Inherited Colon Cancer: Peutz-Jeghers Syndrome, Juvenile Polyposis Syndrome, and Cowden Syndrome

Colorectal cancer (CRC) is the third most common type of non– ‒skin cancer in both men and women. As with other cancers, the majority are sporadic, 15% are familial, and 5% to 10% are hereditary. Thus, in 25% of CRC cases a familial clustering is present, and further risk assessment and possibly genetic testing are indicated. The 2 most well-described forms of inherited CRC are familial adenomatous polyposis (FAP) and Lynch syndrome, also known as hereditary nonpolyposis syndrome. FAP is characterized by 100s to 1000s of colonic polyps, whereas Lynch syndrome has a more diverse phenotype and is associated with at least 10 extracolonic cancers. Both have been discussed in previous articles.

Mutations in 12 genes (MLH1, MSH2, EPCAM, MSH6, PMS2, APC, MUTYH, SMAD4, BMPR1A, STK11, PTEN, and CHEK2) have consistently been shown to be associated with an actionable, elevated risk of CRC, ranging from 15% to 95%. With the exception of MUTYH, all are inherited in an autosomal dominant fashion. Other genes also have been implicated in elevated CRC risk; however, the exact risks are less defined. As each gene is associated with extracolonic cancers and colon cancer is considered a preventable cancer, pinpointing the causative gene is critical for the medical management of the individual undergoing risk assessment and his or her at-risk family members.

Of the 5% to 10% of inherited CRCs, approximately 2% to 3% are due to Lynch syndrome. By solely focusing on the identification of Lynch syndrome in CRC families, at least half of the patients with other identifiable inherited risk may be missed. Therefore, when developing a genetic testing strategy for a CRC family, it is important to assess the patient for all inherited CRC syndromes. As Colon Cancer Awareness Month (March) approaches, it is a good time to review 3 syndromes that have overlapping phenotypes with both FAP and Lynch syndrome.

Peutz-Jeghers Syndrome

Peutz-Jeghers syndrome (PJS) is an autosomal dominant syndrome associated with mutations in the STK11 gene. The cumulative risk for CRC to age 65 years is 39%. Extracolonic risks include gastric (29%), small bowel (13%), pancreatico-biliary (32%), breast (32%-54%), lung (7%-17%), and uterine cancer (95%).^1-3 Women also are at risk for adenoma malignum of the cervix and for ovarian cancer, specifically sex cord tumors with annular tubules (SCTATs) and mucinous ovarian cancer. Men sometimes develop calcifying Sertoli cell tumors of the testes.

The hallmark features of the syndrome are Peutz-Jeghers (PJ) hamartomatous polyps and mucocutaneous pigmentation. The polyps can be found throughout the gastrointestinal tract but are most common in the small intestine. It is not unusual for a patient to present with chronic bleeding, anemia, and/or intussusception due to the polyps. Although PJ polyps are a hallmark feature, it is important to realize that individuals also may develop other types of polyps, including adenomas, in the colon. Thus, not only do the extracolonic cancers overlap with other CRC syndromes, such as Lynch syndrome, but the polyp burden does as well.

Additionally, children may have dark blue to dark brown macules around the mouth, eyes, nostrils, perianal area, buccal mucosa, and fingers. Often these macules fade and, thus, may not be obvious when assessing an adult for the syndrome. They are rarely present at birth. Variable expressivity within families is common—further challenging a diagnosis. A diagnosis of PJS is made when a mutation is found in the STK11 gene or when clinical criteria are met. A clinical diagnosis of PJS is made if any of the following are present⁴:

• Two or more histologically confirmed PJ polyps
• Any number of PJ polyps detected in one individual who has a family history of PJS in a close relative
• Characteristic mucocutaneous pigmentation in an individual who has a family history of PJS in a close relative
• Any number of PJ polyps in an individual who also has characteristic mucocutaneous pigmentation.

Juvenile Polyposis Syndrome

Juvenile polyposis syndrome (JPS) is an autosomal dominant syndrome associated with mutations in the SMAD4 and BMPR1A genes. Its hallmark feature is a type of hamartomatous polyp called a “juvenile” polyp. Similar to the polyp burden in PJS, the number of polyps may vary greatly between individuals, polyps may be found throughout the gastrointestinal tract, and other types of polyps may be present. Individuals have been reported with greater than 100 polyps—again overlapping with phenotypes such as FAP. The risk for CRC is estimated to be 39% to 68%.^5,6 Extracolonic cancers include stomach, pancreas, and possibly small intestine cancers, which also can be found in other CRC syndromes such as Lynch syndrome. Formal risks for extracolonic cancers are not well established.

Individuals with mutations in the SMAD4 gene may additionally have features of hereditary hemorrhagic telangiectasia (HHT). Therefore, patients with an SMAD4 mutation should be screened for features of HHT. HHT is associated with multiple arteriovenous malformations (AVMs), as well as nosebleeds and mucocutaneous telangiectasia.

A diagnosis of JPS is made when a mutation is found in the SMAD4 or BMPR1A gene or clinical criteria are met. A clinical diagnosis of JPS is made if any of the following are present⁷:

• More than 5 juvenile polyps of the colorectum
• Multiple juvenile polyps throughout the gastrointestinal tract
• Any number of juvenile polyps and a family history of juvenile polyps.

