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Annals of Surgical Oncology 8:319-327 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Hamartomatous Polyposis Syndromes: Molecular Genetics, Neoplastic Risk, and Surveillance Recommendations

Debrah A. Wirtzfeld, MD, FRCSC, Nicholas J. Petrelli, MD and Miguel A. Rodriguez-Bigas, MD

Division of Surgical Oncology, Roswell Park Cancer Institute, State University of New York at Buffalo, Buffalo, New York.

Correspondence: Address correspondence and reprint requests to: Miguel Rodriguez-Bigas MD, FACS, Division of Surgical Oncology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY, 14263; Fax: 716-845-3434; E-mail: miguel.rodriguez-bigas{at}roswellpark.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 JUVENILE POLYPOSIS SYNDROME...
 CONCLUSION
 REFERENCES
 
Hamartomatous polyposis syndromes are characterized by an overgrowth of cells or tissues native to the area in which they normally occur. Juvenile polyposis syndrome (JPS) results from germ-line mutations in the SMAD-4 gene (18q21.1) that encodes for an enzyme involved in transforming growth factor beta(TGF-ß) signal transduction. The increased neoplastic risk may result from SMAD-4 mutations in the stromal component, which stimulate epithelial dysplasia and progression to invasive malignancy. Peutz-Jeghers syndrome (PJS) is associated with germ-line mutations in the LKB1 gene (19p13.3) that encodes a multifunctional serine-threonine kinase. These mutations occur in the epithelial component, suggesting a direct tumor suppressor effect. Patients are at an increased risk of intestinal and extraintestinal malignancies, including breast, pancreatic, ovarian, testicular, and cervical cancer. Cowden’s disease is associated with germ-line mutations in the PTEN gene (10q22–23) and an increased risk of breast and thyroid malignancies. Ruvalcaba-Myhre-Smith syndrome is less common; controversy suggests that it may represent a variant of Cowden’s disease.

Conclusions: Genetic alterations underlying hamartomatous polyposis syndromes are diverse. Carcinogenesis may result from either germ-line mutations in the stroma (JPS) or as a direct result of functional deletion of tumor suppressor genes (PJS). Diagnosis depends on clinical presentation and patterns of inheritance within families. Suggested surveillance guidelines for the proband and first-degree relatives are outlined.

Key Words: Hamartomatous polyposis syndromes • Molecular genetics • Surveillance


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
JUVENILE POLYPOSIS SYNDROME...
 CONCLUSION
 REFERENCES
 
Hamartomatous polyps involving the gastrointestinal tract, either as the major manifestation or as a secondary feature of a syndrome complex, are extremely rare. Haggitt and Reid1 classified these syndromes as either adenomatous or hamartomatous based on the main histopathologic features.

Adenomatous polyposis syndromes are characterized by benign epithelial neoplasms arising from or forming glandular type elements.1 The increased risk of malignant degeneration associated with these syndromes is thought to arise secondary to progression through the "adenoma-carcinoma" sequence initially outlined by Vogelstein.2 Conversely, hamartomatous polyposis syndromes are characterized by an overgrowth of cells or tissues native to the area in which they normally occur.1 This typically involves the mesenchymal or stromal components, although the endodermal or ectodermal elements may be less commonly involved. It is important to note that there is an overgrowth of cells or tissues, at least initially, with no presumed neoplastic potential. However, several of these syndromes are associated with specific genetic mutations and an increased lifetime risk of both intestinal and extraintestinal malignancies.

The syndromes associated with hamartomatous polyposis include juvenile polyposis syndrome (JPS), Peutz-Jeghers syndrome (PJS), Cowden’s disease (CD), and Ruvalcaba-Myhre-Smith syndrome (RMS). The mechanism of inheritance for these syndromes is autosomal dominant with variable penetrance, depending on the syndrome. The molecular genetics have not been well established and may include both direct (caretaker) and indirect (landscaper) mechanisms leading to neoplastic transformation.3 The increased risk of invasive malignancy, both intestinal and extraintestinal, varies depending on the syndrome. As such, appropriate surveillance mechanisms are essential for the proband and first-degree relatives.


