Adverse, Non-adverse and Adaptive Responses in Toxicologic Pathology

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1. INHAND Nomenclature Non-Neoplastic – Hepatobiliary Bob Maronpot (Email: maronpot@me.com) (Website: Focusontoxpath.com) Modular Education Course: Toxicologic Pathology of the Hepatobiliary System Embassy Suites Raleigh-Durham Raleigh, North Carolina October 23–26, 2016 Paul Watkins, MD, University of North Carolina Chapel Hill Course Objective The objective of this Society of Toxicologic Pathology (STP) Modular Education course is to educate individuals in the principles of toxicologic pathology of the hepatobiliary system. Course Description The STP course will bring together course attendees and world renowned subject experts for didactic lectures and practical sessions including whole- slide digital images and data sets. The course will be held in an environment that facilitates an intensive learning experience. Practical evaluation and interpretation of toxicologic pathology data will be emphasized. Who Should Attend The STP Modular Education courses are designed with the novice toxicologic pathologist in mind; however, pathology residents/graduate students with an interest in toxicologic pathology or experienced pathologists who desire a more in-depth review in toxicologic pathology of the hepatobiliary system Course Registration (Includes lodging Sunday night to Tuesday night) Early Registration (through August 31, 2016) Registration (September 1–30, 2016) STP Member (Single lodging) $1,350 $1,500 Nonmember (Single lodging) $1,550 $1,700 Student Member* (Single lodging) $750 $800 Local Registration (Lodging not included) Early Registration (through August 31, 2016) ) Registration (September 1–30, 2016) STP Member $750 $900 Nonmember $950 $1,100 STP Modular Course Student Travel Awards The Society of Toxicologic Pathology (STP) is pleased to offer the STP Modular Course Scholarship to eligible students and trainees with demonstrated interest in the field of toxicologic pathology. This scholarship is intended to cultivate those interests by exposing trainees to in-depth applicable knowledge in subspecialties of Toxicologic Pathology, while also facilitating interactions and networking opportunities for trainees interested in pursuing a career in Toxicologic Pathology.
2. Acknowledgements •  Photomicrographs from NTP Archives •  Photomicrographs and information from the NTP Non- Neoplastic Lesion Atlas (http://ntp.niehs.nih.gov/nnl/) •  Photomicrographs from important colleagues •  Dave Malarkey •  Rick Hailey •  Jerry Ward Disclaimer Opinions expressed are mine and not necessarily in agreement with my INHAND colleagues or the NTP
3. Categorization of Hepatic Responses •  Cytoplasmic Alteration Cytologic Alteration •  Clear cell change •  Hypertrophy – Enzyme induction •  Peroxisome proliferation •  Fatty change •  Cholestasis •  Atrophy •  Infiltration/Inflammation •  Cystic Change •  Cystic degeneration •  Biliary cysts •  Vascular Effects •  Angiectasis •  Infarction •  Cell Death •  Necrosis & Apoptosis •  Proliferative Responses •  Foci, Hyperplasia •  Cholangiofibrosis
4. Hepatodiaphragmatic Nodule
5. Hepatodiaphragmatic Nodule ies gs, on- unt on nal for all or- of og- tis forms and be of different origin. They mostly occur as isolated effects and are considered by the pathologist in distinguishing background hepatic lesions versus xenobiotic-induced lesions that occur in rodent preclinical toxicity studies. Hepatodiaphragmatic Nodule (Figures 3 and 4) Pathogenesis: Developmental alteration. Diagnostic features: Visible grossly and tinctorially similar to normal hepatic parenchyma. Rounded extensions usually of the medial lobe(s). Increased mitoses, cytological alterations, and nuclear alterations may be present. Linear chromatin structures with small lateral projec- tions are pathognostic. at Society of Toxicologic Pathology on August 8, 2013
6. Hepatodiaphragmatic Nodule e m es s, n- nt n al or ll r- of g- is Developmental anomalies occasionally occur in the liver of rodents. These malformations might be expressed in different forms and be of different origin. They mostly occur as isolated effects and are considered by the pathologist in distinguishing background hepatic lesions versus xenobiotic-induced lesions that occur in rodent preclinical toxicity studies. Hepatodiaphragmatic Nodule (Figures 3 and 4) Pathogenesis: Developmental alteration. Diagnostic features: Visible grossly and tinctorially similar to normal hepatic parenchyma. Rounded extensions usually of the medial lobe(s). Increased mitoses, cytological alterations, and nuclear alterations may be present. Linear chromatin structures with small lateral projec- tions are pathognostic. Society of Toxicologic Pathology on August 8, 2013
