Immune checkpoint inhibitor-induced diarrhea/colitis: Endoscopic and pathologic findings

Table 1 Summary of endoscopic and pathological findings of immune-related diarrhea and colitis

Endoscopic and pathological findings of immune-related diarrhea and colitis
Endoscopic findings
Endoscopic features	(1) Exudates; (2) loss of vascular pattern; (3) granular or edematous mucosa; (4) patch or diffuse erythema; (5) aphtha; (6) ulceration
Inflammatory distribution	(1) Diffuse; (2) patchy (dominantly more diffuse than patchy)
Risk factors for steroid-refractory colitis	(1) Extensively inflamed area (e.g., pancolitis); (2) deeper ulceration
Pathological findings
Anti-CTLA-4 associated colitis	Like autoimmune colitis: (1) lamina propria expansion due to dense lymphoplasmacytic infiltrate; (2) increased intraepithelial lymphocytosis; (3) apoptosis in the crypts; (4) neutrophilic cryptitis and crypt abscess; (5) occasional prominent eosinophilia in the lamina propria; (6) the lack of findings of basal plasmacytosis, crypt distortion, or granulomas
Anti-PD1/anti-PDL1-associated colitis	(1) Expansion of lamina propria by lymphoplasmacytic infiltrate; (2) the increase in intraepithelial neutrophils and neutrophilic crypt abscess; (3) crypt distortion; (4) increased crypt cell apoptosis

CTLA-4: Cytotoxic T-lymphocyte antigen-4; PD1: Programmed cell death protein 1; PDL1: Programmed cell death receptor ligand 1.

Table 2 Definition of diarrhea and colitis based on Common Terminology Criteria for Adverse Events v5.0[32]

CTCAE Term	Definition	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5	CTCAE v5.0 Change
Diarrhea	A disorder characterized by an increase in frequency and/or loose or watery bowel movements	Increase of < 4 stools per day over baseline; mild increase in ostomy output compared to baseline	Increase of 4-6 stools per day over baseline; moderate increase in ostomy output compared to baseline; limiting instrumental ADL	Increase of ≥ 7 stools per day over baseline; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self-care ADL	Life-threatening consequences; urgent intervention indicated	Death	Clarification: Grade 2, 3, Definition
Colitis	A disorder characterized by inflammation of the colon	Asymptomatic; clinical or diagnostic observations only; intervention not indicated	Abdominal pain; mucus or blood in stool	Severe abdominal pain; peritoneal signs	Life-threatening consequences; urgent intervention indicated	Death	Addition: Navigational note; Clarification: Grade 3

ADL: Activities of daily living; CTCAE: Common Terminology Criteria for Adverse Events.

