Signalment:  

AN-02-189-6: 3.5 Mo, male, B6, 129 hydrid, Mus musculus, mouse
AN-02-326-6: 5 Mo, male, B6, 129 hydrid, Mus Musculus, mouse
AN-02-395-8: 3 Mo, female, B6, 129 hydrid, Mus musculus, mouse
AN-04-734-8: 6 Mo, male, B6, 129 hydrid, Mus musculus, mouse All four mice are homozygous mice for the p53 gene. The mice were on studies to access the influence of p53 on tumor development. All four mice were having labored breath and were submitted for necropsy.

Gross Description:  

A large pale gray mass filled the anterior thoracic cavity. One or more red nodules were present in various locations of the heart.

Histopathologic Description:

There are one or more nodules in the heart ventricular and/or septal wall of the heart and they consists of blood filled vascular channels of varying size. The vascular channels are lined by cells with spindle, round or oval nuclei with thin attenuated cytoplasm. The nuclei vary in size, have finely stippled to open chromatin and one or more small nucleoli. The tumors have a high mitotic rate, and an occasional atypical mitosis. In focal areas at the periphery of the nodules the tumor cells infiltrate the adjacent myocardium or epicardium. 

The tumors have multifocal CD31expression, diffuse CD34 expression and diffuse VEGFR-2 expression in the cells lining the vascular channels. The cytologic morphology and IHC profile are considered to be consistent with a hemangiosarcoma. In the lung, sections of some of the AN02-326 slides there are large tumor cells in a small artery and in the lymphomatous infiltrate surrounding the artery. The size of the nucleus of these cells suggests the cells may be metastatic hemangiosarcoma cells. Since it was not possible to confirm this with IHC, it is also possible the cells are lymphoma cells. In a few slides of AN-02-395 there are metastatic foci of tumor cells in the mediastinal fat. In one of the foci tumor is altering the integrity of a blood vessel. 

A lymphoma is present in three of the cases associated with this submission. In case AN02-189 the lymphoma extensively involves the mediastinum, one of the mediastinal lymph nodes and the lung focally. In case AN02-326 the lymphoma involves both thymic lobes and does not extend outside of the thymic lobes. In case AN02-395 the lymphoma involves both thymic lobes, breaches the thymic capsule and extends into the adjacent mediastinal fat. The lymphoma associated with all three cases has a high mitotic rate, mild to moderate apoptosis and a starry sky appearance due to tingible body macrophages. The lymphoma cells have nuclei that are predominantly smaller than or equal to that of macrophage nuclei. The lymphoma cells have nuclei that are round, angular or irregular in shape and scanty cytoplasm. Predominantly, the nuclei have fine chromatin and inconspicuous or small nucleoli. However, a few cells have a large nucleus with medium size amphophilic nucleoli. The lymphoma cells of all three cases express CD3 and TdT with strong intensity. The cytologic morphology and IHC profile of the lymphomas in all three cases are consistent with a T-cell lymphoblastic lymphoma. 

Morphologic Diagnosis:  

AN-02-189; Heart, ventricular wall left: Hemangiosarcoma. Mediastinum: T-lymphoblastic lymphoma.

AN-02-326; Heart; ventricular wall right left septum: Hemangiosarcoma multiple. Thymus: T-lymphoblastic lymphoma, bilateral noninvasive nodule with invasion of the epicardium.

AN-02-395; Heart; ventricular, septum right: Hemangiosarcoma. Mediastinum, fat: Hemangiosarcoma, multifocal, metastatic.

AN02-734: Heart; ventricular wall: Hemangiosarcoma, invasive; mediastinal, fat: Steatites. 

Lab Results:  

Lymphoma cells express CD3 and TdT. Vascular tumors had variable expression of CD31, CD34 and VEGRF-2.

Condition:  

Hemangiosarcoma; T-cell lymphoma

Contributor Comment:  

It is reported in the literature (1,2 4-6) that the majority of p53-/- mice die by six months of age due to their tumor load. Lymphomas, sarcomas and carcinomas occur in varying proportions depending on whether the mice are p53-/- or p53+/- (2, 4). Lymphomas are more common that sarcomas in p53-/- mice. In contrast, sarcomas are more common than lymphomas in p53+/- mice. The sarcomas consist of a variety of lineages with hemangiosarcomas and osteosarcomas being the most common (2, 4). Compared to wild type mice, hemangiosarcomas occur at a high frequency in both p53-/- and p53+/- mice. The incidence of hemangiosarcoma is 20-23% in p53-/- mice and 4-6% in p53+/- mice (1, 2, 4). Except for one report the incidences of hemangiosarcomas occurring in the heart of p53-deleted mice is not indicated and in that report a hemangiosarcoma was also present the perirenal fat (1). The fact that a p53 deficient mouse may have a hemangiosarcoma in multiple tissues may account for the lack of tissue delineation of the hemangiosarcomas in these reports. In the contributors experience hemangiosarcomas often occur in variety of organs including the heart in mice with a p53 deletion. The problem arises in determining whether the hemangiosarcomas are metastases of a monocentric tumor or whether the hemangiosarcomas in the various tissues are primary tumors of multicentric origin. Except for small metastatic foci in AN-02-326 and AN-02-395, the heart was the only organ identified at necropsy and histiologic examination of multiple tissues to have a hemangiosarcoma in the 4 cases associated with this submission. Therefore, it was felt the hemangiosarcoma in these cases represent examples of a primary hemangiosarcoma arising within the heart. 