7. Hepatodiaphragmatic Nodule This is probably pathognomonic.
8. Ectopic Pancreas
9. Subendothelial Hepatocytes
10. Subendothelial Hepatocytes
11. Subendothelial Hepatocytes female B6C3F1 mice were 3/50, 1/50, 15/50, 47/50, and 0/49, 2/ 50, 20/50, 46/50, respectively. Although there was a high inci- inflammation, pigmentation, hepatoblastomas, hepatocellular adenomas, and hepatocellular carcinomas. However, the lesion FIGURE 7.—Continued 168 ELMORE ET AL. TOXICOLOGIC PATHOLOGY Vol. 41, No. 2, 2013 2012 NTP SATELLITE SYMPOSIUM 169 170 ELMORE ET AL. TOXICOLOGIC PATHOLOGY Toxicologic Pathology 41: 151-180 (2013)
12. Amyloidosis ho- located centrally in hepatocytes that exhibit positive immuno- histochemical staining for LAMP-2 (Figure 17) but is nega- tive for Oil-Red-O and adipophilin is indicative of phospholipid accumulation (Obert et al. 2007). Amyloidosis (Figures 18 and 19) Pathogenesis: Cellular process related to misfolding of protein. Diagnostic features: Deposition of pale, homogeneous, amorphous eosi- nophilic material. Deposition often peri-sinusoidal, periportal, or involving blood vessel walls. Localization is extracellular.s. at Society of Toxicologic Pathology on August 8, 2013
13. Pigmentation 007). n a ally rada rred and alls. ften gen- nflu- Coe Liu tion pria ung, isto- ain- ight d by rmal phic s ar m Pigmentation (Pigment Deposition) (Figures 21–25) Pathogenesis: Incidental occurrence and secondary to cellular and erythryoid breakdown products; lipid peroxidation of cel- lular membranes; altered heme metabolism. Diagnostic features: Lipofuscin: Pigment can be seen in hepatocytes as well as in Kupffer cells. May vary from pale yellow to deep granular brown. May be sudanophilic with autofluorescence under ultraviolet light. Often located adjacent to bile canaliculi. Iron/hemosiderin: Can be yellow to brown. May be finely granular. Usually appears intracellularly in Kupffer cells and hepatocytes. Porphyrin: Pigment is dense dark brown to red-brown and when viewed with polarization is bright red with a centrally located dark ‘‘Maltese cross.’’ Brilliant red fluorescence when viewed in fresh frozen sections; fades with exposure to ultravio- let light. Most often located in bile ductules and bile canaliculi. Bile (cholestasis) (Figures 23–25):
14. Pigmentation
15. Mineralization Male B6C3F1 Mouse Tx: 2-Chloronitrobenzene Dx: Chronic inflammation with mineralization
16. Pigmentation – Bile Can be yellow to brown. May be finely granular. Usually appears intracellularly in Kupffer cells and hepatocytes. Porphyrin: Pigment is dense dark brown to red-brown and when viewed with polarization is bright red with a centrally located dark ‘‘Maltese cross.’’ Brilliant red fluorescence when viewed in fresh frozen sections; fades with exposure to ultravio- let light. Most often located in bile ductules and bile canaliculi. Bile (cholestasis) (Figures 23–25): Appears as elongated pale green-brown plugs within bile caniculi. Will appear in Kupffer cells following rupture of caniculi. Can appear as finely granular pigment within in hepa- tocytes, which is common in human liver but much less common in rodents. Not a common xenobiotic response in rodents; more common in humans and monkeys.
17. Cholestasis
18. Mineralization (Vowles and Francis 2002; Kanel and Korula 2005) and by immunohistochemistry. Mineralization (Figure 20) Pathogenesis: Hypercalcemia secondary to diet or abnormal calcium metabolism; hepatocellular necrosis (dystrophic mineralization). Diagnostic features: Intra- or extracellular basophilic deposits, sometimes with calcification. Differential diagnosis: Artifact—hematoxylin stain deposits in clear spaces. Pigment deposits—may be tinctorially different from mineralization and often seen within macrophages. Intrabiliary accumulation of test compound or Iron/hemosiderin: Can be yellow to brown. May be finely granular. Usually appears intracellularly in hepatocytes. Porphyrin: Pigment is dense dark brown to re viewed with polarization is bright r located dark ‘‘Maltese cross.’’ Brilliant red fluorescence when frozen sections; fades with expo let light. Most often located in bile d canaliculi. Bile (cholestasis) (Figures 23–25): Appears as elongated pale green-b
19. Inclusions thus showing birefringence. Inclusions, Intranuclear, and Cytoplasmic (Figures 29–32) Synonyms: Inclusion bodies, intranuclear cytoplasmic invagi- nation, acidophilic inclusions, globular bodies. Pathogenesis: Protrusion of cytoplasm into an invagination of the hepatocyte nuclear membrane without the actual protrusion necessarily being present in the plane of section. Seen in spe- cific viral infections. Deposition of protein material within hepatocyte cytoplasm. Diagnostic features: Intranuclear inclusions are round, distinct, usually eccentrically located, and may partially or almost completely fill the nucleus. Contents of intranuclear inclusion bodies are often eosinophilic and may be granular or flocculent. Intracytoplasmic inclusions are round to oval, homo- genous, eosinophilic, and occur as single or multiple structures in the cytoplasm. Differential diagnosis: