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Ambe et al. Mini-invasive Surg 2018;2:37 I http://dx.doi.org/10.20517/2574-1225.2018.45 Page 9 of 13

Since PJS is not associated with complete penetrance with regard to CRC there is no indication for prophy-
lactic surgery. The indications for surgical management are therefore usually symptom related. This is es-
pecially true for surgical management of small bowel polyps. The small bowel must be monitored regularly,
preferably with video endoscopy and polyps with a size > 1.5 cm should be prophylactically removed, pref-
erably via doubl-balloon endoscopy. Surgical resection of large colonic polyps is indicated following failure
of endoscopic polypectomy. Equally, severe dysplasia and malignant transformation constitute absolute
indications for surgery. The principles of oncologic resection should be followed when dealing with CRC in
a patient with PJS.

PPAP
PPAP is a dominantly inherited condition caused by germline mutations in the DNA polymerases POLE
[62]
and POLD . These mutations have been identified in families with a history of unexplained adenomatous
polyposis and CRC [63,64] . Extra-colonic manifestations including endometrial, brain and duodenal tumors
[65]
have been reported in association with PPAP . Typically, a large number of polyps (up to a few hundreds)
[66]
are present by the age of 35-40 years . Therefore, PPAP should be considered if clinical and endoscopic
aspects of FAP, aFAP or MAP are present in the absence of the respective mutations following genetic
analysis. Also and interestingly, this syndrome may clinically be consistent with LS, including MSI in the
neoplastic tissue.

Estimated risks of PPAP - associated CRC patients with POLE mutations by the age of 70 years were re-
[67]
ported in a recent publication by Buchanan et al. to be 40% for males and 32% for females. The corre-
sponding risks in patients with POLD mutations were 63% in males and 52% in females. These estimates
must be interpreted with caution due to limited data on this newly described syndrome.

An evidence based management algorithm for PPAP is so far not available. Thus surveillance and surgi-
cal management of patients with PPAP should follow the principles of “best clinical practice” analogue to
similar syndroms (aFAP and MAP and LS).

NTHL1-ASSOCIATED POLYPOSIS
NTHL1-associated polyposis (NAP) is a recessively inherited polyposis syndrome caused by mutations in
[68]
base excision repair gene NTHL1 . Homozygous germline mutations in NTHL1 have been identified in
[69]
cases with a family history of adenomatous polyposis and CRC . Besides, extra-colonic manifestations
[70]
might be present . More insight is needed to be able to define the spectrum of presentation and the risk of
CRC in patients with NAP. To date, surgical management is symptom related, with no indication for pro-
phylactic surgery at this time.

MSH3 POLYPSIS
Adenomatous polyposis has recently been described in connection with biallelic germline mutations in
[71]
MSH3, an MMR gene . The resulting CRC demonstrates microsatellite instability. Although data on this
new polyposis syndrome are limited, surveillance and management should follow the principles of “best
clinical practice” analogue to LS. Clinically, the phenotype might be indistinguishable from FAP and fol-
low the same (individualized) management recommendations.

DISCUSSION
The management of patients with hereditary predisposition for CRC warrants a good understanding of the
underlying syndrome. The syndrome-associated risk for CRC must be considered, especially in the event
of a CRC and required surgery. Besides, heterogeneity in mutational status as well as clinical presentation