What is the histology of epithelial hyperplasia and what drives its development?

Epithelial Hyperplasia: Histologic Features and Pathophysiologic Drivers

Histologic Appearance

Epithelial hyperplasia is characterized by an increased number of epithelial cells without cytologic atypia, maintaining normal cellular architecture and organization. The specific histologic features vary by anatomic location and underlying etiology.

General Histologic Features

• Increased cell number with preservation of normal cellular polarity and architecture distinguishes hyperplasia from dysplasia or neoplasia 1
• Cells remain cuboidal, columnar, ciliated, or mucous in type depending on the tissue of origin, without nuclear atypia 1
• The epithelium maintains its normal stratification pattern and relationship to the basement membrane 1

Site-Specific Histologic Patterns

Respiratory Tract:

• Diffuse or focal increase in respiratory epithelial cell numbers, often with luminal protrusions forming papillae 1
• Mucous (goblet) cell metaplastic hyperplasia may occur as a variant, where respiratory epithelium is replaced by mucous cells in single or pseudostratified layers 1
• Normal bronchiolar and alveolar architecture is preserved 1

Gastrointestinal Tract:

• Basal zone hyperplasia occupying more than 20% of the epithelial thickness, commonly seen in esophageal conditions 1
• Architectural changes include crowding of glands, mucosal thickening, and crypt lengthening with excessive budding 1
• Surface and crypts lined by tall columnar cells with mucus differentiation, though nuclei remain basally located without stratification (distinguishing it from dysplasia) 1

Glomerular Epithelium:

• Hypertrophy and hyperplasia of glomerular epithelial cells overlying collapsed capillary tufts, some containing intracytoplasmic protein resorption droplets 1, 2
• May form pseudocrescents in severe cases 1

Neuroendocrine Cells:

• Clusters of uniform small cells with scant cytoplasm and round to oval nuclei with dense speckled chromatin, thickening bronchiolar walls 1
• Requires immunohistochemical confirmation with synaptophysin, CGRP, or chromogranin 1

Pathophysiologic Drivers of Hyperplasia

Regenerative/Reparative Response

Environmental injury triggers epithelial proliferation as a physiologic repair mechanism, representing the most common driver of epithelial hyperplasia.

• Toxic agent exposure (including tobacco smoke) causes epithelial damage requiring repair through controlled proliferation 1
• The key distinguishing features of regenerative hyperplasia are absence of progression to neoplasia and presence of inflammation/necrosis from the inciting agent 1
• Reactive oxygen species generated during inflammation cause DNA damage that may perpetuate the hyperplastic response 1

Chronic Inflammation

• Prolonged inflammatory states drive sustained epithelial proliferation through complex intercellular signaling 1
• In inflammatory bowel disease, hyperplasia develops only in areas with chronic inflammation and represents a response to ongoing tissue injury 1
• The communication system involves growth factors, cytokines, peptides, and lipid metabolites that regulate proliferation, migration, and apoptosis 1

Viral Infection

• Human papillomavirus (HPV) types 13 and 32 specifically drive focal epithelial hyperplasia (Heck's disease) in oral mucosa 3, 4, 5
• Viral-induced hyperplasia results from viral oncoproteins disrupting normal cell cycle regulation while maintaining differentiation 3, 4

Drug-Induced Mechanisms

• Tenofovir nephrotoxicity causes proximal tubular epithelial irregularity with atypical nuclei, though this represents toxic injury rather than true hyperplasia 1
• The mechanism involves mitochondrial dysfunction with giant mitochondria formation 1

Genetic Susceptibility

• Field cancerization creates areas where histologically normal-appearing tissue harbors molecular abnormalities, predisposing to hyperplastic changes 1
• Genetic factors including MUC5B promoter variants and telomere biology gene mutations influence susceptibility to epithelial proliferative responses 1

Critical Distinction: Hyperplasia vs. Dysplasia

The absence of cytologic atypia is the fundamental feature separating benign hyperplasia from premalignant dysplasia.

• Hyperplasia maintains normal nuclear-to-cytoplasmic ratio, nuclear polarity, and chromatin pattern 1
• Dysplasia exhibits hyperchromatic enlarged nuclei, nuclear crowding, stratification, and loss of polarity 1
• In regenerative hyperplasia, mitotic figures remain confined to basal layers, unlike dysplasia where mitoses appear in upper epithelial layers 1

Clinical Pitfall

Pseudoepitheliomatous hyperplasia (PEH) can closely simulate squamous cell carcinoma histologically and requires careful evaluation to avoid misdiagnosis 6. PEH occurs with prolonged inflammation, chronic infection, or in association with cutaneous neoplasms, and is distinguished by maintenance of cellular maturation and absence of true invasion 6.