Enlarged nucleolus—one or more deeply basophilic structures in normal size nuclei. Viral inclusion bodies (cytomegalic virus, experi- mental viral infections). Cytoplasmic vacuole artifact—postmortem plasma influx (Li et al. 2003). plasmic inclusions such as Mallory bodies, lamellated, and crystalloid inclusions have been described in mice treated with different chemicals and in lysosomal storage diseases (Gebbia et al. 1985; Meierhenry et al. 1983; Rijhsinghani et al. 1980; Shio et al. 1982). Cytoplasmic vacuoles can occur in hepatocytes and endothelial cells in a postmortem time-dependent manner in fasted and non-fasted rats (Li et al. 2003). This artifact is espe- cially common in rats that are not exsanguinated at necropsy and the cytoplasmic vacuoles represent plasma influx into to affected cells (Figure 33). This artifact is more common in males than in females. Hypertrophy, Hepatocellular (Figures 34–41) Synonyms: Hepatocytomegaly. Pathogenesis: Metabolic enzyme induction causing increase in endoplasmic reticulum; increase in peroxisomes; increase in mitochondria. Diagnostic features: Enlarged hepatocytes may be tinctorially distinct. Cytoplasm may be homogeneous or granular. Zonal pattern of distribution (centrilobular, peripor- tal, midzonal) may be present. Involving most or all lobules. Loss of hepatocellular plate architecture is possible. Sinusoidal compression. Concurrent degeneration and/or single cell necrosis is possible. at Society of Toxicologic Pathology on August 8, 2013tpx.sagepub.comDownloaded from
20. Intrahepatocytic Erythrocytes
21. Intrahepatocytic Erythrocytes
22. Intrahepatocytic Erythrocytes FIGURE 7.—A–F, Series of images characterizing the lesion of ‘‘intrahepatocytic erythrocytes.’’ A, Low-magnification image showing the loca- tion of several areas containing intrahepatocytic erythrocytes near the edge of the liver (arrows; HE). B, Higher magnification of (A) illus- trating intrahepatocellular erythrocytes with some adjacent hepatocytes containing a decreased cytoplasmic density. (HE). C D, Higher Toxicologic Pathology 41: 151-180 (2013)
23. Hyaline Degeneration (Inclusions) High-Dose Male B6C3F1 Mouse Tx: Ethylene glycol
24. Hyaline Degeneration (Inclusions) High-Dose Male B6C3F1 Mouse Tx: Ethylene glycol
25. Hyaline Bodies
26. Hyaline Bodies
27. Hyaline Bodies
28. Plasma Influx This is an artifact
29. Crystals 1990). Crystals (Figures 26–28) Pathogenesis: Hyperlipidemia (cholesterol crystals), Chi313 (Ym1) protein (eosinophilic biliary crystals). Diagnostic features: Rhomboid or needle-like structures often birefringent under polarized light. Needle-like crystals in the mouse can be intracellular or extracellular and may be associated with intense eosinophilic epithelial cytoplasm and extracellular crystals of various sizes. ciety of Toxicologic Pathology on August 8, 2013
30. Crystals
31. Cytologic Alteration of necropsy during the day. Failure to accumulate glycogen because of inanition or abnormal glycogen retention may result from treatment-induced metabolic perturbations. Cytoplasmic Alteration (Figure 44) Synonyms: Cytoplasmic alteration, cytoplasmic change, granu- lar change, granular degeneration, hyaline degeneration, glyco- gen accumulation; ground glass change. Pathogenesis: Often xenobiotic-induced and may be associated with other forms of liver damage. Diagnostic features: Affected cells may show increased cytoplasmic gran- ularity, cell swelling, and eosinophilia. Differential diagnosis: to disturbance of cell m Diagnostic features: Cytoplasmic va centrally located Lobular location with increased c Differential diagnosis: Cytoplasmic va influx. Glycogen accum enlarged; cytopl Comment: Because of d rity, accumulation of i causes vacuolation and
32. Clear cell change – Glycogen accumulaJon In the INHAND document this change falls under the diagnostic category of Cytoplasmic Alteration A proposed alternative has been suggested by SEND for consideration: Rarefaction For example: Rarefaction, hepatocyte, increased, diffuse
33. Intracytoplasmic Glycogen Liver without Glycogen
34. PAS with diastase PAS
35. N M G L L G M M P RER Glycogen
36. Clear cell change – Glycogen accumulaJon
37. Normal glycogen accumulaJon Glycogen depleJon Glycogen
38. Normal glycogen accumulaJon Excessive glycogen Glycogen
39. Fatty Change at p- be or- in or al. ns. ns th es. re m, tic gi- a- to adaptive changes usually do not result in illness or death of rodents. Often these processes are dose and chemical related. Fatty Change Synonyms/subtypes: Lipidosis, vacuolation, lipid, macrovesi- cular and/or microvesicular steatosis, phospholipidosis.1 Pathogenesis: Perturbations in lipid metabolism and disposition. Diagnostic features: Macrovesicular fatty change (Figures 5 and 6). Hepatocytes contain a large well-defined single rounded vacuole within each cell. Nucleus and cytoplasm displaced to the periphery. A few hepatocytes may contain one or more smaller vacuoles. Microvesicular fatty change (Figure 7). Hepatocytes partially or completely filled with numerous small lipid vacuoles. Affected hepatocytes may have a ‘‘foamy’’ appearance. Smal