Proceedings of the 2022 National Toxicology Program Satellite Symposium

Abstract

The 2022 annual National Toxicology Program Satellite Symposium, entitled "Pathology Potpourri," was held in Austin, Texas at the Society of Toxicologic Pathology's 40th annual meeting during a half-day session on Sunday, June 19. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers' talks along with select images that were used by the audience for voting and discussion. Various lesions and topics covered during the symposium included induced and spontaneous neoplastic and nonneoplastic lesions in the mouse lung, spontaneous lesions in the reproductive tract of a female cynomolgus macaque, induced vascular lesions in a mouse asthma model and interesting case studies in a rhesus macaque, dog and genetically engineered mouse model.

Keywords: INHAND; NTP satellite symposium; acute myeloid leukemia; alveolar-bronchiolar neoplasms; animal models; degenerative myelopathy; endometriosis; inhaled particulates; irradiation; medial hypertrophy; pulmonary ossification.

Figure 1.

Mouse lung tumors, B6C3F1/N mouse. A-D) Alveolar/bronchiolar adenoma. A) A discrete, well-demarcated neoplasm is within the peripheral lung causing minimal compression of the surrounding lung tissue. 2X. HE. B) On higher magnification, deeply basophilic neoplastic cells are arranged in delicate papillary structures and are uniform in appearance with no apparent mitotic activity. 20X. HE. C) A discrete, well-demarcated neoplasm is within the peripheral lung causing minimal compression of the surrounding lung tissue. 4X. HE. D) On higher magnification, the neoplasm is composed of epithelial cells forming solid nests, supported by a fine fibrovascular stroma that completely obliterate the alveolar spaces. 20X. HE. E-H) Alveolar/bronchiolar carcinoma. E) A fairly well demarcated, solid, neoplasm is within the peripheral lung. 2X. HE. F) On higher magnification, the neoplasm is composed of pleomorphic epithelial cells arranged in papillary structures exhibiting increased mitotic activity and areas of single-cell necrosis. 20X. HE. G) A fairly well demarcated neoplasm is within the peripheral lung with evidence of infiltration within the surrounding tissue and a necrotic center infiltrated by large numbers of macrophages. 2X. HE. H) On higher magnification, the neoplasm is composed of pleomorphic, epithelial cells arranged in papillary structures and supported by a fine, fibrovascular stroma. 20X. HE.

Figure 2.

(A) Low magnification image of transverse section of uterus from a cynomologus monkey showing thickened endometrium. (B) higher magnification of (A) showing proliferating endometrial glands and stroma within the endometrium. (C) high magnification showing a well-differentiated endometrial gland deep within the myometrium. (D) Low magnification of ovary containing a large cyst and multifocal aggregates of glands and stroma outside the ovary. (E) higher magnification of (D) showing glands and stroma within the adipose tissue outside the ovary. H&E.

Figure 3.

A-H, Acute myeloid leukemia in a 13-year-old male rhesus macaque that received 6.5 Gy whole body irradiation and had a 2 month history of progressive thrombocytopenia. A gross photograph (A) demonstrates petechial hemorrhages around the face, which are also present on the epicardium (B) and serosal surface of the urinary bladder (C). A low magnification H&E-stained photomicrograph of the liver (D) demonstrates the infiltration and expansion of a portal tract by round cells, which at higher magnification (E) predominantly have round nuclei with vesiculate chromatin and prominent nuclei, admixed with rare mitotic figures and cells with segmented nuclei. A low magnification H&E stained photomicrograph of the humeral bone marrow (F) is markedly hypercellular, and higher magnification (G) demonstrates effacement of the marrow by a similar population to that observed in the portal tract. Four IHC-stained panels of humeral bone marrow (H) demonstrate diffuse strong cytoplasmic reactivity to myeloperoxidase, and negative staining for CD61, CD3/CD20, and Ham56.

Figure 3.

