Intraepithelial lymphocytosis in architecturally preserved proximal small intestinal mucosa: an increasing diagnostic problem with a wide differential diagnosis

Arch Pathol Lab Med. 2006 Jul;130(7):1020-5. doi: 10.5858/2006-130-1020-ILIAPP.


Context: An increased intraepithelial lymphocyte density in an architecturally normal proximal small intestinal mucosal biopsy is a common finding facing surgical pathologists dealing with gastrointestinal biopsy specimens. Approximately 1% to 2% of all proximal small intestinal biopsies will show this change. It is increasingly recognized by surgical pathologists that gluten-sensitive enteropathy is an important cause of this pattern; however, gluten-sensitive enteropathy accounts for the minority of all cases. A wide variety of immunologic stimuli can raise intraepithelial lymphocyte numbers. Among the other common associations are enteric infection, autoimmune disease, drugs, and gastric Helicobacter infection.

Objective: To outline the causes of intraepithelial lymphocytosis, to highlight the importance and the difficulties faced in establishing gluten-sensitive enteropathy as the cause, and to aid the surgical pathologist in the routine sign out of these cases.

Data sources: A review of the literature detailing the causes or associations of proximal small intestinal intraepithelial lymphocytosis is presented.

Conclusions: Increased lymphocyte numbers in the epithelium of architecturally preserved proximal small intestinal biopsies is a morphologic feature associated with a broad differential diagnosis.

Publication types

  • Review

MeSH terms

  • Autoimmune Diseases / diagnosis
  • Biopsy
  • Celiac Disease / diagnosis
  • Diagnosis, Differential
  • Drug-Related Side Effects and Adverse Reactions / diagnosis
  • Food Hypersensitivity / diagnosis
  • Glutens / immunology
  • Humans
  • Intestinal Diseases / diagnosis*
  • Intestinal Diseases / etiology
  • Intestinal Diseases, Parasitic / diagnosis
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / pathology*
  • Intestinal Neoplasms / diagnosis
  • Intestine, Small / immunology
  • Intestine, Small / pathology*
  • Lymphocytes / immunology
  • Lymphocytes / pathology
  • Lymphocytosis / etiology
  • Lymphocytosis / pathology*


  • Glutens