Cowden Syndrome

Cowden syndrome (CS) is an autosomal dominant syndrome associated with mutations in the PTEN gene. Extracolonic cancers include thyroid, breast, endometrial, colon, and renal cell carcinoma. In addition, the syndrome places individuals at an increased risk for benign tumors of the skin, thyroid, breast, and endometrium. Skin findings include trichilemmomas, papillomatous papules, and acral/plantar keratoses. Adenomatous nodules, follicular adenomas, and multinodular goiter are common, as well as benign breast disease and uterine fibroids.⁸ Macrocephaly also is seen.

Historically, cancer risks have been estimated to be approximately 25% to 50% for breast, 5% to 10% for endometrial, and 3% to 10% for thyroid cancer,8 but recent data suggest that lifetime risks may be much higher. Cumulative lifetime risks to age 70 years were estimated at 81% for breast, 21% for thyroid, 19% for endometrium, 16% for CRC, and 15% for kidney cancer.⁹ Once again, these are cancers that are also found in other CRC syndromes, including Lynch syndrome. Similar to PJS and JPS, gastrointestinal polyposis is common and can occur throughout the entire tract. A recent study examining the colonic polyposis in patients with CS found that 90% had polyps and 70% had more than 50 polyps. Furthermore, the polyps were of various types and included hamartomatous, inflammatory, adenomatous, ganglioneuromatous, hyperplastic, and juvenile polyps.¹⁰

A diagnosis of CS is made when a mutation is found in the PTEN gene or when diagnostic clinical criteria are met. An individual who does not have a family member previously diagnosed with CS meets diagnostic criteria when any of the following are met¹¹:

• Pathognomonic mucocutaneous lesions combined with 1 of the following:
  • Six or more facial papules, of which 3 or more must be trichilemmomas
  • Cutaneous facial papules and oral mucosal papillomatosis
  • Oral mucosal papillomatosis and acral keratoses
  • Six or more palmoplantar keratoses
  • Two or more major criteria
  • One major and 3 or more minor criteria
  • Four or more minor criteria

Pathognomonic criteria

• Adult Lhermitte-Duclos disease (LDD), defined as the presence of a cerebellar dysplastic gangliocytoma
• Mucocutaneous lesions
  • Trichilemmomas
  • Acral keratoses
  • Papillomatous lesions
  • Mucosal lesions

Major criteria

• Breast cancer
• Epithelial thyroid cancer (nonmedullary), especially follicular thyroid cancer
• Macrocephaly (occipital frontal circumference ≥97th percentile)
• Endometrial carcinoma

Minor criteria

• Other thyroid lesions (eg, adenoma, multinodular goiter)
• Intellectual disability (IQ ≤75)
• Hamartomatous intestinal polyps
• Fibrocystic disease of the breast
• Lipomas
• Fibromas
• Genitourinary tumors (especially renal cell carcinoma)
• Genitourinary malformation
• Uterine fibroids

Take-Home Messages

• As Colon Cancer Awareness Month and Lynch Syndrome Awareness Day (March 22) approach, take a moment to review inherited CRC syndromes—up to 25% of CRC survivors in your practice may need additional risk assessment and possibly genetic testing.
• Historically, inherited CRC has been divided into 2 categories: polyposis and nonpolyposis syndromes. However, as more is learned about these syndromes, it has been found that their phenotypes are diverse and often overlap.
• Identifying individuals with in- herited CRC risk allows for medical interventions for prevention and early detection in the patient and his or her at-risk family members.

References

1. Hearle N, Schumacher V, Menko FH, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res. 2006;12(10):3209-3215.
2. Korsse SE, Harinck F, van Lier MG, et al. Pancreatic cancer risk in Peutz-Jeghers syndrome patients: a large cohort study and implications for surveillance. J Med Genet. 2013;50(1):59-64.
3. Genetics of colorectal cancer (PDQ). National Cancer Institute website. http://www.cancer.gov/can certopics/pdq/genetics/colorectal/HealthProfessional/Page4#Reference4.392. Accessed January 10, 2013.
4. Beggs AD, Latchford AR, Vasen HF, et al. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut. 2010;59(7):975-986.
5. Brosens LA, Langeveld D, van Hattem WA, et al. Juvenile polyposis syndrome. World J Gastroenterol. 2011;17(44):4839-4844.
6. Brosens LA, van Hattem A, Hylind LM, et al. Risk of colorectal cancer in juvenile polyposis. Gut. 2007;56(7):965-967.
7. Haidle JL, Howe JR. Juvenile polyposis syndrome. In: Pagan RA, Bird TD, Dolan CR, et al, eds. GeneReviews. http://www.ncbi.nlm.nih.gov/books/NBK1116/. Accessed January 10, 2013.
8. Pilarski R. Cowden syndrome: a critical review of the clinical literature. J Genet Couns. 2009;18(1):
13-27.
9. Riegert-Johnson DL, Gleeson FC, Roberts M, et al. Cancer and Lhermitte-Duclos disease are common in Cowden syndrome patients. Hered Cancer Clin Pract. 2010;8(1):6.
10. Stanich PP, Owens VL, Sweetser S, et al. Colonic polyposis and neoplasia in Cowden syndrome. Mayo Clin Proc. 2011;86(6):489-492.
11. Eng C. PTEN hamartoma tumor syndrome (PHTS). In: Pagon RA, Bird TD, Dolan CR, et al, eds. GeneReviews. http://www.ncbi.nlm.nih.gov/books/NBK1488/. Accessed January 22, 2013.