A-H, Acute myeloid leukemia in a 13-year-old male rhesus macaque that received 6.5 Gy whole body irradiation and had a 2 month history of progressive thrombocytopenia. A gross photograph (A) demonstrates petechial hemorrhages around the face, which are also present on the epicardium (B) and serosal surface of the urinary bladder (C). A low magnification H&E-stained photomicrograph of the liver (D) demonstrates the infiltration and expansion of a portal tract by round cells, which at higher magnification (E) predominantly have round nuclei with vesiculate chromatin and prominent nuclei, admixed with rare mitotic figures and cells with segmented nuclei. A low magnification H&E stained photomicrograph of the humeral bone marrow (F) is markedly hypercellular, and higher magnification (G) demonstrates effacement of the marrow by a similar population to that observed in the portal tract. Four IHC-stained panels of humeral bone marrow (H) demonstrate diffuse strong cytoplasmic reactivity to myeloperoxidase, and negative staining for CD61, CD3/CD20, and Ham56.

Figure 4.

Examples of lung findings from B6C3F1/N mice (A, C-F) and Sprague Dawley rats (B) from a NTP chronic whole body inhalation study. A, Coarse granules and clumps of black material are present within alveolar macrophages in alveolar spaces and within the interstitium (arrow). B, In the rat, alveolar spaces contain individual to aggregated macrophages with abundant foamy cytoplasm, sometimes with intracellular black granular material. Alveoli are multifocally lined by a single layer of cuboidal pneumocytes (arrow). C and D, In mice alveolar spaces are obscured by consolidated foci of inflammation composed primarily of macrophages admixed with neutrophils and lymphocytes (C). Affected foci contain multinucleated giant cells with intracellular black granular material (D, arrows) and alveoli lined by a single layer of cuboidal pneumocytes (D, arrowhead). E and F, The alveolar parenchyma is obscured by a poorly circumscribed mass composed of solid nests (E). Higher magnification (F) shows neoplastic cells making up the nests progress in a concentric but disorderly manner from basophilic and plump to flattened and eosinophilic and contain central keratin (F, arrow). There are frequent mitotic figures (F, arrowhead).

Figure 5.

Degenerative myelopathy, thoracolumbar spinal cord, NSG mouse. A) There is locally extensive vacuolation present ventrally and laterally within the white matter of the spinal cord. H&E, 10X. B) Vacuolation is accompanied by digestion chambers containing gitter cells, swollen axons (spheroids) and mild gliosis. H&E, 20X. C) There is vacuolation extending within the ventral spinal nerve root (arrow) and spinal nerve (arrowhead). H&E, 4X. D) Higher magnification of the lesion at arrow in Figure B, showing dilation of myelin sheaths, vacuolation, and axonal swelling (spheroids, arrowhead) in the ventral nerve root. H&E, 20X. E) Degenerative neuropathy, thoracolumbar spinal cord, NSG mouse. Higher magnification of lesion at arrowhead in Figure B, demonstrating vacuolation, spheroid formation, and dilation of myelin sheaths within the ventral spinal nerve. H&E, 20X. F) Dilation of myelin sheaths and spheroid formation in the associated sciatic nerve. H&E, 20X.

Figure 6.

Dendriform pulmonary ossification in a 12-year-old dog (A-E). On gross examination (A) innumerable bony masses were scattered throughout the parenchyma of all lung lobes. Histologic sections of lung (B-E) are stained with H&E. At low magnification (B) there is multifocal to coalescing expansion of the pulmonary parenchyma by irregular spicules of woven bone. At higher magnification (C) the spicules are generally contained within alveolar septa with occasional extension into alveolar spaces through ruptured septa (arrow). Alveolar septa are further expanded by mature fibrous stroma (asterisk). At high magnification (D) there are occasional small bone marrow cavities within the spicules of bone containing adipose tissue admixed with erythrocyte and myeloid precursor cells. (E) Few, patchy, loose aggregates of macrophages, lymphocytes, and plasma cells (arrow) are scattered throughout areas of alveolar fibrosis and ossification. Alveoli within affected areas are often lined by cuboidal cells (arrowhead), which is consistent with type II pneumocyte hyperplasia. Renal cortex from a 12-year-old dog with homozygous FAN1 mutations (F-H). Histologic sections are stained with H&E. At low magnification (F) the interstitium is expanded by patchy, mild fibrosis (asterisk) and tubules are often slightly dilated and lined by attenuated epithelium (arrowhead). High magnification (G-H) highlights tubular epithelial attenuation (black arrowhead) and interstitial fibrosis (asterisk). (G) Karyomegalic tubular epithelial cells (arrow) are scattered throughout the cortex. (H) Tubular epithelial cells occasionally contain acidophilic brick-shaped intranuclear inclusion bodies (yellow arrowhead). Scattered within the fibrotic interstitium (asterisk) are few lymphocytes and plasma cells (blue arrowhead).

