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Fig. 6.67 A - C Multiple polyps in juvenile polyposis. The contour of polyps is highly irregular, fronded, in contrast to solitary sporadic juvenile polyps.

Synonyms

Generalized juvenile polyposis; juvenile polyposis coli; juvenile polyposis of infancy; juvenile polyposis of the stomach; familial juvenile polyposis; hamartoma-tous gastrointestinal polyposis.

Diagnostic criteria

Following the initial report by Stemper in 1975 {1831}, the following diagnostic criteria have been established: (1) more than 5 juvenile polyps of the colorectum, or (2) juvenile polyps throughout the gastrointestinal tract, or (3) any number of juvenile polyps with a family history of JP {847}. Other syndromes that display hamartomatous gastrointestinal polyps should be ruled out clinically or by pathological examination.

Epidemiology

Incidence

JP is ten-fold less common than familial adenomatous polyposis {838}, with an incidence of from 0.6 to 1 case per 100,000 in Western nations {297, 215}. JP may be the most common gastrointestinal polyposis syndrome in developing counties {1576, 2109}, and approximately half of cases arise in patients with no family history {316}.

Age and sex distribution Two-thirds of patients with juvenile poly-posis present within the first 2 decades of life, with a mean age at diagnosis of 18.5 years {316}. Some present in infancy, and others not until their seventh decade {749}. Though extensive epidemiological data do not exist, incomplete penetrance and approximately equal distribution between the sexes can be presumed.

Localization

Polyps occur with equal frequency throughout the colon and may range in number from one to more than a hundred. Some patients develop upper gastrointestinal tract polyps, most often in the stomach, but also in the small intestine. Generalized juvenile gastrointestinal polyposis is defined by the presence of polyps in the stomach, small intestine and colon {1643}.

Clinical features

Signs and symptoms. Patients with juvenile polyposis usually present with gastrointestinal bleeding, manifesting as haematochezia. Melaena, prolapsed rectal polyps, passage of tissue per rectum, intussusception, abdominal pain, and anaemia are also common.

Imaging. Air contrast barium enema and upper gastrointestinal series may demonstrate filling defects, but are non-diagnostic for juvenile polyps.

Endoscopy. Biopsy or excision of polyps by colonoscopy can be both diagnostic and therapeutic. Small juvenile polyps may resemble hyperplastic polyps, while larger polyps generally have a well-defined stalk with a bright red, rounded head, which may be eroded. In the stomach, polyps are less often pedunculated and are more commonly diffuse.

Macroscopy

Most subjects with juvenile polyposis have between 50-200 polyps throughout the colorectum. The rare and often lethal form occurring in infancy may be associated with a diffuse gastrointestinal poly-posis {1643}. In cases presenting in later childhood to adulthood, completely unaffected mucosa separates the lesions. This is unlike the dense mucosal carpeting that is characteristic of familial adeno-matous polyposis. The polyps are usually pedunculated, but can be sessile in the stomach. Smaller examples have the spherical head of a typical solitary juvenile polyp. They may grow up to 5 cm in diameter, with a multilobated head. The individual lobes are relatively smooth and separated by deep, well-defined clefts. The multilobated polyp therefore appears like a cluster of smaller juvenile polyps attached to a common stalk. Such multi-lobated or atypical juvenile polyps account for about 20% of the total number of polyps {847}.

Fig. 6.69 Juvenile polyp with intraepithelial neopla-sia and early adenocarcinoma.

Fig. 6.68 A, B Juvenile polyposis. The bizarre architecture differs from the round, uniform structure of sporadic juvenile polyps.

Fig. 6.69 Juvenile polyp with intraepithelial neopla-sia and early adenocarcinoma.

Fig. 6.70 A, B Intraepithelial neoplasia in a juvenile polyp.

Fig. 6.71 TGF-p superfamily signaling through signal-transducing SMAD (1,2,3,4,5 and 8) and inhibitory SMAD (6 and 7) proteins. SMAD4, the protein defective in juvenile polyposis, plays a key role in the network. After type I receptor activation, SMADs 1,2,3,5 and 8 become phosphorylated, form homomeric complexes with each other, and assemble into heteromeric complexes with SMAD4. The complexes translocate into the nucleus, where they regulate transcription of target genes. Inhibitory Smads act opposite from R-Smads by competing with them for interaction with activated type I receptors or by directly competing with SMADs 1,2,3,5 and 8 for heteromeric complex formation with SMAD4. From: E. Piek et al. FASEBJ13: 2105 (1999).

