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CASE I – DI00-34 (AFIP 2739227)
Signalment: 18-month-old, female, FVB mouse (Mus musculus)
History: This mouse was noted to have a grossly distended abdomen. It was euthanized with CO2.
Gross Pathology: At necropsy, a mass effacing the uterus and left ovary was observed. Smaller masses were also observed in the left kidney, iliac lymph nodes and lung.
Laboratory Results: None.
Contributor’s Diagnosis and Comment: Histiocytic sarcoma (liver, uterus, lung and kidney) with secondary hyaline droplet nephropathy, moderate, diffuse.
The uterus, left ovary with fallopian tube and iliac lymph nodes were completely effaced by a densely cellular mass consisting of round to oval spindle cells with abundant eosinophilic cytoplasm and rounded or reniform nuclei. In some sections of the tumor, a pseudo-rosetting pattern was present. Serosal implants were present on the renal capsule, splenic mesentery and ovarian ligaments. Intravascular and perivascular tumor infiltrates were also observed in the renal and pulmonary parenchyma.
The submitted tissue is kidney. Depending on the section, the histiocytic sarcoma infiltrates either the renal parenchyma or extends along the renal capsule. In addition to the neoplastic cells, the section also demonstrates moderate, diffuse hyaline droplet accumulation in the proximal renal tubular epithelium.
Histiocytic sarcoma is generally seen in mature rats and mice of both sexes. The tumor is usually multicentric, involving mainly the liver, spleen, uterus, abdominal lymph nodes and lung, spreading along serosal surfaces to involve other organs. With large tumor burdens, prominent eosinophilic (hyaline) droplets accumulate in the proximal renal tubular epithelial cells, in proportion to tumor burden. In H&E stained sections, the droplets are best visualized using an alcoholic-based eosin, rather than an aqueous eosin solution. The droplets are positive for lysozyme by immunohistochemistry, consistent with the proposed macrophage origin of the histiocytic sarcoma. Hyaline droplets in animals with histiocytic sarcoma are negative for a1-proteinase inhibitor, a2m -globulin, immunoglobulins and albumin. Hyaline droplet accumulation secondary to histiocytic sarcoma should be distinguished from chemically-induced hyaline droplet nephropathy in male rats consisting of a2m -globulin.
AFIP Diagnosis: Kidney: Histiocytic sarcoma, with tubular epithelial cell hyaline droplets, FVB mouse (Mus musculus), rodent.
Conference Comment:
Histiocytic sarcoma of rats and mice most frequently arises in the livers of males and the uteri of females. The incidence can vary from 1% to 22% in different mouse strains. Histomorphology consists of round to spindle-shaped cells arranged in haphazard streams and whorls.
Immunohistochemical staining for histiocytic markers is often variable, but murine histiocytic sarcomas have been shown to be positive for Mac-2, lysozyme, and c-fms (the receptor for the macrophage colony-stimulating factor, CSF-1). The presence of erythrophagocytosis or multinucleated giant cell macrophages also is occasionally seen. Secretion of lysozyme by the neoplasm with subsequent glomerular filtration and uptake of the enzyme by renal tubules is the proposed mechanism for tubular epithelial cell hyaline droplet accumulation in cases of histiocytic sarcoma.
Histiocytic sarcoma is often multicentric, and usually has some degree of hepatic involvement. The fairly consistent involvement of the liver and the presence of neoplastic cells infiltrating hepatic sinusoids have led to the suggestion that the liver is the tissue of origin of this neoplasm.
Contributor: Pfizer Global Research and Development, Department of Pathology, Eastern Point Road, Groton, CT 06340
References: 1. Hard GC, Snowden RT: Hyaline droplet accumulation in rodent kidney proximal tubules: an association with histiocytic sarcoma. Toxicol Pathol 19:88-97, 1991
2. Luz A, Murray AB: Hyaline droplet accumulation in kidney proximal tubules of mice with histiocytic sarcoma. Toxicol Pathol 19:670-671, 1991
3. Ward JM, Sheldon W: Expression of mononuclear phagocyte antigens in histiocytic sarcoma of mice. Vet Pathol 30:560-565, 1993
4. Maronpot RR: Pathology of the Mouse, pp. 158-159, 224, 438-439. Cache River Press, 1999
CASE II – 990679-13 (AFIP 2740765)
Signalment: 12-month-old, female, Sprague-Dawley rat, (Rattus norvegicus)
History: Irradiated with 500c GY protons at 60-days-of-age. Continuous tamoxifen (selective estrogen receptor modulator) chemoprevention. Euthanized at 12-months-of-age.
Gross Pathology: Multiple mammary tumors. Multiple 1 mm nodules in lung. Normal pituitary gland.
Laboratory Results: None provided.
