Clinical and molecular heterogeneity of microsatellite instability-high colorectal cancer in older adults

Table 1 Clinicopathological characteristics of patients with colorectal cancer (n = 573)

Characteristics		n (%)
Age		70 (24-93)
	Male	320 (55.8)
	Female	253 (44.2)
Location	Right	140 (24.4)
	Left	433 (75.6)
Tumor size (mm)	mean ± SD	47.1 ± 22.9
Histological type	Tubular	497 (86.7)
	Poorly differentiated	19 (3.3)
	Mucinous	34 (5.9)
	Medullary	4 (0.7)
	Papillary	16 (2.8)
	Other (goblet cell, endocrine)	3 (0.5)
MSI	MSI-H	43 (7.5)
	MSS	530 (92.5)
MSI-H prevalence by age group	≤ 70 years	22/288 (7.6)
	≥ 71 years	21/285 (7.4)
Lynch syndrome (definitive diagnosis)		15 (2.6)

The characteristics of patients who underwent surgical resection and microsatellite instability/mismatch repair testing are summarized. Continuous variables are expressed as medians (ranges) or mean ± SD, and categorical variables as n (%).

MSI-H: Microsatellite instability-high; MSS: Microsatellite stability.

Table 2 Comparison of clinicopathological characteristics between microsatellite instability-high and microsatellite stability colorectal cancer, median (range)/n (%)

Characteristics	MSI-H (n = 43)	MSS (n = 530)	P value
Age	70 (30-89)	70 (24-93)	0.638
≥ 71 years	21 (48.8)	264 (49.8)	1
Sex			0.206
Male	20 (46.5)	300 (56.6)
Female	23 (53.5)	230 (43.4)
CEA (ng/mL)	3.3 (0.6-107)	3.8 (0.5-1736)	0.061
CA19-9 (U/mL)	13 (2-440)	12 (1-43749)	0.421
Tumor location			< 0.001
Right/left	31/12	109/421
Genetic findings
RAS	31/8/4	270/237/23	0.001
Wild/mut/NA
BRAF V600E	22/16/5	495/7/28	< 0.001
Wild/mut/NA
Pathological findings
Histological type	22/6/10/4/1/0	475/13/24/0/15/3	< 0.001
Tub/por/muc/med/pap/other
Mucinous component			< 0.001
Yes/no	31/12	132/398
Poorly component			0.334
Yes/no	14/29	216/314
Tumor size (mm), mean ± SD	52.0 ± 31.6	46.7 ± 22.1	0.148
T	0/5/9/25/4	5/45/71/326/83	0.458
0/1/2/3/4
Lymph node metastasis			< 0.001
No/yes	34/9	277/253
Distant metastasis			< 0.001
No/yes	42/1	462/68
Infiltration pattern	11/31/1	62/454/14	0.041
Expansive type/not expansive type/NA
Lymphatic invasion	11/32/0	168/358/4	0.631
No/yes/NA
Venous invasion	18/25/0	126/401/3	0.041
No/yes/NA

The characteristics of patients with microsatellite instability-high (n = 43) and microsatellite stability (n = 530) colorectal cancer were compared. For RAS and BRAF mutations, analyses were performed using available case data (n = 546 and n = 540, respectively). Continuous variables are expressed as medians (ranges) or mean ± SD, and categorical variables as n (%).

MSI-H: Microsatellite instability-high; MSS: Microsatellite stable; CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9.