Fig. 6.71 TGF-p superfamily signaling through signal-transducing SMAD (1,2,3,4,5 and 8) and inhibitory SMAD (6 and 7) proteins. SMAD4, the protein defective in juvenile polyposis, plays a key role in the network. After type I receptor activation, SMADs 1,2,3,5 and 8 become phosphorylated, form homomeric complexes with each other, and assemble into heteromeric complexes with SMAD4. The complexes translocate into the nucleus, where they regulate transcription of target genes. Inhibitory Smads act opposite from R-Smads by competing with them for interaction with activated type I receptors or by directly competing with SMADs 1,2,3,5 and 8 for heteromeric complex formation with SMAD4. From: E. Piek et al. FASEBJ13: 2105 (1999).

Histopathology

Smaller polyps are indistinguishable from their sporadic counterparts. In the multi-lobated or atypical variety the lobes may be either rounded or finger-like. There is a relative increase in the amount of epithelium versus stroma. Glands show more budding and branching but less cystic change than the classical solitary polyp {847}.

Cancer in juvenile polyposis

There are two histogenetic explanations for the well documented association between colorectal cancer and juvenile polyposis. Cancers could arise in coexisting adenomas. Alternatively, they may develop through dysplastic change within a juvenile polyp. While both mechanisms may apply, pure adenomas are uncommon in juvenile polyposis. By contrast, foci of low-grade dysplasia may be demonstrated in 50% of atypical or multi-lobated juvenile polyps. The dysplastic areas may increase in size, generating a mixed juvenile polyp/adenoma. The ade-nomatous component may be tubular, tubulovillous or villous. Carcinomas are more likely to be poorly differentiated and/or mucinous {847}.

Extraintestinal manifestations

Congenital anomalies have been reported in 11 to 15% of JP patients {316, 727}, with the majority occurring in sporadic cases {217}. These anomalies most commonly involve the heart, central nervous system, soft tissues, gastrointestinal tract and genitourinary system {316, 1202}. Several patients have been reported with ganglioneuromatous proliferation within juvenile polyps {428, 1218, 1513, 2081}, and others with pulmonary arteriovenous malformations and hyper-trophic osteoarthropathy {348, 1760, 101, 333}.

Genetics

JP is autosomal dominant. Germline mutations in SMAD4/DPC4 tumour suppressor gene account for some of the cases {748, 751}. SMAD4 maps to chromosome 18q21.1 {651}, i.e. a region that is often deleted in colorectal carcinomas.

Gene structure and product

SMAD4 has 11 exons, encoding 552 amino acids. It is expressed ubiquitously in different human organ systems, as well as during murine embryogenesis. The gene product is an important cellular mediator of TGF-p signals relevant for development and control of cell growth and an obligate partner for SMAD2 and SMAD3 proteins in the signalling pathway from the TGF-p receptor complex to the nucleus {2099}.

Gene mutations

While relatively few germline mutations

Cowden syndrome

Definition

Cowden syndrome (CS) is an autosomal dominant disorder characterized by multiple hamartomas involving organs derived from all three germ cell layers. The classical hamartoma associated with CS is the trichilemmoma. Affected family members have a high risk of developing breast and non-medullary thyroid carcinomas. Clinical manifestaions further include mucocutaneous lesions, thyroid abnormalities, fibrocystic disease of the breast, gastrointestinal hamartomas, early-onset uterine leiomyomas, macro-cephaly, mental retardation and dysplas-tic gangliocytoma of the cerebellum (Lhermitte-Duclos). The syndrome is caused by germline mutations of the PTEN / MMAC1 gene.

MIM No. 158350

Synonyms

Cowden disease; multiple hamartoma syndrome.

have been described thus far, three studies have confirmed, in different white populations, the frequent occurrence of a four base pair deletion in SMAD4 exon 9 {531, 751, 1622}. Haplotype analyses indicate that this is due to a mutation hotspot, rather than an ancient founder mutation {531, 751}. The families segregating this particular mutation tend to be large, perhaps indicating high penetrance. It seems likely that SMAD4 is not the only gene underlying JP since only a subset of the families have SMAD4 germline mutations {531, 748, 751, 1622}, and many families are not compatible with 18q linkage {748, 751, 1622}. The PTEN gene has also been proposed as underlying JP {1421}, but this report has not been confirmed by other studies and the present notion is that individuals with PTEN mutations should be considered having Cowden syndrome, with a risk of breast and thyroid cancer {469}.

Prognostic factors

The most severe form of juvenile polyposis presents in infancy, with diarrhoea, anemia, and hypoalbuminemia; these patients rarely survive past 2 years of age. Although polyps in juvenile polyposis patients have classically been described as hamartomas, they do have malignant potential. The risk of colorectal carcinoma is approximately 30-40% and that of upper gastrointestinal carcinoma is 10-15% {749}. Typical age of colon carcinoma diagnosis is between 34 and 43 years (range 15-68 years), and upper gastrointestinal carcinoma 58 years (range 21-73 years) {749, 847, 834}. Most cases occur in patients who have not been screened radiologically or endo-scopically, suggesting that cancers may be preventable through close surveillance.

