JPC SYSTEMIC PATHOLOGY

RESPIRATORY SYSTEM

September 2023

P-N02

 

Signalment (JPC #1945165): Mouse 

 

HISTORY: Unknown

 

HISTOPATHOLOGIC DESCRIPTION: Lung: Expanding the pulmonary parenchyma, compressing adjacent alveoli and bronchioles, and elevating the pleura is an unencapsulated, well demarcated, moderately cellular, multilobular neoplasm composed of cuboidal to columnar cells arranged in cords and papillary projections supported by a fine fibrovascular stroma. Neoplastic cells have distinct cell borders, a moderate amount of a finely granular, eosinophilic cytoplasm, and irregularly round, centrally located nuclei with coarsely stippled chromatin and 1-3 small basophilic nucleoli. Mitotic figures are <1 per 10 HPF (2.37mm²). In the adjacent pulmonary parenchyma, alveoli are filled with macrophages and multinucleated giant macrophages which are often packed with acicular to rhomboid-shaped, intensely eosinophilic crystals; similar macrophages are occasionally admixed with neoplastic cells. Multifocally, bronchiolar epithelial cytoplasm is expanded by similar eosinophilic crystalline material. Alveolar septa are mildly expanded by low numbers of neutrophils and macrophages. Multifocally, there are peribronchiolar and perivascular aggregates of lymphocytes and plasma cells (mild BALT hyperplasia).

 

MORPHOLOGIC DIAGNOSIS: 1. Lung: Pulmonary adenocarcinoma, mouse, murine.

2. Lung: Alveolitis, granulomatous, multifocal, moderate, with abundant intrahistiocytic and intraepithelial eosinophilic crystalline material (acidophilic macrophage pneumonia).

 

GENERAL DISCUSSION 

• NOTE: This systemic focuses on non-viral pulmonary neoplasms; see P-V16 for retrovirus induced ovine pulmonary carcinoma
• In mice, pulmonary adenoma/adenocarcinoma is very common, especially A strain mice, and can be further subtyped as solid, papillary and lepidic
  1. Also common in: Outbred Swiss, FVB, BALB/c, 129, B6:129 hybrids
  2. Onset may be enhanced by viral infections (i.e., Sendai virus)
• In domestic species, primary pulmonary neoplasms are generally uncommon, however they are most common in dogs and cats and rare in other domestic species; most are malignant and typically of epithelial origin

 

PATHOGENESIS:  

• Highest incidence in strain A mice due to mutation in K-RAS proto-oncogene
• Arise from club cells or type II pneumocytes in the bronchioloalveolar region 
• In cats, oncogene HER2 is overexpressed (Muscatello et al, Vet Pathol 2021)
• There is increased Foxp3 T-reg cells and CCR4/CCL17 expression in canine pulmonary adenocarcinoma (Maeda et al, Vet Pathol 2020)

 

TYPICAL CLINICAL FINDINGS:

• Dyspnea, cough, lethargy, anorexia, weight loss
• Mice: Often found incidentally at necropsy
• Dogs: Average 11 years old; may detect paraneoplastic syndromes such as hypercalcemia, endocrinopathies, and pulmonary hypertrophic osteopathy 
• Cats: Average 12 years old; Persian’s predisposed; often subclinical and instead present with clinical signs related to metastasis to other viscera, brain, muscle, eye, bone or skin, especially lameness (due to metastasis to digits)
  1. Has an unusual pattern of metastasis in cats; memory aides include “feline lung-digit (FLD) syndrome” or “feline muscle, ocular, digit, aorta, lung (MODAL) syndrome”

 

TYPICAL GROSS FINDINGS:

• Firm, white-tan-gray, soft to firm, bulging, well circumscribed nodule(s) within the lung parenchyma
• +/- regions of necrosis and hemorrhage, creating a “craterous” or “umbilicated” appearance
• +/- pleural effusion, intra-pleural nodules 