Table 3 Clinicopathological characteristics of older and younger patients with microsatellite instability-high colorectal cancer, mean ± SD/median (range)

Characteristics	≥ 71 years (n = 21)	≤ 70 years (n = 22)	P value
Age	78.8 ± 5.3	56.8 ± 10.2	< 0.001
Sex			0.763
Male/female	9/12 (57.1)	11/11
CEA (ng/mL)	4.6 (1.0-107)	2.1 (0.6-36.3)	0.02
CA19-9 (U/mL)	17 (2-440)	10.5 (2-265)	0.458
Tumor location			0.00153
Right/left	20/1	11/11
RAS	18/3/0	13/5/4	0.0864
Wild/mut/NA
BRAF V600E	7/14/0	16/2/4	< 0.001
Wild/mut/NA
Histological type	8/3/6/3/1/0	14/3/4/1/0/0	0.422
Tub/por/muc/med/pap/other
Mucinous component			1
Yes/no	15/6	16/6
Poorly component			0.203
Yes/no	9/12	5/17
Tumor size (mm)	54.1 ± 30.6	49.9 ± 33.1	0.663
T	1/5/12/3	4/4/13/1	0.454
1/2/3/4
Lymph node metastasis			0.281
No/yes	15/6	19/3
Distant metastasis			0.488
No/yes	20/1	22/0
Infiltration pattern	5/15/1	6/16/0	1
Expansive type/not expansive type/NA
Lymphatic invasion	3/18	8/14	0.162
No/yes
Venous invasion	8/13	10/12	0.76
No/yes
Lynch syndrome, n (%)	1 (4.8)	14 (63.6)	< 0.001

Patients with microsatellite instability-high colorectal cancer were stratified into older group (≥ 71 years, n = 21) and younger (≤ 70 years, n = 22) groups. Continuous variables are expressed as median (range) or mean ± SD, and categorical variables as n (%).

CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9.

Table 4 Clinical and molecular profiles of older patients with microsatellite instability-high colorectal cancer showing non-typical sporadic patterns

Case	1	2	3	4	5	6	7
Age (years)	80	76	72	79	85	76	80
Sex	Male	Male	Female	Female	Female	Male	Male
Lynch syndrome	Not evaluated	Not evaluated	Yes	No	No	Not evaluated	Not evaluated
Primary site	Lower rectum	Cecum	Cecum	Cecum	Trans	Trans	Trans
Histological type	Tub2	Tub1	Pap	Muc	Tub2	Muc	Muc
Presumed causative genes	MSH2	NA	MSH6	MLH1	MLH1	MLH1	MLH1
BRAF V600E	WT	WT	WT	WT	WT	WT	WT
RAS	Mut	Mut	Mut	WT	WT	WT	WT
Family history	Mother colon cancer (unknown)	Father colon cancer (unknown), brother liver cancer, cholangiocarcinoma (unknown)	Father: Lung cancer, laryngeal cancer; mother: Gastric cancer (70-79 years); sister: Sigmoid colon cancer (50-59 years)	Mother endometrial cancer (40-49 years). Father lung cancer	Daughter: Breast cancer (60-69 years)	None	Mother and brother: Cancer death (origin, year unknown)
Past cancer history	None	None	40-49 years rectal cancer; 60-69 years endometrial cancer	None	None	None	None
Amsterdam II criteria	Not met	Not met	Not met	Not met	Not met	Not met	Not met
Revised Bethesda Guidelines	Not evaluated	Not evaluated	Met	Met	Not met	Not met	Not evaluated
Remarks				Excluded by genetic testing	Excluded by genetic testing
Recurrence	Dissemination, CR by ICI	None	None	Dissemination, CR by ICI	Liver metastasis (synchronous), CR by ICI	None	None
Prognosis	Alive (61.3 months)	Alive (52.7 months)	Alive (24.1 months)	Alive (74.2 months)	Alive (75.4 months)	Alive (52.7 months)	Alive (42.3 months)

Detailed clinical and molecular profiles of older patients (≥ 71 years) with microsatellite instability-high colorectal cancer are presented, excluding those with both MLH1 deficiency and BRAF mutations. Lynch syndrome was evaluated by immunohistochemistry, genetic testing, and clinical criteria. Family history was based on patient recall. Three cases could not be assessed using the Revised Bethesda Guidelines because of insufficient information.

CR: Complete response; ICI: Immune checkpoint inhibitors.