Diagnostic criteria

Because of the variable and broad expression of CS and the lack of uniform diagnostic criteria prior to 1996, the International Cowden Consortium {1334} compiled operational diagnostic criteria for CS (Table 6.05), based on the published literature and their own clinical experience {467}. Trichilemmomas and papillomatous papules are particularly important to recognize. CS usually presents by the late 20s. It has variable expression and an age-related pene-trance although the exact penetrance is unknown. By the third decade, 99% of affected individuals have developed the mucocutaneous stigmata although any of the other features could be present already (see Table 6.05). Because the clinical literature on CS consists mostly of reports of the most florid and unusual families or case reports by subspecialists interested in their respective organ systems, the spectrum of component signs is unknown. Despite this, the most com monly reported manifestations are muco-cutaneous lesions, thyroid abnormalities, fibrocystic disease and carcinoma of the breast, gastrointestinal hamartomas, multiple, early-onset uterine leiomyoma, macrocephaly (specifically, megen-cephaly) and mental retardation {1819, 665, 1152, 1096}.

Epidemiology

The single most comprehensive clinical epidemiological study estimated the prevalence to be 1 per million population {1819, 1334}. Once the gene was identified {1071}, a molecular-based estimate of prevalence in the same population was 1:200 000 {1333}. Because of the difficulty in recognizing this syndrome, prevalence figures are likely underestimates.

Intestinal neoplasms

Hamartomatous polyps. In a small but systematic study comprising 9 well documented CS individuals, 7 of whom had a

Fig. 6.72 A, B Colonic polyps in Cowden syndrome. Distorted glands and fibrous proliferation in lamina propria.

germline PTEN mutation, all 9 had hamar-tomatous polyps {2075}. Several varieties of hamartomatous polyps are seen in this syndrome, including lipomatous and gan-glioneuromatous lesions {2075}. Presumably, these polyps can occur anywhere in the gastrointestinal tract. Those in the colon and rectum usually measure from 3 to 10 millimetres but can reach 2 centimetres in diameter. Some of the polyps are no more than tags of mucosa but others have a more definite structure. Most are composed of a mixture of connective tissues normally present in the mucosa, principally smooth muscle in continuity with the muscularis mucosae {242}. Examples containing adipose tissue have been described. The mucosal glands within the lesion are normal or elongated and irregularly formed but the epithelium is normal and includes goblet cells and columnar cells {242}. Lesions in which autonomic nerves are predominant, giving a ganglioneuroma-like appearance, have been described but seem to be exceptional {1017}. The vast majority of CS hamartomatous polyps are asymptomatic. In a study of 9 CS individuals, glycogenic acanthosis of the oesophagus was found in 6 of the 7 with PTEN mutation {2075}.

Gastrointestinal malignancies are generally not increased in CS {1819, 468} although rare individual CS families appear to have an increased prevalence of colon cancer (Eng, unpublished observations).

Extraintestinal manifestations

Breast cancer. The two most commonly recognized cancers in CS are carcinoma of the breast and thyroid {1819}. In the general population, lifetime risks for breast and thyroid cancers are approximately 11% (in women), and 1%, respectively. Breast cancer has been rarely observed in men with CS {1167}. In women with CS, lifetime risk estimates for the development of breast cancer range from 25 to 50% {1819, 665, 1096, 467}. The mean age at diagnosis is likely 10 years earlier than breast cancer occurring in the general population {1819, 1096}. Although Rachel Cowden died of breast cancer at the age of 31 {196, 1081} and the earliest recorded age at diagnosis of breast cancer is 14 {1819}, the great majority of breast cancers are diagnosed after the age of 30-35 (range 14 - 65) {1096}. The predominant histology is ductal adenocarcinoma. Most CS breast carcinomas occur in the context of DCIS, atypical ductal hyperplasia, adenosis and sclerosis {1691}. Thyroid cancer. The lifetime risk for thyroid cancer can be as high as 10% in males and females with CS. Because of small numbers, it is unclear if the age of onset is truly earlier than that of the general population. Histologically, the thyroid cancer is predominantly follicular carcinoma although papillary histology has also been rarely observed {1819, 665, 1152} (Eng, unpublished observations). Medullary thyroid carcinoma has not been observed in patients with CS. Benign tumours. The most important benign tumours are trichilemmomas and papillomatous papules of the skin. Apart from those of the skin, benign tumours or disorders of breast and thyroid are the most frequently noted and probably represent true component features of this syndrome (Table 6.05). Fibroadenomas and fibrocystic disease of the breast are common signs in CS, as are follicular adenomas and multinodular goitre of the thyroid. An unusual central nervous system tumour, cerebellar dysplastic gan-gliocytoma or Lhermitte-Duclos disease, has recently been associated with CS {1445, 468, 932}.