Contributor’s Diagnosis and Comment: Lung, mammary carcinoma, metastatic, multifocal with occasional apoptosis and neutrophilic infiltrates.
The female Sprague-Dawley rat responds to carcinogen exposure by developing mammary cancer with varying degrees of hormone-dependence. It is an excellent model of breast cancer, since the tumors in rats, like humans, have a heterogenous response to estrogens or selective estrogen receptor modulators like tamoxifen. Tamoxifen is an antagonist of the estrogen receptor in the mammary gland and is widely prescribed for chemotherapy and, more recently, chemoprevention of breast cancer. Progression of tamoxifen-resistant tumors occurs during prolonged treatment and may, in some cases, relate to a switch by tumor cells from recognizing tamoxifen as an antagonist to recognizing it as an agonist. The histopathologic patterns characteristic of rat mammary adenocarcinomas include papillary, cribriform, cystic, tubular, comedo, and solid, or some combination of these. The primary mammary gland tumor, in this case, consisted almost entirely of solid sheets of epithelial cells and a small peripheral focus with a papillary pattern. A solid histological pattern and lung metastases is an infrequent but interesting occurrence in the Sprague-Dawley rat mammary carcinoma model. To date, it has not been associated with specific factors such as chemical-induction, radiation-induction or tamoxifen-resistance, but, like breast cancer in humans, undifferentiated mammary tumors are most likely to metastasize.
AFIP Diagnosis: Lung: Malignant neoplasm, multifocal, perivascular and subpleural, Sprague-Dawley rat (Rattus norvegicus), rodent.
Conference Comment: Conference participants were unable to make a specific diagnosis based on the histologic sections of lung. However, the perivascular accumulations of atypical, mitotically active cells were considered consistent with a malignant neoplasm. After the conference, the contributor provided sections of the mammary carcinoma and a lymph node with metastatic mammary carcinoma. After examination of those sections, it was concluded that, as the contributor indicated, the malignant neoplasm in the lung is metastatic mammary carcinoma.
Contributor: Johns Hopkins University, Division of Comparative Medicine, 459 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205
References: 1. Boorman GA, Anderson LE, Morris JE, Sasser LB, Mann PC, Grumbein SL, Hailey JR, McNally A, Sills RC, Haseman JK: Effect of 26 weeks magnetic field exposures in a SMBA initiation-promotion mammary gland model in Sprague-Dawley rats. Carcinogenesis 20:899-904, 1999
2. Norris JD, Paige LA, Christensen DJ, Chang CY, Huacani MR, Fan D, Hamilton PT, Fowlkes DM, McDonnell DP: Peptide antagonists of the human estrogen receptor. Science 285:744-746, 1999
3. Russo J, Russo IH, van Zwieten MJ, Rogers AE, Gusterson BA: Classification of neoplastic and non-neoplastic lesions of the rat mammary gland. In: Monographs on Pathology of Laboratory Animals: Integument and Mammary Glands, ed. Jones TC, Mohr U, Hunt R, pp. 275-304. Springer-Verlag, Berlin, Germany, 1989
CASE III – MK9800557 (AFIP 2740382)
Signalment: 3-year-old, male, rhesus monkey (Macaca mulatta)
History: This monkey was on a gene therapy research protocol, involving total body irradiation and autologous bone marrow transplantation. Prior to receiving total body irradiation (6.5 Gy on successive days for a total dose of 13 Gy) bone marrow was extracted and cultured. Following the radiation, the animal was infused with the cultured bone marrow cells. Four and one half months after radiation, the monkey developed respiratory distress, which worsened despite palliative therapy (corticosteroids and antibiotics). He was euthanized one month later.
Gross Pathology: At necropsy, the animal was well hydrated with moderate body fat stores. The lungs were diffusely tan to clay colored and firm to rubbery; they failed to collapse when the chest was opened and sank in formalin.
Laboratory Results: Bacterial culture of the lung was negative.
Contributor’s Diagnosis and Comment: Lung: Interstitial fibrosis, diffuse, severe, with mild mixed inflammatory cell infiltrate, alveolar histiocytosis, type II pneumocyte hyperplasia, and variable (between sections) pleural fibrosis and fibrinous alveolar exudate.