Figure 6.

Dendriform pulmonary ossification in a 12-year-old dog (A-E). On gross examination (A) innumerable bony masses were scattered throughout the parenchyma of all lung lobes. Histologic sections of lung (B-E) are stained with H&E. At low magnification (B) there is multifocal to coalescing expansion of the pulmonary parenchyma by irregular spicules of woven bone. At higher magnification (C) the spicules are generally contained within alveolar septa with occasional extension into alveolar spaces through ruptured septa (arrow). Alveolar septa are further expanded by mature fibrous stroma (asterisk). At high magnification (D) there are occasional small bone marrow cavities within the spicules of bone containing adipose tissue admixed with erythrocyte and myeloid precursor cells. (E) Few, patchy, loose aggregates of macrophages, lymphocytes, and plasma cells (arrow) are scattered throughout areas of alveolar fibrosis and ossification. Alveoli within affected areas are often lined by cuboidal cells (arrowhead), which is consistent with type II pneumocyte hyperplasia. Renal cortex from a 12-year-old dog with homozygous FAN1 mutations (F-H). Histologic sections are stained with H&E. At low magnification (F) the interstitium is expanded by patchy, mild fibrosis (asterisk) and tubules are often slightly dilated and lined by attenuated epithelium (arrowhead). High magnification (G-H) highlights tubular epithelial attenuation (black arrowhead) and interstitial fibrosis (asterisk). (G) Karyomegalic tubular epithelial cells (arrow) are scattered throughout the cortex. (H) Tubular epithelial cells occasionally contain acidophilic brick-shaped intranuclear inclusion bodies (yellow arrowhead). Scattered within the fibrotic interstitium (asterisk) are few lymphocytes and plasma cells (blue arrowhead).

Figure 7.

Medial hypertrophy of pulmonary arteries in mice used in murine asthma model. (A) Pulmonary arteries (arrows) in a MMP-19 −/− mouse treated with house dust mite extract. H&E (B) Photomicrograph of pulmonary arteries (arrows) in a wild-type mouse similarlyu treated with house dust mite extract. H&E (C) Masson’s Trichrome stained section from case depicted in (A) showing increased collagen and extacellular matix in the thickened wall of the vessel. Photomicrographs of lungs from MMP-19 −/− mice treated with saline (D) or house dust mite extract (E) for six weeks. Note markedly thickened small pulmonary artery (arrow) at terminal bronchiole (TB) alveolar duct junction region in animal with inflamed lung in (E) relative to the control in (D). H&E Photomicrographs of lungs from MMP-19 −/− mice treated house dust mite extract for six weeks demonstrating numerous eosinophils in the inflammatory infiltrate. (F) Immunostain for eosinophil major basic protein showing numerous eosinophils (arrowheads) within thick perivascular cuffs of lymphoid cells as well as scattered throughout the pulmonary parenchyma. (G) Thickened pulmonary artery circumscribed by numerous eosinophils. H&E.

Figure 7.

Medial hypertrophy of pulmonary arteries in mice used in murine asthma model. (A) Pulmonary arteries (arrows) in a MMP-19 −/− mouse treated with house dust mite extract. H&E (B) Photomicrograph of pulmonary arteries (arrows) in a wild-type mouse similarlyu treated with house dust mite extract. H&E (C) Masson’s Trichrome stained section from case depicted in (A) showing increased collagen and extacellular matix in the thickened wall of the vessel. Photomicrographs of lungs from MMP-19 −/− mice treated with saline (D) or house dust mite extract (E) for six weeks. Note markedly thickened small pulmonary artery (arrow) at terminal bronchiole (TB) alveolar duct junction region in animal with inflamed lung in (E) relative to the control in (D). H&E Photomicrographs of lungs from MMP-19 −/− mice treated house dust mite extract for six weeks demonstrating numerous eosinophils in the inflammatory infiltrate. (F) Immunostain for eosinophil major basic protein showing numerous eosinophils (arrowheads) within thick perivascular cuffs of lymphoid cells as well as scattered throughout the pulmonary parenchyma. (G) Thickened pulmonary artery circumscribed by numerous eosinophils. H&E.