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• Adenomas are well demarcated, compressive neoplasms with bland cuboidal to columnar often non-ciliated epithelial cells and rare mitoses
• Carcinomas are invasive neoplasms with pleomorphic epithelial cells and non-lepidic growth patterns and subclassified by level of invasion:  
  • Note that invasion indicates invasion of neoplastic cells into tumor stroma, vessels or pleura, NOT into adjacent lung tissue; will see fibroblastic/myofibroblastic (desmoplastic) reaction containing neoplastic cells 
  • Adenocarcinoma in situ: Small (<3cm in domestic species) with neoplastic cells continuously lining the surface of pre-existing alveoli (lepidic) with crowding or loss of stratification; typically no necrosis, invasion, or atypia present 
  • Minimally invasive adenocarcinoma: Small (<3cm in domestic species) solitary lesion, but with a small foci (<0.5cm) of invasion into tumor stroma or pleura
  • Invasive adenocarcinoma: Evidence of invasion in area >0.5cm
• It can be difficult to determine the origin of primary lung neoplasms – conducting component (bronchogenic carcinoma), transitional component (bronchiolar carcinoma), air exchange component (alveolar carcinoma), or bronchial glands (bronchial gland carcinoma); thus, all are called pulmonary adenoma/adenocarcinoma and further subclassified by predominant histologic pattern:
  • Lepidic: Cuboidal neoplastic cells line pre-existing alveolar septa with minimal architecture distortion and little to no stromal invasion; may see “finger-like ingrowths,” but anything with secondary or tertiary branching is papillary; special stains to identify elastic fibers (remnant of alveolar wall) confirms it  
  • Papillary: Loss of alveolar pattern with formation of arborizing fronds lined by columnar neoplastic cells and supported by eosinophilic stroma 
  • Micropapillary: Neoplastic cells forming “tiny finger-like” protrusions into spaces within the mass, but lacking the papillary fibrovascular cores
  • Acinar: Cuboidal neoplastic cells form gland-like structures supported by abundant stroma with intra-luminal secretory material 
  • Squamous: Islands and lobules of large polygonal neoplastic cells with abundant, bright eosinophilic cytoplasm 
  • Adenosquamous: Both acinar/tubular and squamous patterns of differentiation (at least 10% of each) with prominent atypia, higher grade and aggressive growth 
  • Solid: Sheets of polygonal to round neoplastic cells lacking other patterns; recent report in dogs (Michishita et al, J Comp Pathol 2023)
  • Other: Mucinous (cells with abundant cytoplasmic mucin), colloid (abundant mucin distending air spaces within the tumor)
• Additional patterns/entities:
  • Bronchial gland carcinoma: Low-grade malignancy with clear evidence its arising from the wall of a bronchus 
  • Large cell carcinoma: Anaplastic adenocarcinoma with large, polyhedral, sometimes individualized neoplastic cells with abundant vacuolated cytoplasm, vacuolated cytoplasm, and pleomorphism; lacks keratinization, intercellular bridges, acini, or mucin 
  • Carcinosarcoma: Has both adenocarcinomatous and sarcomatous components, representing an epithelial-mesenchymal transition 
• Dogs: Grading based on overall differentiation, degree of nuclear pleomorphism, mitotic rate, nucleolar size, tumor necrosis, fibrosis, and mass demarcation 
  • Best predictive outcome with degree of differentiation, mitotic rate (cutoff of >1 and >3 mitotic figures per high power-field, necrosis of >50% of tumor, and nucleolar size)
  • More aggressive neoplasms tend to be acinar or solid, disordered or with multiple layers of neoplastic cells lining papillae, invasive into stroma, poorly demarcated, or those with adjacent alveolar filled with clusters of neoplastic cells 
  • Lepidic and papillary subtypes are most common in dogs and carry a better prognosis 
• Cats: Histologic pattern does not correlate to clinical outcome (unlike dogs); tumors >1 cm are more likely to metastasize 

 

ADDITIONAL DIAGNOSTIC TESTS:

• IHC:
  1. Thyroid transcription factor-1 (TTF-1): Marker for club cells and type II pneumocytes; detected in 64-95% of pulmonary adenocarcinoma of bronchoalveolar origin, but NOT those arising from large airways
  2. Pancytokeratin, Napsin A, SP-A, and p40 (adenosquamous/squamous subtypes) positive, except Napsin A is NEGATVE in cats
  3. In less differentiated tumors, vimentin can be co-expressed 
• Cytology: Solid subtype: Highly cellular with scattered and clustered large round cells (Michishita et al, J Comp Pathol 2023)

 

DIFFERENTIAL DIAGNOSIS:

• Metastatic tumors (mammary gland, liver, Harderian gland, etc)
• Alveolar epithelial cell hyperplasia or atypical adenomatous hyperplasia: Non-neoplastic lesion with increased bronchioloalveolar epithelial cells and fibrosis with no disruption of architecture (lepidic) and a gradual transition with normal adjacent alveoli; alveolar epithelium may be dysplastic; distinction between hyperplasia and adenoma based mostly on size (<0.5cm in domestic species)
• Peribronchiolar metaplasia (Lambertosis): Non-neoplastic condition secondary to bronchiolar injury; hyperplasia of terminal bronchiolar epithelium with alveolar extension of club cells, goblet cells, and/or squamous cells 
• Neuroendocrine tumor (carcinoid) of lungs: Sporadically reported in lungs of dogs; arises from neuroendocrine cells in airway epithelium; multiple, firm masses close to mainstem bronchi; packets, palisades, or pseudorosettes of polygonal cells with fine pale eosinophilic granular cytoplasm on a fine fibrovascular stroma with mall nuclei and rare/absent mitotic figures; weak SYN+ 
• Granular cell tumor (P-N03): Rare, locally invasive tumor of old horses; typically incidental; arises from Schwann cells (presumed); single or multiple, well demarcated, white nodules centered around bronchi/bronchioles with occasional protrusion into the lumen; large, polygonal cells with abundant cytoplasm containing acidophilic PAS-positive granules; immunoreactive for S-100 
• Histiocytic sarcoma (P-N05A): Need to differentiate from large cell carcinoma
• Pulmonary blastoma: Varying degrees of malignant epithelial (cuboidal cells in nests or tubules) and mesenchymal (embryonal stellate-type cells with loose matrix) components  
• Feline pulmonary fibrosis (IPF): A heterogenous lesion with smooth muscle proliferation, fibrosis, and honey comb lung formation, which can look similar to pulmonary adenocarcinoma
• Feline pulmonary Langerhans cell histiocytosis (P-N05B): Histiocytosis usually accompanied by systemic histiocytosis

 

COMPARATIVE PATHOLOGY: 

• Canine: One case report of a pulmonary adenocarcinoma producing insulin-like growth factor 2 and clinical hypoglycemia (Noguchi et al, Vet Pathol 2020)
• Guinea Pig: Pulmonary neoplasia represents 35% of neoplasia reported in guinea pigs, with most of them being benign papillary (bronchogenic) adenomas 
• NHP: Primary lung cancer is rare, but have been reported in several species; the most common are bronchioloalveolar adenomas, which are often an incidental finding in rhesus macaques 
• Cattle: Lung carcinomas are rare; present was yellow-tan nodules separated by thick, fibrous connective tissue septa 
• Sheep/Goats: Retrovirus induced ovine pulmonary carcinoma (P-V16); carcinoma in situ and lepidic-predominant adenocarcinoma are characteristic 

 

REFERENCES:

1. Caswell JL, Williams KJ: Respiratory system. In: Maxie MG ed. Jubb, Kennedy, and Palmer's Pathology of Domestic Animals. Vol 2, 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:495-498.
2. Lopez A, Martinson SA. Respiratory system, thoracic cavities, mediastinum, and pleurae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022: 593-594.  
3. Maeda S, Nakazawa M, Uchida M, et al. Foxp3+ regulatory T-cells associated with CCL17/CCR4 expression in carcinomas of dogs. Vet Pathol. 2020:57(4):497-506. 
4. Miller AD. Neoplasia and proliferative disorders of nonhumane primates. In: Abee CR, Mansfield K, Tardif S, eds. Nonhuman Primates in Biomedical Research. Vol 2. 2^nd Ed. San Diego, CA: Academic Press;2012:341-343. 
5. Michishita M, Hanari N, Oda H, et al. Pulmonary solid adenocarcinoma in a dog. J Comp Pathol. 2023;online before publish. 
6. Muscatello LV, Oto ED, Dignazzi M, et al. HER2 overexpression and amplification in feline pulmonary carcinoma. Vet Pathol. 2021:58(3):527-530. 
7. Noguchi S, Kubo Y, Araki M, et al. Big insulin-like growth factor 2 producing tumor in a hypoglycemic dog. Vet Pathol. 2020;57(3):432-436. 
8. Percy DH, Barthold SW, Griffey SM. Pathology of Laboratory Rodents and Rabbits. 4rd ed. Ames, IA: Blackwell Publishing; 2016:108, 112-113, 251.
9. Santos IR, Raiter J, Lamego E, et al. Feline pulmonary carcinoma: gross, histological, metastatic, and immunohistochemical aspects. Vet Pathol. 2023;60(1):8-20. 

 

 

 

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