Proceedings of the 2009 National Toxicology Program Satellite Symposium

Abstract

The National Toxicology Program (NTP) Satellite Symposium is a one-day meeting that is held in conjunction with the annual Society of Toxicologic Pathology (STP) meeting. The topic of the 2009 Symposium was "Tumor Pathology and INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Nomenclature." The goal of this article is to provide summaries of each speaker's presentation, including the diagnostic or nomenclature issues that were presented, along with a few select images that were used for voting. The results of the voting process and interesting points of discussion that were raised during the presentation are also provided. A supplemental file with voting choices and voting results for each case presented at the symposium is available at http://tpx.sagepub.com/supplemental.

Figure 1

(A) Malignant pheochromocytoma with neoplastic cells in the periadrenal vasculature. (B) Pleomorphic neoplastic cells from the malignant pheochromocytoma shown in (A). (C) Neoplastic cells in the lumen of a periadrenal blood vessel from the malignant pheochromocy-toma shown in (A). (D) Compressive adrenal medullary mass with necrosis. (E) Cellular features of an adrenal medullary neuroblastoma. Note the closely packed neoplastic neuroblasts with scant cytoplasm. (F) Cellular features of the malignant pheochromocytoma shown in (D). Note the sheet of neoplastic chromaffin cells with abundant cytoplasm. (G) Focal hyperplasia of the adrenal medulla.

Figure 1

(A) Malignant pheochromocytoma with neoplastic cells in the periadrenal vasculature. (B) Pleomorphic neoplastic cells from the malignant pheochromocytoma shown in (A). (C) Neoplastic cells in the lumen of a periadrenal blood vessel from the malignant pheochromocy-toma shown in (A). (D) Compressive adrenal medullary mass with necrosis. (E) Cellular features of an adrenal medullary neuroblastoma. Note the closely packed neoplastic neuroblasts with scant cytoplasm. (F) Cellular features of the malignant pheochromocytoma shown in (D). Note the sheet of neoplastic chromaffin cells with abundant cytoplasm. (G) Focal hyperplasia of the adrenal medulla.

Figure 2

(A) Primary liver neoplasm demonstrating the classic presentation of a hepatocholangiocarcinoma (HCCC) as seen in the B6C3F1 mouse. There is an area of malignant hepatocellular proliferation (arrow) and areas of malignant ductal cell proliferation (arrowhead) adjacent to an area of necrosis and near an area of a cystlike formation (asterisk). (B) A portion of a primary HCCC demonstrating an area of malignant duct proliferation (arrow) and a focus of undifferentiated malignant cell proliferation (arrowhead) in a bed of hepatocellular carcinoma. (C) A primary HCCC demonstrating cords of hepatocellular carcinoma transitioning/blending into malignant cuboidal and columnar epithelium, forming ducts of varying morphological character. (D) A metastatic lesion of an HCCC as seen in the lung. Note the presence of malignant hepatocytes and duct-forming epithelial cells. (E) An HCCC that metastasized to the lung that demonstrates malignant hepatocyte proliferation and adjacent proliferation of an undifferentiated cell type.

Figure 3

(A, B) Low and high magnifications of a histiocytic sarcoma located in the brain of a B6C3F1 mouse. (C, D) Low and high magnification of a urethral transitional cell carcinoma arising from the proximal urethra (arrow) and invading into adjacent tissues, including the secondary sex glands (arrowheads). Hematoxylin and eosin (C) and uroplakin III immunohistochemistry (D). (E–G) Gross image of a thymoma (E) from the anterior mediastinum of a 1.5-year-old female F344 rat and high magnification illustrating the presence of an occasional large myoid cell (arrow) with abundant eosinophilic and granular cytoplasm and striations. Immunohisto-chemically, epithelial nests are strongly positive for cytokeratin (arrowheads), consistent with epithelial components of a thymoma.

Figure 3

(A, B) Low and high magnifications of a histiocytic sarcoma located in the brain of a B6C3F1 mouse. (C, D) Low and high magnification of a urethral transitional cell carcinoma arising from the proximal urethra (arrow) and invading into adjacent tissues, including the secondary sex glands (arrowheads). Hematoxylin and eosin (C) and uroplakin III immunohistochemistry (D). (E–G) Gross image of a thymoma (E) from the anterior mediastinum of a 1.5-year-old female F344 rat and high magnification illustrating the presence of an occasional large myoid cell (arrow) with abundant eosinophilic and granular cytoplasm and striations. Immunohisto-chemically, epithelial nests are strongly positive for cytokeratin (arrowheads), consistent with epithelial components of a thymoma.