Other malignancies and benign tumours have been reported in patients or families with CS. Some authors believe that endometrial carcinoma could be a component tumour of CS as well. It remains to be shown whether other tumours (sarcomas, lymphomas, leukaemia, meningiomas) are true components of CS.

Genetics

Chromosomal location and mode of transmission

CS is an autosomal dominant disorder, with age related penetrance and variable expression {468}. The CS susceptibility gene, PTEN, resides on 10q23.3 {1071, 1334, 1068}.

Gene structure

PTEN/MMAC1/TEP1 consists of 9 exons spanning 120-150 kb of genomic distance {1167, 1820, 1068}. It is believed that intron 1 occupies much of this (approximately 100 kb). PTEN is predicted to encode a 403-amino acid phos-phatase. Similar to other phosphatase genes, PTEN exon 5 specifically encodes a phosphatase core motif. Exons 1 through 6 encode amino acid sequence that is homologous to tensin and auxilin {1065, 1820, 1068}. Gene product

PTEN is virtually ubiquitously expressed {1820}. Detailed expression studies in development have not been performed. However, early embryonic death in pten -/- mice would imply a crucial role for PTEN in early development {1526, 1868, 407}.

PTEN is a tumour suppressor and is a dual specificity phosphatase {1304}. It is a lipid phosphatase whose major substrate is phosphtidylinositol-3,4,5-triphosphate (PIP3) which lies in the PI3 kinase pathway {553, 1814, 1142, 364, 1067}. When PTEN is ample, PIP3 is converted to 4,5-PIP2, which results in hypophosphorylated Akt/PKB, a known cell survival factor. Hypophosphorylated Akt is apoptotic. Transient transfection studies have shown that ectopic expression of PTEN results in apoptosis in breast cancer lines mediated by Akt {1067} and G1 arrest in glioma lines {553, 554}. The G1 arrest is not fully explained by the PTEN-PI3K-Akt pathway. It is also believed that PTEN can dephosphorylate FAK and inhibit integrin and MAP kinase signalling {637, 1892}. Gene mutations

Approximately 70-80% of CS cases, as strictly defined by the Consortium criteria, have a germline PTEN mutation {1167, 1071}. If the diagnostic criteria are relaxed, then mutation frequencies drop to 10-50% {1335, 1964, 1124}. A formal study which ascertained 64 unrelated CS-like cases revealed a mutation frequency of 2% if the criteria are not met, even if the diagnosis is made short of one criterion {1168}.

A single research centre study involving 37 unrelated CS families, ascertained according to the strict diagnostic criteria of the Consortium, revealed a mutation frequency of 80 % {1167}. Exploratory genotype-phenotype analyses revealed that the presence of a germline mutation was associated with a familial risk of developing malignant breast disease {1167}. Further, missense mutations and/or mutations 5' of the phosphatase core motif seem to be associated with a surrogate for disease severity (multiorgan involvement). A small study comprising 13 families with 8 PTENmutation-positive members could not find any genotype-phenotype associations {1333} but this may be due to the small sample size.

Bannayan-Riley-Ruvalcaba syndrome

(BRR). Previously thought to be clinically distinct, BRR (MIM 153480), characterized by macrocephaly, lipomatosis, hae-mangiomatosis and speckled penis, is likely allelic to CS {1169}. Approximately

60% of BRR families and isolated cases combined carry a germline PTENmuta-tion {1170}. There were 11 cases classified as true CS-BRR overlap families in this cohort, and 10 of these had a PTEN mutation. The overlapping mutation spectrum, the existence of true overlap families and the genotype-phenotype associations which suggest that the presence of germline PTENmutation is associated with cancer strongly suggest that CS and BRR are allelic and part of a single spectrum at the molecular level. The aggregate term of PTEN hamartoma tumour syndrome (PHTS) has been suggested {1170}.

The identification of a germline PTEN mutation in a patient previously thought to have juvenile polyposis {1421} excludes that diagnosis, and points to the correct designation as CS or BRR {469, 751, 983, 750, 1171}.

Prognosis

There have been no systematic studies to indicate if CS patients who have cancer have a prognosis different from that of their sporadic counterparts.

Table 6.05

International Cowden Consortium diagnostic criteria for CS.

Table 6.05

International Cowden Consortium diagnostic criteria for CS.

Diagnostic criteria

Operational diagnosis in an individual

Operational diagnosis in a family where one individual is diagnostic for Cowden

Pathognomonic Criteria

1. Mucocutanous lesions alone if:

1. At least one pathognomonic criterion

Mucocutanous lesions:

a) there are 6 or more facial papules, of

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