   JUVENILE POLYPOSIS SYNDROME (JPS)
TOP
 ABSTRACT
 INTRODUCTION
 JUVENILE POLYPOSIS SYNDROME...
CONCLUSION
 REFERENCES
 
Juvenile polyposis syndrome was first described by McColl in 1964.4 It is the most common of the hamartomatous syndromes, and is inherited in an autosomal dominant manner (variable penetrance) with approximately 20%–50% of cases having a family history of juvenile polyposis.5 The average age of onset is approximately 18 years; there is an association with congenital birth defects in 15% of known cases.1 Most commonly, these include malrotation of the midgut, genitourinary defects, and cardiac defects. The majority of congenital defects have been reported in individuals with the nonfamilial variant of the disease, supporting the contention that this disease is multifactorial.

The diagnostic criteria for juvenile polyposis syndrome are somewhat controversial, although most authors would support those outlined by Giardiello et al.6 These criteria include three or greater juvenile polyps of the colon, polyposis involving the entire gastrointestinal tract, or any number of polyps in a proband with a known family history of juvenile polyps. Patients with solitary juvenile polyposis of infancy are not included within this classification because this condition tends to be self-limited.

Presentation
In infancy, patients present with gastrointestinal bleeding, either acute or chronic, intussusception, rectal prolapse, or a protein-losing enteropathy.7 It is important to recognize and diagnose this condition early because supportive care is essential. Those patients with a protein-losing enteropathy require supplementation of fluids and nutrients.

In adulthood, these patients will more commonly present with gastrointestinal blood loss, either acute or chronic. Most of these patients will be shown to have between 50 and 200 polyps, most commonly in the rectosigmoid region. This is in contrast to Peutz-Jeghers syndrome where the polyps are most commonly located in the small bowel, specifically the upper jejunum.

Histopathology
The typical gastrointestinal polyp in juvenile polyposis is unilobulated and smooth (Fig. 1a). At higher power (Fig. 1b), there is a gross infiltration of the lamina propria by chronic inflammatory cells (lymphocytes and plasma cells), leading to attenuation of the underlying smooth muscle layer. Pathognomonic is cystic dilation of glandular type structures lined, at least initially, by a normal-appearing columnar epithelium.



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  		FIG. 1. (A) Gross histology of a typical juvenile polyp; (B) high-power view of juvenile polyp. (Note cystic dilation of epithelial lined spaces which is pathognomonic for a juvenile polyp.)

 
Molecular Genetics
Juvenile polyposis syndrome was initially thought to be associated with mutations in the PTEN (phosphatase with tensin homology) gene (10q22–23).8,9 Mutations in this gene have been shown to be important in a subset of familial thyroid carcinoma, Cowden’s disease, and Ruvalcaba-Myhre-Smith syndrome.10–12 The original kindred in which this mutation was discovered probably represented Cowden’s disease rather than juvenile polyposis syndrome. More recently, it has been shown that germ-line mutations in the SMAD-4 gene (18q21) account for approximately 50% of the reported familial cases of the syndrome.13 This gene encodes a cytoplasmic mediator involved in the transforming growth factor-beta (TGF-ß) signal transduction pathway (Fig. 2). Activation at the receptor level leads to second messenger signaling by serine and threonine kinases. Members of the SMAD family (nine known members to date) are phosphorylated, exclusive of SMAD-4. This leads to the formation of heteromeric complexes between SMAD-4 and other members of this highly preserved family of proteins. Transportation to the nucleus and interaction with cellular DNA leads to growth inhibition. Mutations in the SMAD-4 gene presumably lead to a loss of heteromeric complex formation and resultant growth inhibition and neoplastic progression.



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  		FIG. 2. TGF-ß signal transduction pathway. SMAD-4 forms heteromeric complexes with other members of the SMAD family, resulting in growth inhibition by interaction with nuclear DNA.