Etiology: Delayed onset radiation injury
Radiation injury is believed mediated by free radicals, which can break chemical bonds, including those of DNA molecules. Possible outcomes of radiation on individual cells include:
- no detectable effect
- latent DNA damage which doesn’t affect the cell during its lifetime but may be expressed in subsequent generations
- severe DNA damage, which may allow the cell to survive, but prevents it from effectively dividing and reproducing
- somatic damage leading to immediate cell death
Individuals receiving sublethal doses of radiation survive the acute phase, shed the necrotic cells, and enter a latent stage. The DNA damage that has occurred will not be manifest until the surviving, but damaged, cells need to reproduce. Pulmonary fibrosis, alveolar edema, fibrinous exudation, with hyaline membrane formation, and type II pneumocyte hyperplasia are changes consistent with delayed radiation injury to the lungs. The pulmonary interstitial fibrosis likely results from endothelial damage with resultant fibrin leakage leading to fibroplasia. The type II pneumocyte hyperplasia reflects injury to the type I pneumocytes.
In addition to the pulmonary injury (radiation pneumonitis), total body irradiation also commonly caused clinically significant renal damage (glomerulonephropathy and tubular damage), resulting in hyperproteinuria and edema.
In a retrospective survey of 26 young rhesus monkeys receiving total body irradiation as part of the gene therapy research, 8 had lesions consistent with radiation pneumonopathy, which was first apparent at post irradiation (PI) day 23. All monkeys surviving 95 days PI had pulmonary changes; in 4 of these the changes resulted in respiratory distress. Glomerulonephropathy was encountered in 16 of the 26 monkeys, and was present in all monkeys surviving 47 days PI.
AFIP Diagnosis: Lung: Fibrosis, interstitial, diffuse, severe, with type II pneumocyte hyperplasia, alveolar histiocytosis, and multifocal multinucleate cells, rhesus monkey (Macaca mulatta), nonhuman primate.
Conference Comment: Radiation-induced endothelial cell injury causes large amounts of protein-rich exudate and fibrin to expand alveolar septa and accumulate within alveoli. Compression of the exudate by inspired air against the alveolar walls causes fibrin strands and sloughed epithelial cells to form hyaline membranes that are eventually replaced by collagen. The increasing fibrosis severely impedes oxygen exchange.
The failure of fibrin to be resorbed from the alveoli suggests a malfunction of the alveolar fibrinolytic system. Irradiation has been shown to cause depression in local tissue plasminogen activator levels, presumably due to endothelial cell injury. Fibrosis also occurs in adipose tissue within skeletal muscle, pericardium and subepithelial tissues.
Contributor: Veterinary Resources Program, National Institutes of Health, Bldg 28A, Room 117, 28A Library Drive MSC 5230, Bethesda, MD 20892
References: 1. Busch DB: Radiation and chemotherapy injury: pathophysiology, diagnosis, and treatment. Crit Rev Onc Hemat 15:49-89, 1993
2. Fajardo LF: Basic mechanisms and general morphology of radiation injury. Sem Roentgenology 28:297-302, 1993
3. Adamson IYR, Bowden DH: Endothelial injury and repair in radiation-induced pulmonary fibrosis. Amer J Pathol 112:224-230, 1983
4. White DC: An Atlas of Radiation Histopathology. Technical Information Center, Office of Public Affairs, US Energy Research and Development Administration, 1975
5. Libshitz HI: Radiation changes in the lung. Sem Roentgenology 28:303-320, 1993
6. Riley PA: Free radicals in biology: oxidative stress and the effects of ionizing radiation. Internat J Rad Biol 65:27-33, 1994
7. Miller G, Eckhaus M, Burris J, Donahue RE: Delayed radiation injury in rhesus macaques used in gene therapy research. Vet Pathol 32:571, 1995 [abstract]
CASE IV – 3411/94 (AFIP 2507936)
Signalment: 3.5-year-old, male alpaca (Lama glama pacos)
History: One male and six female alpacas had been held since 1992 in an isolated group because they were positive in antibody tests against Chlamydia psittaci. In October 1994, an eight-year-old female alpaca became ill. The clinical symptoms were intense lameness with swelling of the left tarsus and the fetlock of the right forefoot. Firm papules were present surrounding the mouth and nose. Finally, the animal exhibited opisthotonus and was euthanized.
Subsequently, all animals of this group of alpacas became ill. Lesions were most obvious at the mucocutaneous junctions of the face involving the eyelids and nostrils. They were also present at the external ear and less hairy areas of the skin. All animals suffered from purulent conjunctivitis. Only two animals recovered, whereas the remaining four alpacas had to be euthanized.
Gross Pathology: All euthanized alpacas were dissected. The lesions were similar in each of the dissected animals. The nutritional condition was good. The lymph nodes were edematous and hyperplastic. Lesions were localized at the lips, nostrils, eyelids, corneas of both eyes, external ear, prepuce, axillary and inguinal areas, medial thigh, inner surface of the lips and cheeks, the gums and the surface of the tongue. The lesions were papules, some of which were ulcerated up to 2 cm diameter. The ulcers were covered with thick gray crusts. Both eyes showed ulcerative keratitis.
Laboratory Results: None provided.
