Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2020 for the Clinical Practice of Hereditary Colorectal Cancer

Abstract

Hereditary colorectal cancer (HCRC) accounts for < 5% of all colorectal cancer cases. Some of the unique characteristics commonly encountered in HCRC cases include early age of onset, synchronous/metachronous cancer occurrence, and multiple cancers in other organs. These characteristics necessitate different management approaches, including diagnosis, treatment or surveillance, from sporadic colorectal cancer management. There are two representative HCRC, named familial adenomatous polyposis and Lynch syndrome. Other than these two HCRC syndromes, related disorders have also been reported. Several guidelines for hereditary disorders have already been published worldwide. In Japan, the first guideline for HCRC was prepared by the Japanese Society for Cancer of the Colon and Rectum (JSCCR), published in 2012 and revised in 2016. This revised version of the guideline was immediately translated into English and published in 2017. Since then, several new findings and novel disease concepts related to HCRC have been discovered. The currently diagnosed HCRC rate in daily clinical practice is relatively low; however, this is predicted to increase in the era of cancer genomic medicine, with the advancement of cancer multi-gene panel testing or whole genome testing, among others. Under these circumstances, the JSCCR guidelines 2020 for HCRC were prepared by consensus among members of the JSCCR HCRC Guideline Committee, based on a careful review of the evidence retrieved from literature searches, and considering the medical health insurance system and actual clinical practice settings in Japan. Herein, we present the English version of the JSCCR guidelines 2020 for HCRC.

Keywords: Familial adenomatous polyposis; Guidelines; Hereditary colorectal cancer; Lynch syndrome.

Fig. 1

Percentage of genetically predisposed colorectal cancers among all colorectal cancers. PJS Peutz–Jeghers syndrome, JPS juvenile polyposis syndrome, CS/PHTS Cowden syndrome/PTEN hamartoma tumor syndrome

Fig. 2

Tumorigenesis mechanism in the two-hit theory of tumor suppressor genes by Knudson

Fig. 3

Representative tumorigenesis mechanism of FAP of Lynch syndrome

Fig. 4

Risk assessment of hereditary colorectal cancer

Fig. 5

Flowchart of the diagnosis of hereditary colorectal polyposis. FAP familial adenomatous polyposis, AFAP attenuated FAP, MAP MUTYH-associated polyposis, PPAP polymerase proofreading-associated polyposis, PJS Peutz–Jeghers syndrome, JPS juvenile polyposis syndrome, CS/PHTS Cowden syndrome/PTEN hamartoma tumor syndrome, SPS serrated polyposis syndrome

Fig. 6

Severe/profuse/dense FAP

Fig. 7

Sparse FAP

Fig. 8

Fundic gland polyposis

Fig. 9

Gastric adenoma (left, depressive type; right, elevated type)

Fig. 10

Ampullary adenoma and duodenal adenomas

Fig. 11

Histology of FAP-associated duodenal adenomas. a Low-grade adenoma: the tumor glands are rather uniform and the adenomatous epithelial cells show basally oriented, elongated nuclei. b Intramucosal carcinoma: tumor glands show significant irregularity, nuclear stratification, and occasional prominent nucleoli. Note that high-grade dysplasia in the Spigelman classification includes non-invasive intramucosal carcinoma in the Japanese classification. c Tubular adenoma: this lesion shows a relatively regular tubular architecture. d Tubulo-villous adenoma: this lesion partially exhibits villous architecture, composed of fibrovascular cores lined by dysplastic epithelium

Fig. 12

Evaluation of duodenal adenoma by revised Spigelman’s classification

Fig. 13

Surveillance of duodenal adenoma based on revised Spigelman’s classification

Fig. 14

Intra-abdominal desmoid tumor

Fig. 15

Disease classification and treatment plans for intra-abdominal desmoid tumors

Fig. 16

Dental abnormalities (unerupted teeth)

Fig. 17

Congenital hypertrophy of the retinal pigment epithelium

Fig. 18

Surgical procedures for patients with FAP (Side Memo 7: nomenclature of operative procedures)

Fig. 19

Example of description of pedigree for FAP (Appendix: Principles for writing and reading pedigrees for an outline of description method). Symbol annotation of the pedigree. E+: affected individual with positive test (in this case, pathogenic variant detected with genetic testing of the APC gene). : asymptomatic/presymptomatic individual with pathogenic variant. : personal numbers can be assigned to the upper right of individuals

Fig. 20

Flowchart for prophylactic surgical procedure in patients with FAP

Fig. 21

Diagnostic process for Lynch syndrome. MSI microsatellite instability, IHC immunohistochemistry, MSI-H high-frequency MSI, MSI-L low-frequency MSI, MSS microsatellite stability, MMR mismatch repair, VUS variant of uncertain significance. *Does not continue to genetic testing, ^†Only MLH1 methylation testing may be performed without BRAF V600E testing. ^‡Loss of MMR protein(s) expression probably due to somatic two hits

Fig. 22

Family history fulfilling Amsterdam criteria II [215] (Appendix: Principles of writing and reading pedigrees). a Multiple family members with colorectal cancer. b Multiple family members with colorectal cancer and Lynch syndrome-associated extracolonic cancers

Fig. 23

Histologic characteristics of MSI-H colorectal cancer. A Tumor infiltrating lymphocytes. Numerous intra-epithelial lymphocytes showing clear halos. B Medullary carcinoma. Tumor showing a solid growth pattern without glandular structure. C Mucinous carcinoma. Prominent extracellular mucin noted. D Crohn’s-like lymphocytic reaction. Characterized by peritumoral lymphocytic aggregates

Fig. 24

Example of MSI analysis using the Promega Panel. All five mononucleotide repeat markers (BAT-26, NR-21, BAT-25, MONO-27, NR-24) showed different microsatellite length, indicating to be MSI-H

Fig. 25

MSH2 expression in normal colon mucosa. Strong staining is noted in the germinal center of a lymphoid follicle and at the bottom of glands

Fig. 26

Immunohistochemistry for mismatch repair proteins in the colorectal cancer specimen resected from a patient with Lynch syndrome with a germline MLH1 variant. Loss of MLH1 (a) and PMS2 (c) and retention of MSH2 (b) and MSH6 (d). Stromal cells served as internal positive controls

Fig. 27

Management of individuals without a definitive diagnosis of Lynch syndrome

Fig. 28

Management of families (relatives) of patients who have been definitively diagnosed with Lynch syndrome

Fig. 29

Symbols for family pedigrees

Fig. 30

The first-, second-, or third-degree relatives of the proband

Fig. 31

The gene structure and variant nomenclature