 
The mechanism by which a predominant overgrowth of the stromal/mesenchymal elements can lead to an invasive epithelial malignancy has not been well outlined. It has been shown that the genetic alterations in SMAD-4 occur predominantly in the mesenchymal elements.8 Kinzler and Vogelstein3 have postulated that this leads to the production of a microenvironment which, in some way, influences or "landscapes" the epithelial element of the hamartomatous polyps. With growth of the mesenchymal component, this will result in epithelial dysplasia with progression to invasive malignancy (Fig. 3). Supporting this theory is the fact that as hamartomatous polyps enlarge and the mesenchymal component expands, they take on a more serrated or villous-type configuration associated with a more marked degree of epithelial dysplasia.14 This study showed that, in contrast to smaller "typical" polyps where there was a 9% risk of epithelial dysplasia (typically mild), larger polyps showed a 47% risk. The latter case tended toward a higher degree of moderate to marked epithelial dysplasia. Moreover, there is genetic heterogeneity in that only approximately 50% of cases have been shown to have a SMAD-4 mutation. Genetic alterations in other members of the SMAD family of proteins has not been shown,15 nor have there been consistent mutations of the deleted in colon (DCC) gene which is located at the same genetic locus at SMAD-4.



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  		FIG. 3. Proposed hamartoma-adenoma-carcinoma sequence in juvenile polyposis.

 
Neoplastic Risk
The neoplastic risk associated with juvenile polyposis syndrome has, until recently, been somewhat controversial. In a large retrospective review from St. Mark’s Polyposis Registry published in 1988,14 1032 juvenile polyps from 87 patients were examined. Pathologic specimens were available for reevaluation from 80 patients. Eighteen of 80 (22%) patients subsequently developed colorectal cancer. The mean age at time of diagnosis was 34; five patients were not resectable for cure. Tumors from nine of these patients showed mucinous features and/or poor differentiation.

Coburn et al.16 examined 218 patients who met the criteria for the syndrome. Of these, 36 (17%) went on to develop gastrointestinal malignancies, most commonly colorectal but also upper gastrointestinal malignancies. The mean age at the time of diagnosis was 33 years.

Desai et al.5 reevaluated the data from the St. Mark’s Polyposis Registry in 1995. They estimated that the projected incidence of colorectal cancer alone by the age of 60 was approximately 68%.

Management and Surveillance
The management and surveillance of these individuals is predicated on their increased risk of upper and lower gastrointestinal malignancies (Fig. 4). It will be determined by clinical symptoms and the extent of polyposis. The proband and first-degree relatives should be screened, probably starting in the later teen years, by upper and lower gastrointestinal endoscopy. If this initial screen is negative, surveillance by upper and lower endoscopy should be performed in 3 years. This should be repeated every 3 years as long as surveillance reveals no pathology. If the initial screen is positive, therapy will depend on the extent of polyposis and the ability to address this endoscopically. Diffuse polyposis may need to be remedied by colectomy or gastrectomy. Surveillance should then be undertaken on an annual basis until the patient is free of polyps upon repeat examination. Once this is achieved, the interval can then be lengthened to every 3 years, provided the examination does not reveal signs of pathology. Development of invasive colorectal adenocarcinoma mandates total abdominal colectomy with ileorectal anastomosis or restorative proctocolectomy, depending on the extent of rectal polyposis. Howe et al.17 recommend incorporating genetic testing into this algorithm. However, given the presumed genetic heterogeneity of this syndrome, failure to show a mutation in SMAD-4 does not support lengthening the surveillance interval to 10 years as they suggest.



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  		FIG. 4. Juvenile polyposis syndrome: Proposed algorithm for endoscopic surveillance and treatment in proband and first-degree relatives.

 
PEUTZ-JEGHER’S SYNDROME (PJS)
The original description of this rare hereditary syndrome is credited to Peutz in 1921.18 In 1949, Jegher’s description drew attention to the association between cutaneous melanin deposition, gastrointestinal polyposis, and the risk of invasive carcinoma.19 It is the second most common hamartomatous syndrome, occurring as an autosomal dominant condition with variable penetrance.