Figure 4

(A) Typical skin lesion from a Tg.AC mouse (squamous papilloma). (B) Skin lesion from a Tg.AC mouse (squamous papilloma). (C) Malignant squamous cell transformation adjacent to a papilloma in a Tg.AC mouse. (D) Odontoma with tooth elements from a Tg.AC mouse. (E) Atypical odontoma from the oral cavity of a Tg.AC mouse. (F) Erythroleukemia in the bone marrow of a Tg.AC mouse. (G) Erythroleukemia in the bone marrow of a Tg.AC mouse (higher magnification). (H) Erythroleukemia in the lung of a Tg.AC mouse. Pulmonary capillaries are highly cellular. (I) Splenic extramedullary hematopoiesis in a Tg.AC mouse. Megakaryocytic, myeloid, and erythroid cells are present within the hypercellular splenic parenchyma.

Figure 4

(A) Typical skin lesion from a Tg.AC mouse (squamous papilloma). (B) Skin lesion from a Tg.AC mouse (squamous papilloma). (C) Malignant squamous cell transformation adjacent to a papilloma in a Tg.AC mouse. (D) Odontoma with tooth elements from a Tg.AC mouse. (E) Atypical odontoma from the oral cavity of a Tg.AC mouse. (F) Erythroleukemia in the bone marrow of a Tg.AC mouse. (G) Erythroleukemia in the bone marrow of a Tg.AC mouse (higher magnification). (H) Erythroleukemia in the lung of a Tg.AC mouse. Pulmonary capillaries are highly cellular. (I) Splenic extramedullary hematopoiesis in a Tg.AC mouse. Megakaryocytic, myeloid, and erythroid cells are present within the hypercellular splenic parenchyma.

Figure 5

(A, B) Spleen from a 1.5-year-old female C57BL/6NCrl mouse with a marked degree of hematopoietic cell proliferation. There is expansion of the red pulp by large numbers of hematopoietic cells, resulting in effacement of the white pulp (A). High magnification of this excessive splenic hematopoietic cell proliferation (B) demonstrates a predominance of myeloid cells in various stages of development (arrowheads), as well as erythroid cells (large arrows) and numerous megakaryocytes (small arrows). (C) Low magnification of the liver from the female mouse presented in (A) and (B) demonstrating a severe, multifocal to coalescing, pyogranulomatous hepatitis with intralesional Splendore-Hoeppli material and bacterial colonies. (D) Mouse blood smears demonstrating an increased number of polychromatophilic erythrocytes (arrows) in animals from a four-day study evaluating the effect of analgesia on postsurgical recovery (untreated control, analgesic alone, analgesic and surgery). This blood was collected four days postsurgery. However, these animals also had two previous blood collections (three days prior to surgery and one day postsurgery) prior to collection of blood for the final smear and CBC at day four post surgery. For comparison, the fourth image is that of an age-matched normal animal that was not part of the study (Romanowsky).

Figure 5

(A, B) Spleen from a 1.5-year-old female C57BL/6NCrl mouse with a marked degree of hematopoietic cell proliferation. There is expansion of the red pulp by large numbers of hematopoietic cells, resulting in effacement of the white pulp (A). High magnification of this excessive splenic hematopoietic cell proliferation (B) demonstrates a predominance of myeloid cells in various stages of development (arrowheads), as well as erythroid cells (large arrows) and numerous megakaryocytes (small arrows). (C) Low magnification of the liver from the female mouse presented in (A) and (B) demonstrating a severe, multifocal to coalescing, pyogranulomatous hepatitis with intralesional Splendore-Hoeppli material and bacterial colonies. (D) Mouse blood smears demonstrating an increased number of polychromatophilic erythrocytes (arrows) in animals from a four-day study evaluating the effect of analgesia on postsurgical recovery (untreated control, analgesic alone, analgesic and surgery). This blood was collected four days postsurgery. However, these animals also had two previous blood collections (three days prior to surgery and one day postsurgery) prior to collection of blood for the final smear and CBC at day four post surgery. For comparison, the fourth image is that of an age-matched normal animal that was not part of the study (Romanowsky).

Figure 6

(A) “Malignant” oligodendroglioma characterized by large, well-circumscribed lesions spread over multiple areas of the brain, with necrosis and hemorrhage. (B) Atypical capillary endothelial hyperplasia characteristic of malignant oligodendrogliomas. (C) “Benign” oligoden-droglioma characterized by a small, well-circumscribed lesion that is confined to one major area of the brain. (D) The benign oligodendroglioma often shows a “honeycomb” or “fried egg” cell pattern. (E) Astrocytoma with cells that have protoplasmic or fibrillary differentiation and prominent round or oval nuclei. (F) Necrosis with pseudopalisading is one characteristic feature of astrocytomas. (G) The mixed glioma of the mouse can show both proliferative astrocytoma and oligodendroglioma-like features. (H) A malignant pinealoma often expands by invasion into the adjacent brain tissue and is highly cellular, rich in mitotic figures, and pleomorphic.