Lymphoma occurs in 60-70% of p53-/- mice and approximately 30% of p53+/- mice (1,2 4-6). Approximately, 75% of the lymphomas in these mice are of T-lymphocytic lineage with the vast majority being of the lymphoblastic type. The lymphomas associated with 3 of the cases associated with this submission are a T-cell lymphoblast lymphoma typical of those that develop in p53-/- mice. The primary focus of the submission was to illustrate an example of primary hemangiosarcomas that occur in p53-/- mice. Strain background can effect the types and frequency of tumors in genetic manipulated mice.  However, the incidence of lymphomas and hemangiosarcomas are similar in p53-/- mice of the 129 background and p53-/- mice of the C57Bl/6,129 hybrid background (2,5).

JPC Diagnosis:  

1. Heart, ventricle: Hemangiosarcoma, B6,129 Hybrid mouse (Mus musculus), rodent.
2. Mediastinum; lymph node; thymus; lung: Lymphoma.

Conference Comment:  

The p53 gene encodes a transcriptional regulatory protein that is involved in regulation of the cell cycle and apoptosis following DNA damage.(2) In the normal cell cycle, progression from one stage to the next is controlled by certain cyclin and CDK complexes. The activity of the cyclin and CDK complexes are tightly controlled by CDK inhibitors of two main classes: Cip/Kip (p21 & p27), and INK4/ARF(p16INK4a & p14ARF). Transcriptional activation of the Cip/Kip inhibitor p21 is controlled by p53.(7)

Stage	Cyclin-CDK Complex	Inhibitors
G1	Cyclin D / cdk 4	P16INK4a & p21
G1→S	Cyclin E / cdk 2	P27
S→G2→M	Cyclin A / cdk 2	Â
M	Cyclin B / cdk 1	Â

Loss of functional p53 gene is linked to Li-Fraumeni syndrome in people, and results in an inherited predisposition to cancer development. Genetically engineered p53 knockout or deficient mice have greatly increased incidence of numerous neoplasms including osteosarcoma, soft-tissue sarcomas, and lymphomas.(2)

References:

1. Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA, Butel JS, Bradley A: Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors. Nature 356:215-221, 1992
2. Donehower LA, Harvey M, Vogel H, McArthur MJ, Montgomery CA, Park SH, Thompson T, Ford RJ, Bradley A: Effects of genetic background on tumorigenesis in p53 deficient mice. Mol Carcinog 14:16-22, 1995
3. Fry MM, McGavin MD: Bone marrow, blood cells, and lymphatic system. In: Pathologic Basis of Veterinary Disease, eds. McGavin MD, Zachary JF, 4th ed., pp. 798-802. Elsevier, St. Louis, MO, 2007
4. Harvey M, McArthur MJ, Montgomery CA, Butel JS, Bradley A, Donehower LA: Spontaneous and carcinogen-induced tumorigenesis in p53 deficient mice. Nat Genet 5:225-229, 1993
5. Harvey M, McArthur MJ, Montgomery CA, Bradley A, Donehower LA: Genetic background alters the spectrum of tumors that develop in p53-deficient mice. FASEB J 7:938-943, 1993
6. Jacks T, Remington L, Williams BO, Schmitt EM, Halachmi S, Bronson RT, Weinberg RA: Tumor spectrum analysis in p53-mutant mice. Curr Biol 4:1-7, 1994
7. Kumar V, Abbas, AK, Fausto N: Robbins and Cotran Pathologic Basis of Disease, eds., 7th ed., pp. 289-292. Elsevier Saunders, Philadelphia, PA, 1999
8. Mahler JF, Flagler ND, Malarkey DE, Mann PC, Haseman JK, Eastin W: Spontaneous and chemically induced proliferative lesions in Tg.AC transgenic and p53-heterozygous mice. Toxicol Pathol 26:501-511, 1998
9. Maxie MG, Robinson WF: Cardiovascular system. In: Jubb, Kennedy, and Palmers Pathology of Domestic Animals, ed. Maxie MG, 5th ed., vol. 3, p. 209. Elsevier Limited, St. Louis, MO, 2007
10. Percy DH, Barthold SW: Pathology of Laboratory Rodents and Rabbits, 3rd ed., pp. 48, 114-115, 170-170, 182-185, 205, Backwell Publishing, Ames, IA, 2007
11. Petruska JM, Frank DW, Freeman GB, Evans EW, MacDonald JS: Toxicity and carcinogenicity studies of chlorpromazine hydrochloride and p-Cresidine in the p53 heterozygous mouse model. Toxicol Pathol 30:696-704, 2002
12. Storer RD, French JE, Haseman J, Hajian G, LeGrand EK, Long GG, Mixson, LA, Ochoa R, Sagartz JE, Soper KA: p53+/- Hemizygous knockout mouse: overview of available data. Toxicol Pathol 29:30-50, 2001
13. Usui T, Mutai M, Hisada S, Takoaka M, Soper KA, McCullough B, Alden C: CB6F1-rasH2 mouse: overview of available data. Toxicol Pathol 29:90-108, 2001
14. Valli VEO: Hematopoietic system. In: Jubb, Kennedy, and Palmers Pathology of Domestic Animals, ed. Maxie MG, 5th ed., vol. 3, pp. 209-210. Elsevier Limited, St. Louis, MO, 2007
15. Van Vleet JF, Ferrans VJ: Cardiovascular system. In: Pathologic Basis of Veterinary Disease, eds. McGavin MD, Zachary JF, 4th ed., pp. 593-597. Elsevier, St. Louis, MO, 2007

A virtual slide is not available for this case.

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