Histopathological features of colitis due to immunotherapies

Magali Svrcek, H-ECCO Member

Magali Svrcek
Magali Svrcek

Immune checkpoints (ICK) are downregulators of T cell immunity. Immune checkpoint inhibitors (ICKi), by blocking the co-inhibitory receptors on T cells to activate their cytotoxic immune function, have become a major therapeutic tool in oncology, notably for the treatment of metastatic melanoma, non-small cell lung carcinoma, renal cell carcinoma, urothelial carcinoma and mismatch repair (MMR) deficient/microsatellite-unstable tumours. In particular, therapeutic monoclonal antibodies have emerged against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), which primarily inhibits T cell activation, and programmed cell death 1 (PD-1), which limits the effector function of activated T cells in the periphery. Food and Drug Administration-approved ICKi include ipilimumab (CTLA-4 inhibitor), pembrolizumab and nivolumab (anti-PD-1) and atezolizumab (anti-PD-L1).

By unbalancing the immune system, ICK blockade favours the development of autoimmune manifestations that most commonly affect the skin, gastrointestinal tract, liver, endocrine organs and lungs. Enterocolitis is among the most frequent immune-related adverse events associated with anti-CTLA-4, with severe (grade III and IV) diarrhoea in around 10% of cases [1]. Significant cases of colitis with perforation have been reported following treatment with anti-CTLA-4. However, despite being better tolerated than anti-CTLA-4, anti-PD-1 can also induce colitis.

The histological features of ICKi-associated colitis show a spectrum of patterns of injury. Moreover, there is significant overlap between ICKi-associated colitis and other colitides, such as infection, Inflammatory Bowel Disease (IBD), graft-versus-host disease and other drug-related colitides, making the differential diagnosis challenging, especially in the absence of correlation with clinical history, in particular medication history. The pathological features of anti-CTLA-4-associated colitis have been examined in some detail, and commonly consist of autoimmune-like colopathy, including (i) dense, lymphoplasmocytic lamina propria expansion; (ii) increased intraepithelial lymphocytes and (iii) increased apoptosis and cryptitis, but few or no features of chronicity (lack of basal lymphoplasmocytic infiltrate, architectural distortion or granulomas) [2, 3]. There is little information regarding the pathological features of anti-PD-1 colitis. Briefly, there are two major patterns of colitis: (i) anti-PD-1 colitis most commonly presents as an active colitis with neutrophilic crypt microabscesses and with prominent crypt epithelial cell apoptosis and crypt atrophy/dropout. These latter features are reminiscent of other colitides with prominent apoptosis, such as acute graft-versus-host disease or certain drug-induced colitides; (ii) less commonly, anti-PD-1 colitis exhibits a lymphocytic colitis pattern, a finding that has been more associated with anti-CTLA-4 [4–6]. A single case of an-anti-PD-1-associated collagenous colitis has also been reported [7]. Importantly, features of IBD-type chronicity can be seen in patients with recurrent anti-PD-1 colitis, which may develop many months after the patient has stopped receiving anti-PD-1 therapy [5].

As the use of ICKi continues to increase, it is essential for pathologists to be able to recognise colitis due to these therapies when evaluating colon biopsies so that an adequate therapy can be promptly initiated (withdrawal of ICKi and appropriate administration of immunosuppressive agents). Areas of diagnostic difficulty remain, in particular the histological features from patients with prior documented IBD and patients receiving both anti-PD-1 and anti-CTLA-4, either sequentially or in combination. Further investigation will address these complex issues.


  1. Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139–48.
  2. Oble DA, Mino-Kenudson M, Goldsmith J, et al. Alpha-CTLA-4 mAb-associated panenteritis: a histologic and immunohistochemical analysis. Am J Surg Pathol. 2008;32:1130–7.
  3. Assarzadegan N, Montgomery E, Anders RA. Immune checkpoint inhibitor colitis: the flip side of the wonder drugs. Virchows Arch. 2018;472:125–33.
  4. Gonzalez RS, Salaria SN, Bohannon CD, et al. PD-1 inhibitor gastroenterocolitis: case series and appraisal of 'immunomodulatory gastroenterocolitis'. Histopathology. 2017;70:558–67.
  5. Chen JH, Pezhouh MK, Lauwers GY, Masia R. Histopathologic features of colitis due to immunotherapy with Anti-PD-1 antibodies. Am J Surg Pathol. 2017;41:643–54.
  6. Gonzalez RS, Salaria SN, Bohannon CD, et al. PD-1 inhibitor gastroenterocolitis: case series and appraisal of 'immunomodulatory gastroenterocolitis'. Histopathology. 2017;70:558–67.
  7. Baroudjian B, Lourenco N, Pagès C, et al. Anti-PD1-induced collagenous colitis in a melanoma patient. Melanoma Res. 2016;26:308–11.

Posted in ECCO News, Volume 14, Issue 2, Committee News, H-ECCO