The syndrome is associated with hamartomatous polyps of the gastrointestinal tract and cutaneous melanin deposition. The most common location of Peutz-Jeghers polyps is in the upper gastrointestinal tract, specifically the upper jejunum. Melanin deposition occurs most commonly in the perioral region or buccal mucosa (Fig. 5a), but can also occur in the genital region or on the hands and feet (Fig. 5b).



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  		FIG. 5. Clinical manifestations of Peutz-Jeghers syndrome: (A) perioral mucocutaneous pigmentation and (B) melanin deposition of the digits.

 
The initial presentation of a patient with Peutz-Jeghers syndrome occurs most commonly with abdominal pain secondary to obstruction or impending obstruction with polyp intussusception or gastrointestinal blood loss.20 These patients can also suffer from gastrointestinal malignancy as their primary presentation. In fact, Jegher’s initial description19 mentioned that approximately one half of his patients presented with a gastrointestinal malignancy, usually advanced.

Histopathology
The typical Peutz-Jeghers polyp (Fig. 6) is somewhat different histologically from that seen in patients with juvenile polyposis. Instead of the dense inflammatory response, a hypertrophy or hyperplasia of the smooth muscle layer occurs that extends in a treelike manner into the superficial epithelial layer. This has been termed "arborization". The extensive dilation of cystic-filled spaces, pathognomonic for the juvenile polyp, is not seen in Peutz-Jeghers syndrome. The initial estimate of neoplastic risk was somewhat higher than current estimates due to the presence of "pseudoinvasion".20 As the smooth muscle extends upward toward the epithelial layer, invagination of the epithelium will result in islands of epithelial cells trapped within the underlying smooth muscle. To diagnose malignancy, there must be an elevated mitotic rate or cellular atypia suggestive of neoplastic disease.



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  		FIG. 6. Gross histology of a Peutz-Jeghers polyp. Hypertrophy of the smooth muscle layer is the prominent feature.

 
Molecular Genetics
Genetic alterations in the LKB1/STK (19p13) gene are responsible for approximately 50% of the cases of Peutz-Jeghers.21 This gene encodes for a multifunctional serine-threonine kinase, important in second messenger signal transduction. Although the exact mechanism of action has not been outlined, the function of this protein product is likely to be important in growth inhibition as has been shown with SMAD-4. Unlike SMAD-4, the genetic alterations are confined to the epithelial component.22 Thus, unlike the landscaper effect of the mesenchymal component proposed by Kinzler and Vogelstein,3 genetic alterations in LKB1 may represent loss of heterozygosity (LOH) at a tumor suppressor gene locus. More recently, LKB1 promoter hypermethylation has been shown to be present in a subset of patients with a strong family history suggestive of Peutz-Jeghers syndrome.23

The genesis of polyposis, as well as associated clinical features and malignancies, is likely to be more complex. Alterations in particular genes, along with modifying environmental and epigenetic influences, are probably important to a greater or lesser degree, depending on the syndrome and whether sporadic or familial variants are being considered.

Neoplastic Risk
There is an increased risk of colorectal cancer and extraintestinal malignancy associated with Peutz-Jeghers syndrome.24–27 Giardiello et al.24 documented a history of invasive malignancy in 15 of 31 patients (48%) with PJS (relative risk = 18). Four of these malignancies were gastrointestinal; eleven were extraintestinal. This was supported by a review of patients from the St. Mark’s Polyposis Registry.25 In the latter series, 16 of 72 patients (22%) went on to develop some form of invasive malignancy. Nine were gastrointestinal (relative risk = 13) and seven were extraintestinal (relative risk = 9). The relative risk of dying from invasive malignancy was the same, as all but one patient with a basal cell carcinoma of the face went on to succumb to their disease.