Table 3 Summary of incidence of immune-related diarrhea and colitis

ICPI	Target	Author	Year	Plus other drugs	n	Cancer type	Any gradediarrhea/colitis, n (%)	Grade 3-5diarrhea/colitis, n (%)
Nivolumab	PD-1	Topalian et al[41]	2012	None	296	Solid cancer	33 (11)/ND	3 (1)/ND
		Weber et al[42]	2013	None ipilimumab-naive	34	Melanoma	13 (38.2)/0 (0)	Not observed1
				Ipilimumab-refractory	56		11 (19.6)/0 (0)
		Weber et al[43]	2015	None	268	Melanoma2	30 (11.2)/ND	1 (0.4)/ND
		Larkin et al[44]	2015	None	315	Melanoma	60 (19.2)/4 (1.3)	7 (2.2)/2 (0.6)
		Ferris et al[45]	2016	None	236	SCCHN	16 (6.8)/0 (0)	0 (0)/0 (0)
		Kang et al[46]	2017	None	330	GC/GEJC	23 (7)/2 (1)	2 (1)/1 (< 1)
Pembrolizumab	PD-1	Hamid et al[47]	2013	None	135	Melanoma	27 (20)	1(1)
		Garon et al[48]	2015	None	495	NSCLC	40 (8.1)/ND	3 (0.6)/ND
		Ribas et al[49]	2015	None	361	Melanoma2	32 (8.9)/5 (1.4)	2 (0.6)/2 (0.6)
		Herbst et al[50]	2016	None	690	NSCLC	46 (6.7)/6 (0.9)	2 (0.3)/4 (0.6)
		Ribas et al[51]	2016	None	655	Melanoma	115 (18)/11(2)	6 (1)/7 (1.1)
		Mok et al[52]	2019	None	636	NSCLC	34 (5)/7 (1)	5 (< 1)/4 (< 1)
Ipilimumab	CTLA-4	Weber et al[53]	2008	None	88	Melanoma	ND	5 (5.6)/4 (4.5)
		Weber et al[54]	2009	None	57	Melanoma	20 (35)/ND	10 (18)/ND
				budesonide	58		19 (33)/ND	8 (14)/ND
		Wolchok et al[55]	2010	None	214	Melanoma	58 (27)/ND	11(5.1)/ND
		Hodi et al[56]	2010	None	131	Melanoma	43 (32.8)/10 (7.6)	7 (5.3)/7 (5.3)
				gp100	380		146 (38.4)/20 (5.3)3	17 (4.5)/12(3.2)3
		Robert et al[57]	2011	Dacarbazine	247	Melanoma	81 (32.8)/11 (4.5)	10 (4.0)/5 (2.0)
		Margolin et al[58]	2012	None	72	Melanoma	30 (42)/ND	6 (8.3)/ND
		Kwon et al[59]	2014	None	399	Prostate cancer	199 (51)/27 (7)	64 (16)/18 (5)
		Larkin et al[44]	2015	None	311	Melanoma	103 (33.1)/36 (11.6)	19 (6.1)/27 (8.7)
		Eggermont et al[35]	2016	None	471	Melanoma	194 (41.2)/73 (15.5)	46 (9.8)/39 (8.2)
Ipilimumab plus nivolumab	CTLA4 and PD1	Wolchok et al[60]	2013	None	53	Melanoma	18 (34.0)/5 (9)	3 (6)/2 (4)
		Larkin et al[44]	2015	None	315	Melanoma	138 (44.1)/37 (11.8)	29 (9.3)/24 (7.7)
		Schadendorf et al[61]	2017	None	407	Melanoma	30 (7.4)/40 (9.8)	25 (6.1)/32 (7.9)
		Wolchok et al[62]	2017	None	313	Melanoma	142 (45)/40 (13)	29 (9)/26 (8)
		Hellmann et al[63]	2017	None	77	NSCLC	16 (21)/4 (5.2)	1 (1.3)/3 (3.9)
		Motzer et al[64]	2018	None	547	Renal cell carcinoma	145 (27)/ND	21 (4)/ND
Durvalumab	PD-L1	Antonia et al[65]	2017	None	473	NSCLC	87 (18.3)/ND	3 (0.6)/ND
		Motzer et al[66]	2018	None	475	NSCLC	88 (18.5)/ND	3 (0.6)/ND
		Loibl et al[67]	2019	None	92	Breast cancer	26 (28.3)/ND	3 (3.3)/ND
Atezolizumab	PD-L1	Herbst et al[68]	2014	None	277	Solid tumors or hematological malignancies	29 (10.5)/ND	0 (0)/ND
		Rosenberg et al[69]	2016	None	311	Urothelial carcinoma	24 (8)/3 (1)	1 (0.3)/2 (1)
		Fehrenbacher et al[70]	2016	None	142	NSCLC	ND	ND/2 (1)
		Socinski et al[71]	2018	ABCP	393	NSCLC	70 (17.8)	11 (2.8)
Avelumab	PD-L1	Chung et al[72]	2019	None	150	GC/GEJC	ND/2 (1.3)	ND/1 (0.7)4
		Barlesi et al[73]	2019	None	396	NSCLC	24 (6)/ND	0 (0)/ND

¹Dose-limiting colitis was not observed in this trial;

²Progressed after ipilimumab;

³Immune-related event;

⁴No atezolizumab-related grade 4 but adverse events were reported, but only one patient showed Grade 5 cardiac failure. SCCHN: Squamous cell carcinoma of the head and neck; NSCLC: Non-small-cell lung cancer; ABCP: Atezolizumab plus bevacizumab plus carboplatin plus paclitaxel; GC/GEJC: Gastric/gastroesophageal cancer; ND: Not described.