JPC SYSTEMIC PATHOLOGY

RESPIRATORY SYSTEM

October 2026 P-M04 (NP)

HISTOPATHOLOGIC DESCRIPTION:

Lung: Approximately 60% of the distal margins of lung are consolidated, characterized by alveoli that are filled and expanded by accumulations of amorphous, homogeneous, amphophilic, anisotropic, hyaline material up to 200 µm in diameter. Often surrounding the hyaline material, there is granulomatous inflammation characterized by macrophages that occasionally contain phagocytized material, rare multinucleated giant cells, and lamellar bands of reactive fibroblasts and collagen (fibrosis), admixed with few plasma cells and lymphocytes. Multifocally there is moderate type II pneumocyte hyperplasia and small clusters of macrophages that contain brown to black, granular, intracytoplasmic pigment (anthracosilicosis). The perivascular and peribronchiolar adventitia is expanded by clear space with ectatic lymphatics (edema) and few lymphocytes and plasma cells.

HISTOPATHOLOGIC DESCRIPTION:

Lung: Multifocally, 60% of lung is characterized by alveoli that are variably filled and expanded with abundant acicular to rhomboid-shaped, intensely eosinophilic crystals that are often intracellular within macrophages and rare multinucleated giant cells. Multifocally, bronchiolar epithelial cytoplasm is expanded by similar eosinophilic crystalline material. In severely affected areas, alveolar septa are thickened by moderate type II pneumocyte hyperplasia and a mild increase in fibrous connective tissue (fibrosis). Occasionally, alveolar macrophages contain intracytoplasmic, light brown, granular to globular pigment (hemosiderin). The perivascular and peribronchiolar adventitia is expanded by clear space with ectatic lymphatics (edema) and low numbers of lymphocytes and plasma cells.

GENERAL DISCUSSION:

Important note: This systemic document presents two unrelated entities, both with amorphous material that accumulates in pulmonary macrophages

Pulmonary hyalinosis

• Occasional incidental finding in older dogs, mostly brachycephalic breeds, especially boxers
• Pulmonary granulomas with PAS-positive bodies

Eosinophilic crystalline pneumonia (ECP)

• Prevalent in wild mice and all domestic mouse strains; B6 (especially moth-eaten mutation), 129, and Swiss strains have higher prevalence and earlier onset; increased prevalence in older mice
• Intrahistiocytic and free, complex crystals composed primarily of acidophilic Ym1 (Chinitase-like protein 3, Chil3) rodent-specific chitinase accumulate within macrophages, alveolae, and airways

PATHOGENESIS:

Pulmonary hyalinosis:

• Unknown, suspected response to chronic lung injury (e.g. pneumoconiosis or experimental radiation pneumonitis)

Eosinophilic crystalline pneumonia:

• May arise spontaneously, as a response to pulmonary inflammation or secondary to pulmonary neoplasia
• Spontaneous form may be related to deficiency in p47phox

TYPICAL CLINICAL FINDINGS:

Pulmonary hyalinosis: None; often incidental finding

Eosinophilic crystalline pneumonia: Dyspnea; fatal in severely afflicted mice, especially B6 mice

TYPICAL GROSS FINDINGS:

Pulmonary hyalinosis: Grayish white to tan, nodular or confluent, firm to gritty, mainly subpleural foci, especially at the narrow ventral margins of the lungs

Eosinophilic crystalline pneumonia: Lobar to diffuse, tan to red discoloration of the non-collapsing lungs

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Pulmonary hyalinosis:

• Multifocal accumulations of noncellular, occasionally birefringent hyaline material or laminated, amphophilic to basophilic material within alveolar macrophages and multinucleated giant cells
• Macrophages and giant cells are often surrounded by plasma cells, lymphocytes, and small amounts of fibrous connective tissue

Eosinophilic crystalline pneumonia:

• Free and intrahistiocytic (including multinucleated giant cells) acicular to rhomboid eosinophilic crystals within lumina of alveoli, alveolar ducts, terminal airways, and bronchiolar glands
• May be accompanied by a mild granulomatous interstitial pneumonia

ADDITIONAL DIAGNOSTIC TESTS:

Pulmonary hyalinosis:

• Histochemical stains:
  • Positive: Material is often PAS positive and diastase resistant, Alcian blue positive

DIFFERENTIAL DIAGNOSIS:

Pulmonary hyalinosis:

• Alveolar microlithiasis: numerous phosphorus-rich lamellated “microliths” or “calcospherites”; extracellular material.
• Pulmonary lipidosis: alveoli filled with foamy macrophages containing endogenous or exogenous lipid
• Corpora amylacea: Are NOT birefringent; concentrically laminated; often have pigmented core; incite only slight inflammation; PAS weakly positive

Eosinophilic crystalline pneumonia:

• Pulmonary histiocytosis: Subpleural distribution
• Alveolar lipoproteinosis (phospholipidosis): Intra-alveolar acellular granular acidophilic or amphophilic material; consists of surfactant proteins and phospholipids; strongly PAS positive; TII pneumocyte hypertrophy; associated with toxic aerosol inhalation; occurs in rats, mice and goats
• Gross: Pneumocystis carinii causes non-collapsing pneumonia in immune compromised mice
• Post-study eosinophilic crystal formation; studies are typically focused on particulate inhalation or dietary, toxicity, or drug metabolism
• Cryptococcus neoformans infection

COMPARATIVE PATHOLOGY:

• Primates
• Eosinophil-related diseases
  • Associated Charcot-Leyden crystals resemble the complex crystals in eosinophilic crystalline pneumonia
• Mice and rats
  • Epithelial Hyalinosis
    • Often associated with ECP; similar hyaline eosinophilic material, composed of Ym2 (Chitinase-like protein 4, Chil4) chitinase, is present in the cytoplasm of olfactory, nasal respiratory, middle ear, trachea, lung, stomach, gall bladder, bile duct, and/or pancreatic duct epithelium
    • Square to rhomboid extracellular crystals may accumulate in associated glands, and cause bile duct and gallbladder dilatation and thickening
    • Crystals composed of Ym1 and Ym2 chitinase

REFERENCES:

1. Barthold SW, Imai DM. Pathology of Laboratory Rodents and Rabbits. 5th ed. Wiley; 2025:3, 107-108, 118.
2. Caswell JL, Williams KJ. Respiratory system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. 7th ed. Vol 2. Elsevier; 2025:504-506.
3. Lopez A, Martinson SA. Respiratory System, Thoracic Cavities, Mediastinum, and Pleurae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. Elsevier; 2022:571-572.