Extraintestinal malignancies associated with Peutz-Jeghers syndrome include pancreatic carcinoma, breast carcinoma, ovarian carcinoma, testicular carcinoma in prepubescent males, and adenoma malignum, a well-differentiated multicystic adenocarcinoma of the uterine cervix. If a female is diagnosed with this rare variant form of cervical carcinoma, consideration should be given to the diagnosis of Peutz-Jeghers.

Management and Surveillance
Appropriate surveillance of the proband and first-degree relatives has not been extensively investigated or validated. Recommendations from the St. Marks’s Polyposis Registry28 are outlined in Fig. 7. On an annual basis, assessment should include a hemogram, pelvic ultrasound in females, testicular ultrasound in males, and pancreatic ultrasound in all individuals being surveilled. The authors do not allude to the sensitivity of pancreatic ultrasound or the use of dynamic CT scan and/or serum CA 19–9 measurements in screening for pancreatic adenocarcinoma. Every 2 years, patients should have a "top and tail" endoscopy and some form of examination of the small bowel, preferably an enteroclysis.



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  		FIG. 7. Peutz-Jeghers syndrome: Proposed screening and surveillance program (Adapted with permission from Br J Surg 1995;82:1311–1314).

 
Patients should be screened for breast cancer according to the clinical recommendations for other high-risk individuals, including those with known or suspected BRCA1 or BRCA2 mutations.29 Patients should be encouraged to perform monthly breast self-examination; clinical exams should be performed annually, beginning in the late teen years or as concerns arise. Mammography should begin at the age of 25 years. Pap smears should be done at least every 3 years.

Management of gastrointestinal polyposis is mandated by symptoms and abnormalities on surveillance examination, including the diagnosis of invasive malignancy. Polyps that are symptomatic, >1.5 cm in size, or suspicious for invasive malignancy should be addressed by exploratory celiotomy or enteroscopic polypectomy, if possible. Patients should have complete intraoperative enteroscopic examination of the small bowel and polypectomy as warranted. Extensive small bowel resections should not be undertaken, in an attempt to preserve function and to limit the risk of short bowel syndrome.

COWDEN’S DISEASE (CD)
Presentation
Cowden’s disease was first described in 1963 by Lloyd and Dennis.30 It carries the family name of the patient initially evaluated and described by these authors. It is an autosomal dominant condition with nearly complete penetrance by the age of 20. Also referred to as the "multiple hamartoma-neoplasia syndrome,"31 Cowden’s disease is unique among the hamartomatous syndromes because polyps arise more commonly from ectodermal and/or endodermal elements. Hamartomas involve the skin, intestine, breast, and thyroid gland.32 Eighty percent of patients present with dermatologic manifestations, the most common being a benign tumor of the hair shaft: a trichilemmoma. If a patient is diagnosed with more than one trichilemmoma, consideration should be given to the diagnosis of Cowden’s disease. The second most common area of involvement is the central nervous system. Cowden’s disease in concert with cerebellar gangliocytomatosis is referred to as the Lhermitte-Duclos syndrome. Approximately 40% of affected individuals have macrocephaly as a component of the syndrome.33 Only 35% of patients who meet the diagnostic criteria for Cowden’s disease have gastrointestinal polyposis.

Molecular Genetics
Most patients with Cowden’s disease have been shown to have germ-line mutations in the PTEN gene located at 10q22.34 PTEN is a tumor suppressor gene which has been shown to be involved in other forms of carcinoma such as familial thyroid cancer,35 inherited breast carcinoma,36 prostatic cancer,37 and malignant melanoma.38 This gene has also been referred to as the MMAC1 (mutated in multiple advanced cancers) gene, which emphasizes its nonspecific involvement in various forms of epithelial malignancy.

Neoplastic Risk
The majority of patients with Cowden’s disease will have some form of benign thyroid or breast disease.32 In addition, the projected lifetime risk of thyroid malignancy is 10% and of breast malignancy is approximately 30%–50%.39,40,41 There has been no reported increased risk of invasive gastrointestinal malignancy to date.