Figure 6

(A) “Malignant” oligodendroglioma characterized by large, well-circumscribed lesions spread over multiple areas of the brain, with necrosis and hemorrhage. (B) Atypical capillary endothelial hyperplasia characteristic of malignant oligodendrogliomas. (C) “Benign” oligoden-droglioma characterized by a small, well-circumscribed lesion that is confined to one major area of the brain. (D) The benign oligodendroglioma often shows a “honeycomb” or “fried egg” cell pattern. (E) Astrocytoma with cells that have protoplasmic or fibrillary differentiation and prominent round or oval nuclei. (F) Necrosis with pseudopalisading is one characteristic feature of astrocytomas. (G) The mixed glioma of the mouse can show both proliferative astrocytoma and oligodendroglioma-like features. (H) A malignant pinealoma often expands by invasion into the adjacent brain tissue and is highly cellular, rich in mitotic figures, and pleomorphic.

Figure 7

(A) Lung: hemangiosarcoma with hemorrhage and hemosiderin. (B) Lung, airway: organized fibrinous material and ingrowth of neoplastic endothelial cells. (C) Lung, vessel: neoplastic endothelial cells. (D) Lung: hemangiosarcoma. (E) Lung: small (possibly early) lesion with fibrinous material, fibrosis, and hypertrophic spindle (endothelial?) cells. (F) Lung: changes similar to those in 7E are present in this slightly larger lesion. (G) Lung: some lesions were predominately composed of fibrinous material and hemorrhage. (H) Lung: a larger lesion with fibrosis, hemorrhage, and hemosiderin. (I) Lung: higher magnification of (H). (J) Lung: the morphology of the bottom portion of this lesion looks similar to (I); however, there is unequivocal neoplastic transformation noted in the upper portion. (K) Lung: this lesion was diagnosed as angiomatous hyperplasia/fibrosis in the study, but there was no consensus from the audience.

Figure 7

(A) Lung: hemangiosarcoma with hemorrhage and hemosiderin. (B) Lung, airway: organized fibrinous material and ingrowth of neoplastic endothelial cells. (C) Lung, vessel: neoplastic endothelial cells. (D) Lung: hemangiosarcoma. (E) Lung: small (possibly early) lesion with fibrinous material, fibrosis, and hypertrophic spindle (endothelial?) cells. (F) Lung: changes similar to those in 7E are present in this slightly larger lesion. (G) Lung: some lesions were predominately composed of fibrinous material and hemorrhage. (H) Lung: a larger lesion with fibrosis, hemorrhage, and hemosiderin. (I) Lung: higher magnification of (H). (J) Lung: the morphology of the bottom portion of this lesion looks similar to (I); however, there is unequivocal neoplastic transformation noted in the upper portion. (K) Lung: this lesion was diagnosed as angiomatous hyperplasia/fibrosis in the study, but there was no consensus from the audience.

Figure 8

(A, B) B6C3F1 mouse, cerebellum, low and high magnification, respectively. The cerebellum is invaded and destroyed by a paucicellular meningeal neoplasm composed of spindle to stellate-shaped cells surrounded by a myxoid matrix (myxoid malignant meningioma). (C, D) Fischer 344 rat, forebrain, low and high magnification, respectively. The forebrain is markedly compressed by a well-circumscribed mass composed of small lobules frequently containing small foci of hyalinized collagen and mineralization consistent with psammoma bodies (psammomatous meningioma).

Figure 9

(A) Focal epithelial proliferation in the forestomach of a two-year-old female Wistar rat. Note elevation from the adjacent unaffected epithelium mimicking a “sessile papilloma.” (B) Higher magnification showing prominent development of rete pegs, built up mainly by basal and prickle cells. (C) Focal basal cell hyperplasia in the forestomach of a two-year-old female Wistar rat. Note proliferation of basal cell layers and orderly structure of stratum granulosum and corneum. (D) Higher magnification of (C) showing proliferation of basal cells forming tightly packed papillary projections. (E) Proliferation of basal cells in the gastric glandular mucosa of a two-year-old male Wistar rat. Note proximity to the limiting ridge. (F) Higher magnification of (E) demonstrating the basal cell character of this epithelial proliferation.

Figure 10

(A–D) Pulmonary mucous cell metaplasia in rat lung after intratracheal instillation of diesel engine exhaust. Hematoxylin and eosin. (E) Periodic acid Schiff–positive material within the lesions of exaggerated mucous cell metaplasia. (F) Immunohistochemistry using anti-PCNA and chromogen Fast Red showing proliferating epithelial and inflammatory cells and black pigment from diesel engine exhaust. (G) Immunohistochemistry using anti-CD54 (ICAM-1) and chromogen Fast Red with positive staining of alveolar type I and type II cells in the lung tissue adjacent to the lesion. (H) Immunohistochemistry using anti-Clara cell secretory protein and chromogen Fast Red illustrating the location and number of Clara cells within the treated lung.