Contributor’s Diagnosis and Comment: Skin: ulcerative dermatitis, severe, with predominance around the mucocutaneous junctions of the face, marked hydropic degeneration of stratum spinosum keratinocytes, microvesiculation, epidermal hyperplasia, fibrinonecrotic exudation, and intracytoplasmic inclusion bodies, alpaca (Lama glama pacos), Camelidae.
Cause: Infection with orthopoxvirus (by electron microscopy)
Focal epidermal lesions consisted of epidermal hyperplasia with ballooning degeneration of epithelial cells (leading to so-called reticular degeneration). Epidermal hyperplasia and marked hydropic degeneration of stratum spinosum keratinocytes also were present in the epithelium of the hair follicles. An intense infiltration with neutrophils as well as macrophages and other mononuclear cells was found in the altered areas. A fibrinonecrotic exudate that included bacteria was present in necrotic and ulcerated lesions. Eosinophilic homogeneous intracytoplasmic inclusion bodies, 2-10 m m in diameter, occurred in keratinocytes in the hyperplastic epithelium at the margin of the ulcers and in the epithelium of the external hair root sheaths. Inclusion bodies were also seen in the proliferated epithelial cells of the cornea adjacent to the ulcers. Electron microscopic examination of material from lesions (negative staining and thin sections) showed the presence of typical orthopox virions with a biconcave core and two lateral bodies.
Orthopoxvirus is an ether-resistant DNA virus. It has a complex structure with core, lateral bodies, outer membrane and envelope. Infections are associated with lesions of the skin. The spontaneous disease occurs worldwide in domestic, laboratory, wild and zoo animals. Ten species of orthopoxvirus are recognized: vaccinia virus, cowpox virus, camelpox virus, ectromelia virus, monkeypox virus, Uasin Gishu disease virus, tatera poxvirus, raccoon poxvirus, vole poxvirus, and seal poxvirus.
It is possible that cowpoxvirus infected these alpacas. This virus appears to be maintained in nature in rodents. Since the virus has a wide host range, sporadic cases occur in many other species, presumably due to contact with infected rodents. Other orthopox viruses (e.g., vaccinia virus, camelpox virus) cannot be excluded as the etiologic agent, but no source for such an infection could be detected.
Differential diagnosis to orthopoxvirus infection, as far as these animals are concerned, includes lumpy skin disease and ulcerative dermatitis (both caused by parapoxvirus). The distinction between orthopoxvirus infection and parapoxvirus infection is possible by electron microscopic examination.
In our case, an infection with Chlamydia psittaci, and other secondary bacterial infections, may have complicated the poxvirus infection.
AFIP Diagnosis: Haired skin: Dermatitis, proliferative and necrotizing, subacute, focally extensive, severe, with ballooning degeneration and numerous epithelial intracytoplasmic inclusion bodies, alpaca (Lama pacos), camelid.
Conference Comment: Unlike many of the poxviruses that are host specific, the orthopoxviruses can infect a wide variety of species. Infection is usually through contact or air borne contamination of skin or mucous membranes. The expression of clinical signs is variable depending on the species and strain of animal that is infected. Following infection, and possible viral replication at the site of entrance, the virus travels via the lymphatics to regional lymph nodes for primary or secondary viral replication. Viremia disseminates the infection back to the skin or mucous membranes and to other target organs. Lesions can occur due to viral replication in endothelial cells leading to vasculitis, ischemia and necrosis.
The characteristic poxviral proliferative epithelial changes result from a viral gene whose product has significant homology with epidermal growth factor. Host cell DNA synthesis is stimulated before viral DNA replication begins in the cytoplasm. Proliferating keratinocytes are often a target for viral replication and contain the characteristic intracytoplasmic inclusion bodies. Vesicle formation occurs with degeneration and rupture of the damaged keratinocytes.
Viral isolation and serology, along with electron microscopy, are often required to differentiate the closely related orthopoxviruses from other morphologically similar viruses in the Poxviridae family.
Contributor: Universität Leipzig, Institut für Veterinärpathologie, An den Tierkliniken 33, 04103 Leipzig, Germany
References: 1. Murphy FA, Gibbs EPJ, Horzinek MC, Studdert MJ: Poxviridae. In: Veterinary Virology, 3rd ed., pp. 277-284. Academic Press, Boston, MA, 1999
2. Yager JA, Scott DW, Wilcock BP: The skin and appendages.
In: Pathology of Domestic Animals, ed. Jubb KVF, Kennedy
PC, Palmer N, 4th ed., vol. 1, pp. 629-642. Academic
Press, New York, NY, 1993
*Sponsored by the American Veterinary Medical Association, the American College of Veterinary Pathologists and the C. L. Davis Foundation.
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