Management and Surveillance
Gastrointestinal polyposis should be addressed by endoscopic surveillance. Although no definitive increased risk of colorectal carcinoma has been documented, the syndrome is rare; thus the true risk may be unrecognized.

Screening and surveillance for breast malignancies should include monthly breast self-examination. Clinical examination should be undertaken annually, beginning in the late teen years or as clinically warranted by symptoms. Mammography should be implemented at the age of 25 as previously outlined for Peutz-Jeghers syndrome.

Although no specific recommendations for thyroid surveillance have been published, annual screening by clinical examination should begin in the late teen years or as symptoms warrant. A thyroid ultrasound may be used in parallel every 1 to 2 years.

RUVALCABA-MYHRE-SMITH (BANNAYAN-RILEY-RUVALCABA) SYNDROME
Presentation
This syndrome was only recently described.42,43 Besides hamartomatous polyps of the gastrointestinal tract, it is associated with macrocephaly, mental retardation, delayed psychomotor development, lipid storage myopathy, and Hashimoto’s thyroiditis. Hyperpigmentation of the skin of the penis is seen in the majority of patients and re-emphasizes the association of these syndromes with mucocutaneous melanin deposition.

Molecular Genetics
Ruvalcaba-Myhre-Smith syndrome is an autosomal dominant condition and, like Cowden’s disease, appears to be associated with genetic alterations in the PTEN gene.44 More recently, failure to identify genetic mutations in three sporadic cases suggests that other mechanisms must be involved.45

Neoplastic Risk
There has been no increased risk of colorectal carcinoma, other gastrointestinal malignancies, or extra-intestinal malignancy documented in these patients.

Management and Surveillance
Although there has been no increased risk of invasive malignancy documented in patients with Ruvalcaba-Myhre-Smith syndrome, there is some controversy as to whether or not this syndrome represents a distinct clinical entity.33 Clinically, macrocephaly, delayed psychomotor development, and hyperpigmentation of the skin of the penis can be seen in patients with Cowden’s disease. Furthermore, until recently, the same genetic mutations have been recognized in Cowden’s disease.45 Therefore, careful consideration of other hamartomatous syndromes should be given. The diagnosis of Ruvalcaba-Myhre-Smith syndrome should be one of exclusion.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 JUVENILE POLYPOSIS SYNDROME...
 CONCLUSION
REFERENCES
 
Hamartomatous polyposis syndromes, involving the gastrointestinal tract in most cases, are extremely rare. They account for <1% of the annual incidence of colorectal cancer in the United States and Canada. At least initially, they are characterized by an overgrowth of cells and tissues native to the area in which they normally occur. However, patients are at an increased lifetime risk of both intestinal and extraintestinal malignancies.

The molecular genetics of these rare syndromes have only recently been elucidated; there appears to be still undefined genetic heterogeneity. However, it appears that diverse mechanisms might be involved in the progression through the hamartoma-adenoma-carcinoma sequence. Stromal germ-line mutations in the SMAD-4 gene of juvenile polyps may function to "landscape" the epithelial component that leads to dysplasia and eventually to invasive epithelial malignancy. Conversely, epithelial mutations in the LKB1 gene of patients with Peutz-Jeghers syndrome may interfere with "caretaker" functions within the genome, similar to that seen in hereditary non-polyposis colorectal cancer (HNPCC). The interactions of still unrecognized genetic alterations, epigenetic phenomena, and environmental influences remain to be established. As such, the use of genetic testing outside the realm of established polyposis registries should not be condoned.

Appropriate screening and surveillance will be predicated on clinical presentation and a good personal and family history of polyposis and associated features of these rare syndromes. Although validation of surveillance strategies in these syndromes has not been performed, highly targeted surveillance and management strategies for the proband and first-degree relatives are warranted.

Received for publication May 18, 2000. Accepted for publication November 28, 2000.


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 INTRODUCTION
 JUVENILE POLYPOSIS SYNDROME...
 CONCLUSION
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