The incidence of the PJS is difficult to evaluate, since even in countries with a nationwide adenomatous polyposis registry little attention has been paid to hamartomatous polyposis syndromes, and careful registration and evaluation of this group of patients have not been performed. Based on the experience of polyposis registries, PJS is clearly more rare than familial adenomatous polyposis, which is believed to be the most common polyposis syndrome, with a carrier frequency of 1 in 5000 to 10,000 live births (Phillips et al, 27). A frequency of 1 in 8300 to 1 in 29,000 live births has been estimated (Finan, Ray, 10). The relatively frequent complications due to bowel obstruction today can be adequately treated surgically. Thus the syndrome is likely to have a smaller impact on biological fitness now than some decades ago.
Since the molecular background of the PJS has been revealed recently, it is likely that more attention will be focused on PJS, and more light may be shed on the issue of its incidence. Molecular analyses also may reveal cases that do not fulfill the present diagnostic criteria. One difficulty is that although PJS is considered an autosomal dominant disease, patients frequently lack a PJS family history. Future molecular analyses should reveal the background of such patients, but initial results suggest that germ-line LKB1 defects also play a role in "sporadic" PJS (Ylikorkala et al, 34). Interestingly, de novo mutations appear to be frequent in PJS patients without a family history (Westerman et al, 33). This may reflect the improved biologic fitness of PJS patients, and PJS in the future may be somewhat more common through this effect.
Diagnostic Criteria and Histologic Features
PJS has two clinical hallmarks: mucocutaneous melanin pigmentation and hamartomatous intestinal polyposis. The pigmentation is most often present in and around the mouth but also on hands and feet and axillary pits (Phillips et al, 27). The significance of the pigmentation as a key feature of the syndrome is clear, but the presence of similar melanin spots in up to 15 percent of the normal population hampers the use of this sign in clinical practice (Westerman et al, 32). The degree of pigmentation varies greatly, even within a family (Fig. 34-1). In a subset of the PJS patients the pigmentation diminishes with age, and some never display it.
A. Typical perioral pigmentation in a Peutz-Jeghers patient. B, C. Perioral pigmentation in a 31-year-old patient (B) and his 6-year-old daughter (C) illustrates the variation in pigmentation even within a family and the difficulty in relying on pigmentation in PJS diagnostics.
The presence of intestinal Peutz-Jeghers polyposis is the diagnostic feature of PJS. Peutz-Jeghers polyps are hamartomatous lesions that have pathognomonic histologic characteristics (Fig. 34-2). In contrast to juvenile polyps, for example, Peutz-Jeghers polyps display a core of a prominent tree-like smooth muscle cell structure that extends into the lamina propria. The overlying folded epithelium contains histologically normal cells without features of neoplasia (Phillips et al, 27). The number of polyps in PJS is low compared with familial adenomatous polyposis and varies greatly from zero to dozens of lesions. A single Peutz-Jeghers polyp without a PJS family history or other features of the syndrome may well be a sporadic lesion. Although the polyps may occur anywhere in the gastrointestinal tract, the small intestine is the most commonly affected part of the bowel. PJS patients commonly also display hyperplastic and adenomatous polyps, but the diagnosis is based on the pathognomonic histology of Peutz-Jeghers polyps. Neoplastic changes sometimes may arise in the Peutz-Jeghers polyps themselves (De Facq et al, 7; Defago et al, 8; Hizawa et al, 16).
A. A hamartomatous Peutz-Jeghers polyp. B. Histologic view of the lesion. C. Microscopic view. Note the smooth muscle cell core of the polyp.
While it is clear that pigmentation without any other signs of the syndrome is not a good indicator of PJS (see Fig. 34-1) and that, similarly, one Peutz-Jeghers polyp without family history of PJS may be a sporadic lesion, it is less clear how one should evaluate the family members of diagnosed PJS patients. A recent study that identified a locus predisposing to PJS suggested that all individuals carrying the affected haplotype had one of the two cardinal features of PJS (Hemminki et al, 14). This was slightly unexpected, since PJS-like pigmentation is not rare in the normal population (Westerman et al, 32), and many of the relatives displaying pigmentation did not display a prominent polyposis (Hemminki et al, 14). This emphasizes that pigmentation as evaluated by an experienced physician is a useful clue, but nevertheless, pigmentation as the only sign should be interpreted with caution.
The ultimate diagnostic laboratory test is the detection of a LKB1 germ-line mutation (Hemminki et al, 13). The mutations are usually truncating; this facilitates interpretation of the results. When a mutation in a particular family has been detected, the relatives who are willing to undergo genetic testing can be analyzed with reasonable efficiency.
The different polyposis syndromes have overlapping clinical features. Polyps of mixed histologic subtypes (e.g., adenoma, hyperplastic polyp, hamartoma) are seen relatively commonly in PJS patients, and careful histologic evaluation of the removed lesions is essential. The striking phenotype of familial adenomatous polyposis with typically hundreds or thousands of adenomas is usually easily distinguishable from the other polyposis syndromes including PJS. The two other major hamartomatous polyposis syndromes, Cowden syndrome and juvenile polyposis, are more difficult in this regard. Detection of multiple lesions displaying the pathognomonic polyp core with arborizing smooth muscle pattern forms the basis of the PJS diagnosis. It is still to be determined which number of polyps should be considered suggestive of PJS. The required number also depends on the presence or absence of a family history of PJS. In a patient without any evidence of PJS with one Peutz-Jeghers polyp, the finding may well be sporadic. However, if the patient has a family history of PJS, PJS is likely.