimeric gene, the activation of which is restricted to papillary TC. Because a previous study showed that germline mutations in familial adenomatous polyposis-associated thyroid carcinoma were located between codons 140 and 1513, the search for somatic mutations of the APC gene was restricted to this genomic area. Three of the six patients, belonging to the same kindred, had a germline mutation at codon 1061. The remaining three, one per kindred, had germline mutations at codons 1061, 1061, and 1309, respectively. None of the six patients had loss of heterozygosity for APC or somatic mutation in the explored genomic area (codon 545 and codons 1061-1678). Four of five had activation of ret/PTC in the thyroid tumoral tissue, as ret/PTC1 isoform. Either APC has a tissue-specific dominant effect in the thyroid gland or the germline mutation confers a generic susceptibility to cancer development, but other factors (sex-related factors, environmental radiation, modifier genes) are also required for TC development. This usually involves ret/PTC activation, suggesting a possible cooperation between altered function of APC and gain of function of ret.     

Chemoprevention in familial adenomatous polyposis

Familial adenomatous polyposis (FAP) predictably leads to adenomas and eventual adenocarcinomas in the lower gastrointestinal tract and less frequently, the upper gastrointestinal tract. Chemopreventive strategies have been studied in FAP patients to delay the development of adenomas in the upper and lower gastrointestinal tract, as well as to prevent recurrence of adenomas in the retained rectum of patients after prophylactic surgery with colectomy and ileorectal anastamosis (IRA). The nonsteroidal anti-inflammatory drug (NSAID) sulindac and selective cyclooxygenase-2 (COX-2) inhibitor celecoxib reduce polyposis of the retained rectum after colectomy with IRA. Reports of cardiovascular risks of some NSAIDs and selective COX-2 inhibitors have led to promising studies of lower doses in combination with ursodeoxycholic acid, statin, and difluoromethylornithine. Curcumin and eicosapentaenoic acid show efficacy in small clinical trials of FAP chemoprevention. This article will review the concept of chemoprevention and the current clinical literature in FAP chemoprevention.