Figure 10

(A–D) Pulmonary mucous cell metaplasia in rat lung after intratracheal instillation of diesel engine exhaust. Hematoxylin and eosin. (E) Periodic acid Schiff–positive material within the lesions of exaggerated mucous cell metaplasia. (F) Immunohistochemistry using anti-PCNA and chromogen Fast Red showing proliferating epithelial and inflammatory cells and black pigment from diesel engine exhaust. (G) Immunohistochemistry using anti-CD54 (ICAM-1) and chromogen Fast Red with positive staining of alveolar type I and type II cells in the lung tissue adjacent to the lesion. (H) Immunohistochemistry using anti-Clara cell secretory protein and chromogen Fast Red illustrating the location and number of Clara cells within the treated lung.

Figure 11

(A, B) Low and high magnification, respectively, of granular cell hyperplasia in the uterine cervix of a rat. (C, D) Low and high magnification, respectively, of a benign granular cell tumor in the uterine cervix of a rat. (E) Granular cell aggregate in the uterus of a rat.

Figure 12

(A) This image was projected at the 2008 NTP Satellite Symposium by Dr. Taki Harada and was presented as a representative example of a hyperplasia not associated with hepatotoxicity. The arrows show the edges of the hyperplastic lesion, which is tinctorially similar to the adjacent hepatic parenchyma. Multiple portal triads are present within this hyperplastic lesion. (B) An enlargement of the lower right quadrant of Figure 12A showing a portal triad just above the center of the image. Adjacent uninvolved hepatic parenchyma is present in the lower right corner of the photomicrograph. (C) This early example of focal hyperplasia was provided by Dr. Harada. It is phenotypically similar to surrounding hepatic parenchyma and evident only because of its altered growth pattern and sinusoidal congestion. (D) Another example of a large area of hyperplasia similar to Figure 12A. Macrovesicular fat vacuoles are present within this lesion. (E) Case 1. A discrete nodular lesion from a treated male B6C3F1 mouse. The multiple areas of blue stippling within this nodule are portal triads. Because of the presence of the portal triads, the votes for diagnoses were split between focal hyperplasia and hepatocellular adenoma. (F) Case 1. A higher magnification of Figure 12A showing a portal triad within the nodular lesion. (G) Case 2. This nodular lesion from a treated male B6C3F1 mouse contained portal triads. Based on the voting, this lesion was considered a focus of cellular alteration. (H) Case 2. A higher magnification of Figure 12C showing a portal triad within the nodular lesion. (I) Case 3. This large, protruding mass was one of three seen grossly in the liver of the treated male B6C3F1 mouse. Portal triads were present within as well as at the periphery of this proliferative nodule. The voting clearly favored hepatocellular adenoma for this lesion.

Figure 12

(A) This image was projected at the 2008 NTP Satellite Symposium by Dr. Taki Harada and was presented as a representative example of a hyperplasia not associated with hepatotoxicity. The arrows show the edges of the hyperplastic lesion, which is tinctorially similar to the adjacent hepatic parenchyma. Multiple portal triads are present within this hyperplastic lesion. (B) An enlargement of the lower right quadrant of Figure 12A showing a portal triad just above the center of the image. Adjacent uninvolved hepatic parenchyma is present in the lower right corner of the photomicrograph. (C) This early example of focal hyperplasia was provided by Dr. Harada. It is phenotypically similar to surrounding hepatic parenchyma and evident only because of its altered growth pattern and sinusoidal congestion. (D) Another example of a large area of hyperplasia similar to Figure 12A. Macrovesicular fat vacuoles are present within this lesion. (E) Case 1. A discrete nodular lesion from a treated male B6C3F1 mouse. The multiple areas of blue stippling within this nodule are portal triads. Because of the presence of the portal triads, the votes for diagnoses were split between focal hyperplasia and hepatocellular adenoma. (F) Case 1. A higher magnification of Figure 12A showing a portal triad within the nodular lesion. (G) Case 2. This nodular lesion from a treated male B6C3F1 mouse contained portal triads. Based on the voting, this lesion was considered a focus of cellular alteration. (H) Case 2. A higher magnification of Figure 12C showing a portal triad within the nodular lesion. (I) Case 3. This large, protruding mass was one of three seen grossly in the liver of the treated male B6C3F1 mouse. Portal triads were present within as well as at the periphery of this proliferative nodule. The voting clearly favored hepatocellular adenoma for this lesion.